Semantic coordination through programmable Tuple spaces

Two of the main features of today complex software systems like pervasive computing systems and Internet-based applications are distribution and openness. Distribution revolves around three orthogonal dimensions: (i) distribution of control|systems are characterised by several independent computational entities and devices, each representing an autonomous and proactive locus of control; (ii) spatial distribution|entities and devices are physically distributed and connected in a global (such as the Internet) or local network; and (iii) temporal distribution|interacting system components come and go over time, and are not required to be available for interaction at the same time. Openness deals with the heterogeneity and dynamism of system components: complex computational systems are open to the integration of diverse components, heterogeneous in terms of architecture and technology, and are dynamic since they allow components to be updated, added, or removed while the system is running. The engineering of open and distributed computational systems mandates for the adoption of a software infrastructure whose underlying model and technology could provide the required level of uncoupling among system components. This is the main motivation behind current research trends in the area of coordination middleware to exploit tuple-based coordination models in the engineering of complex software systems, since they intrinsically provide coordinated components with communication uncoupling and further details in the references therein. An additional daunting challenge for tuple-based models comes from knowledge-intensive application scenarios, namely, scenarios where most of the activities are based on knowledge in some form|and where knowledge becomes the prominent means by which systems get coordinated. Handling knowledge in tuple-based systems induces problems in terms of syntax - e.g., two tuples containing the same data may not match due to differences in the tuple structure - and (mostly) of semantics|e.g., two tuples representing the same information may not match based on a dierent syntax adopted. Till now, the problem has been faced by exploiting tuple-based coordination within a middleware for knowledge intensive environments: e.g., experiments with tuple-based coordination within a Semantic Web middleware (surveys analogous approaches). However, they appear to be designed to tackle the design of coordination for specic application contexts like Semantic Web and Semantic Web Services, and they result in a rather involved extension of the tuple space model. The main goal of this thesis was to conceive a more general approach to semantic coordination. In particular, it was developed the model and technology of semantic tuple centres. It is adopted the tuple centre model as main coordination abstraction to manage system interactions. A tuple centre can be seen as a programmable tuple space, i.e. an extension of a Linda tuple space, where the behaviour of the tuple space can be programmed so as to react to interaction events. By encapsulating coordination laws within coordination media, tuple centres promote coordination uncoupling among coordinated components. Then, the tuple centre model was semantically enriched: a main design choice in this work was to try not to completely redesign the existing syntactic tuple space model, but rather provide a smooth extension that { although supporting semantic reasoning { keep the simplicity of tuple and tuple matching as easier as possible. By encapsulating the semantic representation of the domain of discourse within coordination media, semantic tuple centres promote semantic uncoupling among coordinated components. The main contributions of the thesis are: (i) the design of the semantic tuple centre model; (ii) the implementation and evaluation of the model based on an existent coordination infrastructure; (iii) a view of the application scenarios in which semantic tuple centres seem to be suitable as coordination media.

Self-organising coordination systems

Many research fields are pushing the engineering of large-scale, mobile, and open systems towards the adoption of techniques inspired by self-organisation: pervasive computing, but also distributed artificial intelligence, multi-agent systems, social networks, peer-topeer and grid architectures exploit adaptive techniques to make global system properties emerge in spite of the unpredictability of interactions and behaviour. Such a trend is visible also in coordination models and languages, whenever a coordination infrastructure needs to cope with managing interactions in highly dynamic and unpredictable environments. As a consequence, self-organisation can be regarded as a feasible metaphor to define a radically new conceptual coordination framework. The resulting framework defines a novel coordination paradigm, called self-organising coordination, based on the idea of spreading coordination media over the network, and charge them with services to manage interactions based on local criteria, resulting in the emergence of desired and fruitful global coordination properties of the system. Features like topology, locality, time-reactiveness, and stochastic behaviour play a key role in both the definition of such a conceptual framework and the consequent development of self-organising coordination services. According to this framework, the thesis presents several self-organising coordination techniques developed during the PhD course, mainly concerning data distribution in tuplespace-based coordination systems. Some of these techniques have been also implemented in ReSpecT, a coordination language for tuple spaces, based on logic tuples and reactions to events occurring in a tuple space. In addition, the key role played by simulation and formal verification has been investigated, leading to analysing how automatic verification techniques like probabilistic model checking can be exploited in order to formally prove the emergence of desired behaviours when dealing with coordination approaches based on self-organisation. To this end, a concrete case study is presented and discussed.

Ingegneria di sistemi auto‐organizzanti con il paradigma multiagente

Self-organisation is increasingly being regarded as an effective approach to tackle modern systems complexity. The self-organisation approach allows the development of systems exhibiting complex dynamics and adapting to environmental perturbations without requiring a complete knowledge of the future surrounding conditions. However, the development of self-organising systems (SOS) is driven by different principles with respect to traditional software engineering. For instance, engineers typically design systems combining smaller elements where the composition rules depend on the reference paradigm, but typically produce predictable results. Conversely, SOS display non-linear dynamics, which can hardly be captured by deterministic models, and, although robust with respect to external perturbations, are quite sensitive to changes on inner working parameters. In this thesis, we describe methodological aspects concerning the early-design stage of SOS built relying on the Multiagent paradigm: in particular, we refer to the A&A metamodel, where MAS are composed by agents and artefacts, i.e. environmental resources. Then, we describe an architectural pattern that has been extracted from a recurrent solution in designing self-organising systems: this pattern is based on a MAS environment formed by artefacts, modelling non-proactive resources, and environmental agents acting on artefacts so as to enable self-organising mechanisms. In this context, we propose a scientific approach for the early design stage of the engineering of self-organising systems: the process is an iterative one and each cycle is articulated in four stages, modelling, simulation, formal verification, and tuning. During the modelling phase we mainly rely on the existence of a self-organising strategy observed in Nature and, hopefully encoded as a design pattern. Simulations of an abstract system model are used to drive design choices until the required quality properties are obtained, thus providing guarantees that the subsequent design steps would lead to a correct implementation. However, system analysis exclusively based on simulation results does not provide sound guarantees for the engineering of complex systems: to this purpose, we envision the application of formal verification techniques, specifically model checking, in order to exactly characterise the system behaviours. During the tuning stage parameters are tweaked in order to meet the target global dynamics and feasibility constraints. In order to evaluate the methodology, we analysed several systems: in this thesis, we only describe three of them, i.e. the most representative ones for each of the three years of PhD course. We analyse each case study using the presented method, and describe the exploited formal tools and techniques.

Multi-level models and infrastructures for simulating biological system development

The hierarchical organisation of biological systems plays a crucial role in the pattern formation of gene expression resulting from the morphogenetic processes, where autonomous internal dynamics of cells, as well as cell-to-cell interactions through membranes, are responsible for the emergent peculiar structures of the individual phenotype. Being able to reproduce the systems dynamics at different levels of such a hierarchy might be very useful for studying such a complex phenomenon of self-organisation. The idea is to model the phenomenon in terms of a large and dynamic network of compartments, where the interplay between inter-compartment and intra-compartment events determines the emergent behaviour resulting in the formation of spatial patterns. According to these premises the thesis proposes a review of the different approaches already developed in modelling developmental biology problems, as well as the main models and infrastructures available in literature for modelling biological systems, analysing their capabilities in tackling multi-compartment / multi-level models. The thesis then introduces a practical framework, MS-BioNET, for modelling and simulating these scenarios exploiting the potential of multi-level dynamics. This is based on (i) a computational model featuring networks of compartments and an enhanced model of chemical reaction addressing molecule transfer, (ii) a logic-oriented language to flexibly specify complex simulation scenarios, and (iii) a simulation engine based on the many-species/many-channels optimised version of Gillespie’s direct method. The thesis finally proposes the adoption of the agent-based model as an approach capable of capture multi-level dynamics. To overcome the problem of parameter tuning in the model, the simulators are supplied with a module for parameter optimisation. The task is defined as an optimisation problem over the parameter space in which the objective function to be minimised is the distance between the output of the simulator and a target one. The problem is tackled with a metaheuristic algorithm. As an example of application of the MS-BioNET framework and of the agent-based model, a model of the first stages of Drosophila Melanogaster development is realised. The model goal is to generate the early spatial pattern of gap gene expression. The correctness of the models is shown comparing the simulation results with real data of gene expression with spatial and temporal resolution, acquired in free on-line sources.

A tuple space implementation for large-scale infrastructures

Coordinating activities in a distributed system is an open research topic. Several models have been proposed to achieve this purpose such as message passing, publish/subscribe, workflows or tuple spaces. We have focused on the latter model, trying to overcome some of its disadvantages. In particular we have applied spatial database techniques to tuple spaces in order to increase their performance when handling a large number of tuples. Moreover, we have studied how structured peer to peer approaches can be applied to better distribute tuples on large networks. Using some of these result, we have developed a tuple space implementation for the Globus Toolkit that can be used by Grid applications as a coordination service. The development of such a service has been quite challenging due to the limitations imposed by XML serialization that have heavily influenced its design. Nevertheless, we were able to complete its implementation and use it to implement two different types of test applications: a completely parallelizable one and a plasma simulation that is not completely parallelizable. Using this last application we have compared the performance of our service against MPI. Finally, we have developed and tested a simple workflow in order to show the versatility of our service.

Evolutionary methods for self-organizing cooperation in peer-to-peer networks

The Peer-to-Peer network paradigm is drawing the attention of both final users and researchers for its features. P2P networks shift from the classic client-server approach to a high level of decentralization where there is no central control and all the nodes should be able not only to require services, but to provide them to other peers as well. While on one hand such high level of decentralization might lead to interesting properties like scalability and fault tolerance, on the other hand it implies many new problems to deal with. A key feature of many P2P systems is openness, meaning that everybody is potentially able to join a network with no need for subscription or payment systems. The combination of openness and lack of central control makes it feasible for a user to free-ride, that is to increase its own benefit by using services without allocating resources to satisfy other peers’ requests. One of the main goals when designing a P2P system is therefore to achieve cooperation between users. Given the nature of P2P systems based on simple local interactions of many peers having partial knowledge of the whole system, an interesting way to achieve desired properties on a system scale might consist in obtaining them as emergent properties of the many interactions occurring at local node level. Two methods are typically used to face the problem of cooperation in P2P networks: 1) engineering emergent properties when designing the protocol; 2) study the system as a game and apply Game Theory techniques, especially to find Nash Equilibria in the game and to reach them making the system stable against possible deviant behaviors. In this work we present an evolutionary framework to enforce cooperative behaviour in P2P networks that is alternative to both the methods mentioned above. Our approach is based on an evolutionary algorithm inspired by computational sociology and evolutionary game theory, consisting in having each peer periodically trying to copy another peer which is performing better. The proposed algorithms, called SLAC and SLACER, draw inspiration from tag systems originated in computational sociology, the main idea behind the algorithm consists in having low performance nodes copying high performance ones. The algorithm is run locally by every node and leads to an evolution of the network both from the topology and from the nodes’ strategy point of view. Initial tests with a simple Prisoners’ Dilemma application show how SLAC is able to bring the network to a state of high cooperation independently from the initial network conditions. Interesting results are obtained when studying the effect of cheating nodes on SLAC algorithm. In fact in some cases selfish nodes rationally exploiting the system for their own benefit can actually improve system performance from the cooperation formation point of view. The final step is to apply our results to more realistic scenarios. We put our efforts in studying and improving the BitTorrent protocol. BitTorrent was chosen not only for its popularity but because it has many points in common with SLAC and SLACER algorithms, ranging from the game theoretical inspiration (tit-for-tat-like mechanism) to the swarms topology. We discovered fairness, meant as ratio between uploaded and downloaded data, to be a weakness of the original BitTorrent protocol and we drew inspiration from the knowledge of cooperation formation and maintenance mechanism derived from the development and analysis of SLAC and SLACER, to improve fairness and tackle freeriding and cheating in BitTorrent. We produced an extension of BitTorrent called BitFair that has been evaluated through simulation and has shown the abilities of enforcing fairness and tackling free-riding and cheating nodes.

Composti organostannici nell'ambiente marino e membrane biologiche: risposte molecolari e biochimiche nei molluschi bivalvi

Organotin compounds are worldwide diffused environmental contaminants, mainly as consequence of their extensive past use as biocides in antifouling paints. In spite of law restrictions, due to unwanted effects, organotin still persist in waters, being poorly degraded, easily resuspended from sediments and bioaccumulated in exposed organisms. The widespread toxicity and the possible threat to humans, likely to be organotin-exposed through contaminated seafood, make organotin interactions with biomolecules an intriguing biochemical topic, apart from a matter of ecotoxicological concern. Among organotins, tributyltin (TBT) is long known as the most dangerous and abundant chemical species in the Mediterranean Sea. Due to its amphiphilic nature, provided by three lipophilic arms and an electrophilic tin core, TBT can be easily incorporated in biomembranes and affect their functionality. Accordingly, it is known as a membrane-active toxicant and a mitochondrial poison. Up to now the molecular action modes of TBT are still partially unclear and poorly explored in bivalve mollusks, even if the latter play a not neglectable role in the marine trophic chain and efficiently accumulate organotins. The bivalve mollusk Mytilus galloprovincialis, selected for all experiments, is widely cultivated in the Mediterranean and currently used in ecotoxicological studies. Most work of this thesis was devoted to TBT effects on mussel mitochondria, but other possible targets of TBT were also considered. A great deal of literature points out TBT as endocrine disrupter and the masculinization of female marine gastropods, the so-called imposex, currently signals environmental organotin contamination. The hormonal status of TBT-exposed mussels and the possible interaction between hormones and contaminants in modulating microsomal hydroxilases, involved in steroid hormone and organotin detoxification, were the research topics in the period spent in Barcelona (Marco Polo fellowship). The variegated experimental approach, which consisted of two exposure experiments and in vitro tests, and the choice of selected tissues of M. galloprovincialis, the midgut gland for mitochondrial and microsomal preparations for subsequent laboratory assays and the gonads for the endocrine evaluations, aimed at drawing a clarifying pattern on the molecular mechanisms involved in organotin toxicity. TBT was promptly incorporated in midgut gland mitochondria of adult mussels exposed to 0.5 and 1.0 μg/L TBT, and partially degraded to DBT. TBT incorporation was accompanied by a decrease in the mitochondrial oligomycin-sensitive Mg-ATPase activity, while the coexistent oligomycin-insensitive fraction was unaffected. Mitochondrial fatty acids showed a clear rise in n-3 polyunsaturated fatty acids after 120 hr of TBT exposure, mainly referable to an increase in 22:6 level. TBT was also shown to inhibit the ATP hydrolytic activity of the mitochondrial F1FO complex in vitro and to promote an apparent loss of oligomycin sensitivity at higher than 1.0 μM concentration. The complex dose-dependent profile of the inhibition curve lead to the hypothesis of multiple TBT binding sites. At lower than 1.0 μM TBT concentrations the non competitive enzyme inhibition by TBT was ascribed to the non covalent binding of TBT to FO subunit. On the other hand the observed drop in oligomycin sensitivity at higher than 1.0 μM TBT could be related to the onset of covalent bonds involving thiolic groups on the enzyme structure, apparently reached only at high TBT levels. The mitochondrial respiratory complexes were in vitro affected by TBT, apart from the cytocrome c oxidase which was apparently refractory to the contaminant. The most striking inhibitory effect was shown on complex I, and ascribed to possible covalent bonds of TBT with –SH groups on the enzyme complexes. This mechanism, shouldered by the progressive decrease of free cystein residues in the presence of increasing TBT concentrations, suggests that the onset of covalent tin-sulphur bonds in distinct protein structures may constitute the molecular basis of widespread TBT effects on mitochondrial complexes. Energy production disturbances, in turn affecting energy consuming mechanisms, could be involved in other cellular changes. Mussels exposed to a wide range of TBT concentrations (20 - 200 and 2000 ng/L respectively) did not show any change in testosterone and estrogen levels in mature gonads. Most hormones were in the non-biologically active esterified form both in control and in TBT-treated mussels. Probably the endocrine status of sexually mature mussels could be refractory even to high TBT doses. In mussel digestive gland the high biological variability of microsomal 7-benzyloxy-4-trifluoromethylcoumarin-O-Debenzyloxylase (BFCOD) activity, taken as a measure of CYP3A-like efficiency, probably concealed any enzyme response to TBT exposure. On the other hand the TBT-driven enhancement of BFCOD activity in vitro was once again ascribed to covalent binding to thiol groups which, in this case, would stimulate the enzyme activity. In mussels from Barcelona harbour, a highly contaminated site, the enzyme showed a decreased affinity for the 7-benzyloxy-4-trifluoromethylcoumarin (BCF) substrate with respect to mussel sampled from Ebro Delta, a non-polluted marine site. Contaminant exposure may thus alter the kinetic features of enzymes involved in detoxification mechanisms. Contaminants and steroid hormones were clearly shown to mutually interact in the modulation of detoxification mechanisms. The xenoestrogen 17α-ethylenyl estradiol (EE2) displayed a non-competitive mixed inhibition of CYP3A-like activity by a preferential bond to the free enzyme both in Barcelona harbour and Ebro Delta mussels. The possible interaction with co-present contaminants in Barcelona harbour mussels apparently lessened the formation of the ternary complex enzyme-EE2-BCF. The whole of data confirms TBT as membrane toxicant in mussels as in other species and stresses TBT covalent binding to protein thiols as a widespread mechanism of membrane-bound-enzyme activity modulation by the contaminant.

The Domon Family of Plant Plasma Membrane B-Type Cytochromes: Heterologous Expression, Biochemical Characterization and Physiological Roles in Vivo

The DOMON domain is a domain widespread in nature, predicted to fold in a β-sandwich structure. In plants, AIR12 is constituted by a single DOMON domain located in the apoplastic space and is GPI-modified for anchoring to the plasma membrane. Arabidopsis thaliana AIR12 has been heterologously expressed as a recombinant protein (recAtAIR12) in Pichia pastoris. Spectrophotometrical analysis of the purified protein showed that recAtAir12 is a cytochrome b. RecAtAIR12 is highly glycosylated, it is reduced by ascorbate, superoxide and naftoquinones, oxidised by monodehydroascorbate and oxygen and insensitive to hydrogen peroxide. The addition of recAtAIR12 to permeabilized plasma membranes containing NADH, FeEDTA and menadione, caused a statistically significant increase in hydroxyl radicals as detected by electron paramagnetic resonance. In these conditions, recAtAIR12 has thus a pro-oxidant role. Interestingly, AIR12 is related to the cytochrome domain of cellobiose dehydrogenase which is involved in lignin degradation, possibly via reactive oxygen species (ROS) production. In Arabidopsis the Air12 promoter is specifically activated at sites where cell separations occur and ROS, including •OH, are involved in cell wall modifications. air12 knock-out plants infected with Botrytis cinerea are more resistant than wild-type and air12 complemented plants. Also during B. cinerea infection, cell wall modifications and ROS are involved. Our results thus suggest that AIR12 could be involved in cell wall modifying reactions by interacting with ROS and ascorbate. CyDOMs are plasma membrane redox proteins of plants that are predicted to contain an apoplastic DOMON fused with a transmembrane cytochrome b561 domain. CyDOMs have never been purified nor characterised. The trans-membrane portion of a soybean CyDOM was expressed in E. coli but purification could not be achieved. The DOMON domain was expressed in P. pastoris and shown to be itself a cytochrome b that could be reduced by ascorbate.

Irrigation and drainage canals role for plant diversity and nature conservation

Aims: With this research, we wanted to investigate and promote the conservation of biodiversity in the network of drainage canals of the Po Valley Study area: The canal network of Bologna plain, long more than 1150 km (Po Valley, North Italy) Methods: In Chapter II we analyzed the geographical patterns that characterize our transects, the land use of their upstream basins, the water quality at the closure points of their river basins. In Chapter III we described the plant communities with some ecological information and we also tested the effect of the canal size on the plant communities. In Chapter IV we described the relation beetween some functional traits of the plant species sampled and some environmental parameters Results: A total of 272 species were sampled in 118 transects. The plant communities of the drainage canals have been found to have a significant influence: the geographical pattern "proximity to protected areas", the class of land use "agrozootechnical settlements", and some water parameters. The analysis of the parameter "canal depth" indicated a significant distinction between small and large canals based on plant communities. The functional composition of the plant communities was affected by the bank aspect, the inclusion/exclusion from the protected areas and the upstream basin land uses. Moreover, the functional groups of species responded differently to environmental drivers, water quality gradients and were influenced by a combination of environmental stresses Conclusions: This research confirms the key role of the canals network in sustaining the plant richness in oversimplified landscapes. Considering the fragility of the floodplains and the global warming that is taking place, it is necessary to rethink the role of irrigation canals and their plant communities in the near future. This work reinforces the belief that long-term sampling plans and greater knowledge about canal management practices are needed

Oto-Bio-Graphies: auditory perception in twentieth-century self-narratives

Throughout the twentieth century, the study of auditory perception emerged as a significant area of inquiry across various disciplines, particularly within the fields of poststructuralism and psychoanalysis. These theories converge in their understanding of hearing as a fundamental aspect of the development of the subject, leading to a decentering and reformulation of the autobiographical subject, suggesting that the rhythmic is a state of being outside of and prior to the social, verbal, thinking subject. This research aims to examine the connection between auditory perception and the formation of subjectivity in twentieth-century self-narratives. Drawing both from psychoanalysis and poststructuralism, this research proposes a reading of three autobiographical works, namely Elias Canetti’s Die gerettete Zunge, Nathalie Ginzburg’s Lessico famigliare and Nathalie Sarraute’s Enfance. By highlighting the importance of the voice and of the sonorous envelope of childhood, these works artistically anticipate what would be theorised only a few decades later and create the conditions for a pre-verbal apprehension of the world, raising questions about the ineffable source of writing and the writing process itself.

Biochemistry in healthy and neoplastic human tissues: metabolic alteration revealed by HR-MAS nuclear magnetic resonance spectroscopy

This thesis is focused on the metabolomic study of human cancer tissues by ex vivo High Resolution-Magic Angle Spinning (HR-MAS) nuclear magnetic resonance (NMR) spectroscopy. This new technique allows for the acquisition of spectra directly on intact tissues (biopsy or surgery), and it has become very important for integrated metabonomics studies. The objective is to identify metabolites that can be used as markers for the discrimination of the different types of cancer, for the grading, and for the assessment of the evolution of the tumour. Furthermore, an attempt to recognize metabolites, that although involved in the metabolism of tumoral tissues in low concentration, can be important modulators of neoplastic proliferation, was performed. In addition, NMR data was integrated with statistical techniques in order to obtain semi-quantitative information about the metabolite markers. In the case of gliomas, the NMR study was correlated with gene expression of neoplastic tissues. Chapter 1 begins with a general description of a new “omics” study, the metabolomics. The study of metabolism can contribute significantly to biomedical research and, ultimately, to clinical medical practice. This rapidly developing discipline involves the study of the metabolome: the total repertoire of small molecules present in cells, tissues, organs, and biological fluids. Metabolomic approaches are becoming increasingly popular in disease diagnosis and will play an important role on improving our understanding of cancer mechanism. Chapter 2 addresses in more detail the basis of NMR Spectroscopy, presenting the new HR-MAS NMR tool, that is gaining importance in the examination of tumour tissues, and in the assessment of tumour grade. Some advanced chemometric methods were used in an attempt to enhance the interpretation and quantitative information of the HR-MAS NMR data are and presented in chapter 3. Chemometric methods seem to have a high potential in the study of human diseases, as it permits the extraction of new and relevant information from spectroscopic data, allowing a better interpretation of the results. Chapter 4 reports results obtained from HR-MAS NMR analyses performed on different brain tumours: medulloblastoma, meningioms and gliomas. The medulloblastoma study is a case report of primitive neuroectodermal tumor (PNET) localised in the cerebellar region by Magnetic Resonance Imaging (MRI) in a 3-year-old child. In vivo single voxel 1H MRS shows high specificity in detecting the main metabolic alterations in the primitive cerebellar lesion; which consist of very high amounts of the choline-containing compounds and of very low levels of creatine derivatives and N-acetylaspartate. Ex vivo HR-MAS NMR, performed at 9.4 Tesla on the neoplastic specimen collected during surgery, allows the unambiguous identification of several metabolites giving a more in-depth evaluation of the metabolic pattern of the lesion. The ex vivo HR-MAS NMR spectra show higher detail than that obtained in vivo. In addition, the spectroscopic data appear to correlate with some morphological features of the medulloblastoma. The present study shows that ex vivo HR-MAS 1H NMR is able to strongly improve the clinical possibility of in vivo MRS and can be used in conjunction with in vivo spectroscopy for clinical purposes. Three histological subtypes of meningiomas (meningothelial, fibrous and oncocytic) were analysed both by in vivo and ex vivo MRS experiments. The ex vivo HR-MAS investigations are very helpful for the assignment of the in vivo resonances of human meningiomas and for the validation of the quantification procedure of in vivo MR spectra. By using one- and two dimensional experiments, several metabolites in different histological subtypes of meningiomas, were identified. The spectroscopic data confirmed the presence of the typical metabolites of these benign neoplasms and, at the same time, that meningomas with different morphological characteristics have different metabolic profiles, particularly regarding macromolecules and lipids. The profile of total choline metabolites (tCho) and the expression of the Kennedy pathway genes in biopsies of human gliomas were also investigated using HR-MAS NMR, and microfluidic genomic cards. 1H HR-MAS spectra, allowed the resolution and relative quantification by LCModel of the resonances from choline (Cho), phosphorylcholine (PC) and glycerolphorylcholine (GPC), the three main components of the combined tCho peak observed in gliomas by in vivo 1H MRS spectroscopy. All glioma biopsies depicted an increase in tCho as calculated from the addition of Cho, PC and GPC HR-MAS resonances. However, the increase was constantly derived from augmented GPC in low grade NMR gliomas or increased PC content in the high grade gliomas, respectively. This circumstance allowed the unambiguous discrimination of high and low grade gliomas by 1H HR-MAS, which could not be achieved by calculating the tCho/Cr ratio commonly used by in vivo 1H MR spectroscopy. The expression of the genes involved in choline metabolism was investigated in the same biopsies. The present findings offer a convenient procedure to classify accurately glioma grade using 1H HR-MAS, providing in addition the genetic background for the alterations of choline metabolism observed in high and low gliomas grade. Chapter 5 reports the study on human gastrointestinal tract (stomach and colon) neoplasms. The human healthy gastric mucosa, and the characteristics of the biochemical profile of human gastric adenocarcinoma in comparison with that of healthy gastric mucosa were analyzed using ex vivo HR-MAS NMR. Healthy human mucosa is mainly characterized by the presence of small metabolites (more than 50 identified) and macromolecules. The adenocarcinoma spectra were dominated by the presence of signals due to triglycerides, that are usually very low in healthy gastric mucosa. The use of spin-echo experiments enable us to detect some metabolites in the unhealthy tissues and to determine their variation with respect to the healthy ones. Then, the ex vivo HR-MAS NMR analysis was applied to human gastric tissue, to obtain information on the molecular steps involved in the gastric carcinogenesis. A microscopic investigation was also carried out in order to identify and locate the lipids in the cellular and extra-cellular environments. Correlation of the morphological changes detected by transmission (TEM) and scanning (SEM) electron microscopy, with the metabolic profile of gastric mucosa in healthy, gastric atrophy autoimmune diseases (AAG), Helicobacter pylori-related gastritis and adenocarcinoma subjects, were obtained. These ultrastructural studies of AAG and gastric adenocarcinoma revealed lipid intra- and extra-cellularly accumulation associated with a severe prenecrotic hypoxia and mitochondrial degeneration. A deep insight into the metabolic profile of human healthy and neoplastic colon tissues was gained using ex vivo HR-MAS NMR spectroscopy in combination with multivariate methods: Principal Component Analysis (PCA) and Partial Least Squares Discriminant Analysis (PLS-DA). The NMR spectra of healthy tissues highlight different metabolic profiles with respect to those of neoplastic and microscopically normal colon specimens (these last obtained at least 15 cm far from the adenocarcinoma). Furthermore, metabolic variations are detected not only for neoplastic tissues with different histological diagnosis, but also for those classified identical by histological analysis. These findings suggest that the same subclass of colon carcinoma is characterized, at a certain degree, by metabolic heterogeneity. The statistical multivariate approach applied to the NMR data is crucial in order to find metabolic markers of the neoplastic state of colon tissues, and to correctly classify the samples. Significant different levels of choline containing compounds, taurine and myoinositol, were observed. Chapter 6 deals with the metabolic profile of normal and tumoral renal human tissues obtained by ex vivo HR-MAS NMR. The spectra of human normal cortex and medulla show the presence of differently distributed osmolytes as markers of physiological renal condition. The marked decrease or disappearance of these metabolites and the high lipid content (triglycerides and cholesteryl esters) is typical of clear cell renal carcinoma (RCC), while papillary RCC is characterized by the absence of lipids and very high amounts of taurine. This research is a contribution to the biochemical classification of renal neoplastic pathologies, especially for RCCs, which can be evaluated by in vivo MRS for clinical purposes. Moreover, these data help to gain a better knowledge of the molecular processes envolved in the onset of renal carcinogenesis.

Supramolecular hybrid organic-inorganic multicomponent architectures in solution and on surface

Supramolecular architectures can be built-up from a single molecular component (building block) to obtain a complex of organic or inorganic interactions creating a new emergent condensed phase of matter, such as gels, liquid crystals and solid crystal. Further the generation of multicomponent supramolecular hybrid architecture, a mix of organic and inorganic components, increases the complexity of the condensed aggregate with functional properties useful for important areas of research, like material science, medicine and nanotechnology. One may design a molecule storing a recognition pattern and programming a informed self-organization process enables to grow-up into a hierarchical architecture. From a molecular level to a supramolecular level, in a bottom-up fashion, it is possible to create a new emergent structure-function, where the system, as a whole, is open to its own environment to exchange energy, matter and information. “The emergent property of the whole assembly is superior to the sum of a singles parts”. In this thesis I present new architectures and functional materials built through the selfassembly of guanosine, in the absence or in the presence of a cation, in solution and on the surface. By appropriate manipulation of intermolecular non-covalent interactions the spatial (structural) and temporal (dynamic) features of these supramolecular architectures are controlled. Guanosine G7 (5',3'-di-decanoil-deoxi-guanosine) is able to interconvert reversibly between a supramolecular polymer and a discrete octameric species by dynamic cation binding and release. Guanosine G16 (2',3'-O-Isopropylidene-5'-O-decylguanosine) shows selectivity binding from a mix of different cation's nature. Remarkably, reversibility, selectivity, adaptability and serendipity are mutual features to appreciate the creativity of a molecular self-organization complex system into a multilevelscale hierarchical growth. The creativity - in general sense, the creation of a new thing, a new thinking, a new functionality or a new structure - emerges from a contamination process of different disciplines such as biology, chemistry, physics, architecture, design, philosophy and science of complexity.

Aldo Rossi, autobiografia scientifica: scrittura come progetto. Indagine critica tra scrittura e progetto di architettura

«In altri termini mi sfuggiva e ancora oggi mi sfugge gran parte del significato dell’evoluzione del tempo; come se il tempo fosse una materia che osservo dall’esterno. Questa mancanza di evoluzione è fonte di alcune mie sventure ma anche mi appartiene con gioia.» Aldo Rossi, Autobiografia scientifica. The temporal dimension underpinning the draft of Autobiografia scientifica by Aldo Rossi may be referred to what Lucien Lévy-Bruhl, the well-known French anthropologist, defines as “primitive mentality” and “prelogical” conscience : the book of life has lost its page numbers, even punctuation. For Lévy-Bruhl, but certainly for Rossi, life or its summing up becomes a continuous account of ellipses, gaps, repetitions that may be read from left to right or viceversa, from head to foot or viceversa without distinction. Rossi’s autobiographical writing seems to accept and support the confusion with which memories have been collected, recording them after the order memory gives them in the mental distillation or simply according to the chronological order in which they have happened. For Rossi, the confusion reflects the melting of memory elements into a composite image which is the result of a fusion. He is aware that the same sap pervades all memories he is going to put in order: each of them has got a common denominator. Differences have diminished, almost faded; the quick glance is prevalent over the distinction of each episode. Rossi’s writing is beyond the categories dependent on time: past and present, before and now. For Rossi, the only repetition – the repetition the text will make possible for an indefinite number of times – gives peculiarity to the event. As Gilles Deleuze knows, “things” may only last as “singleness”: more frequent the repetition is, more singular is the memory phenomenon that recurs, because only what is singular magnifies itself and happens endlessly forever. Rossi understands that “to raise the first time to nth forever”, repetition becomes glorification . It may be an autobiography that, celebrating the originality, enhances the memory event in the repetition; in fact it greatly differs from the biographical reproduction, in which each repetition is but a weaker echo, a duller copy, provided with a smaller an smaller power in comparison with the original. Paradoxically, for Deleuze the repetition asserts the originality and singularity of what is repeated. Rossi seems to share the thought expressed by Kierkegaard in the essay Repetition: «The hope is a graceful maiden slipping through your fingers; the memory of an elderly woman, indeed pretty, but never satisfactory if necessary; the repetition is a loved friend you are never tired of, as it is only the new to make you bored. The old never bores you and its presence makes you happy [...] life is but a repetition [...] here is the beauty of life» . Rossi knows well that repetition hints at the lasting stability of cosmic time. Kierkegaard goes on: «The world exists, and it exists as a repetition» . Rossi devotes himself, on purpose and in all conscience, to collect, to inventory and «to review life», his own life, according to a recovery not from the past but of the past: a search work, the «recherche du temps perdu», as Proust entitled his masterpiece on memory. If you want the past time to be not wasted, you must give it presence. «Memoria e specifico come caratteristiche per riconoscere se stesso e ciò che è estraneo mi sembravano le più chiare condizioni e spiegazioni della realtà. Non esiste uno specifico senza memoria, e una memoria che non provenga da un momento specifico; e solo questa unione permette la conoscenza della propria individualità e del contrario (self e non-self)» . Rossi wants to understand himself, his own character; it is really his own character that requires to be understood, to increase its own introspective ability and intelligence. «Può sembrare strano che Planck e Dante associno la loro ricerca scientifica e autobiografica con la morte; una morte che è in qualche modo continuazione di energia. In realtà, in ogni artista o tecnico, il principio della continuazione dell’energia si mescola con la ricerca della felicità e della morte» . The eschatological incipit of Rossi’s autobiography refers to Freud’s thought in the exact circularity of Dante’s framework and in as much exact circularity of the statement of the principle of the conservation of energy: in fact it was Freud to connect repetition to death. For Freud, the desire of repetition is an instinct rooted in biology. The primary aim of such an instinct would be to restore a previous condition, so that the repeated history represents a part of the past (even if concealed) and, relieving the removal, reduces anguish and tension. So, Freud ask himself, what is the most remote state to which the instinct, through the repetition, wants to go back? It is a pre-vital condition, inorganic of the pure entropy, a not-to-be condition in which doesn’t exist any tension; in other words, Death. Rossi, with the theme of death, introduces the theme of circularity which further on refers to the sense of continuity in transformation or, in the opposite way, the transformation in continuity. «[...] la descrizione e il rilievo delle forme antiche permettevano una continuità altrimenti irripetibile, permettevano anche una trasformazione, una volta che la vita fosse fermata in forme precise» . Rossi’s attitude seems to hint at the reflection on time and – in a broad sense – at the thought on life and things expressed by T.S. Eliot in Four Quartets: «Time present and time past / Are both perhaps present in time future, / And time future is contained in time past. / I all time is eternally present / All time is unredeemable. / What might have been is an abstraction / Remaining perpetual possibility / Only in a word of speculation. / What might have been and what has been / Point to one end, which is always present. [...]» . Aldo Rossi’s autobiographical story coincides with the description of “things” and the description of himself through the things in the exact parallel with craft or art. He seems to get all things made by man to coincide with the personal or artistic story, with the consequent immediate necessity of formulating a new interpretation: the flow of things has never met a total stop; all that exists nowadays is but a repetition or a variant of something existing some time ago and so on, without any interruption until the early dawnings of human life. Nevertheless, Rossi must operate specific subdivisions inside the continuous connection in time – of his time – even if limited by a present beginning and end of his own existence. This artist, as an “historian” of himself and his own life – as an auto-biographer – enjoys the privilege to be able to decide if and how to operate the cutting in a certain point rather than in another one, without being compelled to justify his choice. In this sense, his story is a matter very ductile and flexible: a good story-teller can choose any moment to start a certain sequence of events. Yet, Rossi is aware that, beyond the mere narration, there is the problem to identify in history - his own personal story – those flakings where a clean cut enables the separation of events of different nature. In order to do it, he has to make not only an inventory of his own “things”, but also to appeal to authority of the Divina Commedia started by Dante when he was 30. «A trent’anni si deve compiere o iniziare qualcosa di definitivo e fare i conti con la propria formazione» . For Rossi, the poet performs his authority not only in the text, but also in his will of setting out on a mystical journey and handing it down through an exact descriptive will. Rossi turns not only to the authority of poetry, but also evokes the authority of science with Max Plank and his Scientific Autobiography, published, in Italian translation, by Einaudi, 1956. Concerning Planck, Rossi resumes an element seemingly secondary in hit account where the German physicist «[...] risale alle scoperte della fisica moderna ritrovando l’impressione che gli fece l’enunciazione del principio di conservazione dell’energia; [...]» . It is again the act of describing that links Rossi to Planck, it is the description of a circularity, the one of conservation of energy, which endorses Rossi’s autobiographical speech looking for both happiness and death. Rossi seems to agree perfectly to the thought of Planck at the opening of his own autobiography: «The decision to devote myself to science was a direct consequence of a discovery which was never ceased to arouse my enthusiasm since my early youth: the laws of human thought coincide with the ones governing the sequences of the impressions we receive from the world surrounding us, so that the mere logic can enable us to penetrate into the latter one’s mechanism. It is essential that the outer world is something independent of man, something absolute. The search of the laws dealing with this absolute seems to me the highest scientific aim in life» . For Rossi the survey of his own life represents a way to change the events into experiences, to concentrate the emotion and group them in meaningful plots: «It seems, as one becomes older. / That the past has another pattern, and ceases to be a mere sequence [...]» Eliot wrote in Four Quartet, which are a meditation on time, old age and memory . And he goes on: «We had the experience but missed the meaning, / And approach to the meaning restores the experience / In a different form, beyond any meaning [...]» . Rossi restores in his autobiography – but not only in it – the most ancient sense of memory, aware that for at least 15 centuries the Latin word memoria was used to show the activity of bringing back images to mind: the psychology of memory, which starts with Aristotele (De Anima), used to consider such a faculty totally essential to mind. Keith Basso writes: «The thought materializes in the form of “images”» . Rossi knows well – as Aristotele said – that if you do not have a collection of mental images to remember – imagination – there is no thought at all. According to this psychological tradition, what today we conventionally call “memory” is but a way of imagining created by time. Rossi, entering consciously this stream of thought, passing through the Renaissance ars memoriae to reach us gives a great importance to the word and assumes it as a real place, much more than a recollection, even more than a production and an emotional elaboration of images.