Le tritium et le carbone 14 sont les principaux contributeurs de l’activité dans les effluents liquides de CNPE (centrale nucléaire de production d’électricité). Ces derniers sont produits principalement dans le circuit primaire par activation neutronique. L’impact dosimétrique dépend des formes sous lesquelles se trouvent le tritium et le carbone 14. L’étude bibliographique a permis d’identifier les molécules organiques susceptibles d’être présentes au sein des effluents liquides. Elles proviennent du conditionnement des différents circuits et de leurs produits de dégradation. Ces molécules transitant par les effluents liquides, elles sont donc susceptibles d’être radiomarquées du fait de la présence avérée de tritium et carbone 14. L’objectif de la thèse est d’identifier les différentes formes organiques présentes et leur potentiel radiomarquage avec le tritium et le carbone 14. L’approche utilisée pour répondre à cette problématique est divisée en deux étapes clés. La première concerne l’identification et la quantification des molécules organiques (par des techniques chromatographiques). La seconde est relative à la quantification des différentes formes (organique et inorganique) du tritium et du carbone 14. Cette dernière est un réel challenge compte tenu de la composition radiologique des effluents. En effet, la fraction organique marquée potentiellement attendue est très faible (1-3%) et la séparation des formes organiques et de la matière organique soluble est délicate. Une étape de séparation est donc nécessaire avant quantification des fractions (organique et inorganique) par scintillation liquide. / Tritium and carbon 14, produced in the primary coolant by neutron activation, are the main contributors to the radioactivity released in the discharges of nuclear power plants. The dosimetric impact depends on the form in which tritium and carbon 14 are found. The bibliographic study identified the organic molecules likely to be present in liquid effluents. They come from the conditioning of the various circuits and their degradation products. These molecules are transiting through liquid effluents and are therefore likely to be radiolabelled due to the proven presence of tritium and carbon-14. The objective of the thesis is to identify the different organic forms present and their potential radiolabelling with tritium and carbon 14. The approach used to address this issue is divided into two key stages. The first concerns the identification and quantification of organic molecules (by chromatographic techniques). The second is related to the quantification of the different forms (organic and inorganic) of tritium and carbon 14. The latter is a real challenge given the radiological composition of the effluents. Indeed, the potentially expected labelled organic fraction is very small (1-3%) and the separation of organic forms and the soluble organic matter is delicate. A separation step is therefore necessary before quantification of the fractions (organic and inorganic) by liquid scintillation.

El problema de la legitimidad de la guerra es uno de los problemas fundamentales de la filosofía política y es de especial relevancia desde el punto de vista moral y jurídico. La teoría de la guerra justa ha cumplido un papel ambivalente en el debate sobre la legitimidad de la guerra. Frente a la corriente realista, que está representada por autores como Tucídides, Hobbes y Maquiavelo, ha cumplido una labor limitadora de la guerra. Al mismo tiempo, frente a la corriente pacifista, que parte de rechazar la guerra en sí misma, ha cumplido una labor justificador de la guerra. El objetivo de esta investigación es realizar una revisión crítica a la teoría de la guerra justa. El trabajo se compone de cinco capítulos en los que se analiza de forma sistemática la teoría de la guerra justa, poniéndola en relación con los problemas actuales. En primer lugar se analiza la naturaleza y fundamentación de la teoría de la guerra justa, prestando especial atención al posicionamiento de la misma como una teoría intermedia entre el realismo y el pacifismo. Durante este capítulo de pone de relieve la necesidad de revisar la fundamentación de la teoría. Se desarrolla en profundidad la denominada “analogía doméstica”, que permite extender las consideraciones de la legítima defensa a nivel individual a la defensa de las comunidades políticas. El segundo capítulo está dedicado al desarrollo y evolución de la teoría de la guerra justa. El análisis parte de las primeras referencias a la necesidad de limitar la guerra en los autores clásicos griegos. Posteriormente se examina el desarrollo formal de la teoría de la guerra justa, que tiene su origen en la obra de Agustín de Hipona, y se consolida en los postulados de Tomás de Aquino y Francisco de Vitoria. La investigación se extiende hasta recientes formulaciones como la de Michael Walzer. El análisis histórico permite mostrar que la teoría de la guerra justa no es una teoría unitaria, sino un conjunto de teorías relacionadas. Este conjunto de teorías comparten un origen común, ya que están ligadas al pensamiento cristiano, pero la doctrina no es unánime en la delimitación sustantiva del IUS AD BELLUM y del IUS IN BELLO Los capítulos tercero, cuarto y quinto están dedicados a analizar sistemáticamente el contenido de la teoría de la guerra justa poniéndolo en relación con problemas actuales. A lo largo de estos capítulos se destaca la dificultad de aplicar una tradición doctrinal que surgió y se desarrollo en contextos muy diferentes del actual. Se destaca su utilidad en estos momentos y también sus insuficiencias, es decir, la ambivalencia de la tradición de la guerra justa. En especial, se profundiza en: los riesgos que conlleva la adopción de un concepto laxo de prevención, tal y como propone la Doctrina Bush; la intervención humanitaria, la teoría medieval del doble efecto y la legitimidad de los daños colaterales; la figura de la emergencia suprema; y en la necesidad del denominado IUS POST BELLUM. La teoría de la guerra justa no ha podido dar respuesta clara a los desafíos que representan las “nuevas guerras”, pero se debe concluir que en estas guerras no se respeta el requisito de proporcionalidad y son, en consecuencia, ilícitas. / This thesis investigates the problem of the legitimacy of the use of force in the context of the Just War Theory. This theory offers a set of criteria to determine when it is legitimate to go to war (jus ad bellum), and how war must be conducted (jus in bello), and is regarded as a middle ground between two opposing traditions: realism (inter arma silent leges) and pacifism (war is evil). This thesis provides a critical review of the Just War Theory in connection with contemporary dilemmas. It highlights the fundamental and ambivalent role it plays in shaping contemporary judgements about warfare, being applied simultaneously as a justification and a limitation of war. The first chapter focuses on the characterisation of the Just War Theory as a moral reflection about war itself. It explores the idea that the foundations of the Just War Theory need to be revised, in particular the so-called “domestic analogy”. The second chapter looks into the historical development of the Just War Theory. The analysis shows that it is not a settle doctrine, but rather a group of theories developed initially during the Middle Ages and rooted in the works of Augustine of Hippo, Thomas Aquinas, Hugo Grotius and Francisco de Vitoria, amongst others. It also explores more recent revisions of the theory by other authors, such as Paul Ramsey and Michael Walzer. The last three chapters review the content of the jus ad bellum, jus in bello and jus post bellum in connection with contemporary issues. In particular, it analyses the “war” against terrorism and the Bush Doctrine, the humanitarian intervention, the theory of the double effect and the need of jus post bellum as part of the theory.

Esta tesis analiza las repercusiones que tiene el estudio de la música en el rendimiento académico del niño y niña de primaria. Para ello se han investigado los principales agentes que confluyen en el proceso de aprendizaje y enseñanza musical: el alumnado de conservatorio / sociedad musical y los profesores que imparten docencia musical. Se realiza en un contexto musicalmente prolífero como es la Comunidad Valenciana que también es referente a nivel nacional e internacional en cuanto a intérpretes y compositores. En el transcurso de ese análisis se tratan cuestiones que condicionan el rendimiento del alumnado: el currículo establecido en España y en la Comunidad, el concepto de rendimiento, el nivel de los alumnos a través de los estudios de rendimiento o el contenido extra musical que trabajan los alumnos que estudian música. Para ello la tesis cuenta con dos grandes apoyos. El primero lo constituyen los datos ofrecidos por diferentes escuelas públicas de etapa primaria de la Comunidad Valenciana. Y el segundo gran apoyo lo constituye la propia experiencia como docente de música de la autora en la escuela primaria. La tesis parte de los estudios pedagógicos y clínicos sobre la respuesta de las personas hacia la música, que es el germen de esta tesis como se refleja en la introducción. Se han establecido tras esa introducción seis apartados que constituyen el corpus de la tesis: el estado de la cuestión en este tipo de estudios, la estructura de la investigación concreta llevada a cabo, el desarrollo musical en el seno del desarrollo psicoevolutivo del alumno, la educación musical en la escuela primaria y en las sociedades musicales y la relación de la música con el resto de materias que es el reflejo más evidente de la repercusión música en el rendimiento. Los datos de tipo cualitativo y cuantitativo facilitados por los colegios y el análisis de aula hace posible que este estudio de caso describa una realidad que muchos docentes intuyen y que se expone de manera más concreta con este estudio. La música influye en la inteligencia del alumno, crea conexiones desde su propio sentido de ser. Trabaja conceptos matemáticos también conceptos lingüísticos o conocimientos del entorno. La capacidad motriz fina y el control motor es también beneficiada asi como la capacidad plástica a través de la audición. De este modo gracias a los datos facilitados por los maestros de música de los centros públicos de la Comunidad y la propia investigación diaria de aula se ha podido llegar a la conclusión de que cualquier niño mejora su rendimiento cuando estudia música, y aún más los niños que se dedican a su estudio a nivel extraescolar. Estos niños (que en la tesis aparecen bajo el nombre de niños/as-músico) desarrollan otro tipo de estrategias de índole social y emocional muy positivas y beneficiosas para su autoestima y para el comportamiento en el aula, el trabajo en equipo, la responsabilidad ante un trabajo bien hecho en las audiciones y conciertos, etc. Esta tesis resulta novedosa porque lleva la investigación a un ámbito muy concreto y fácilmente identificable y hace más fácil al docente el acceso a conocimientos que pueden mejorar su acción pedagógica y como resultado el aprendizaje de sus alumnos. Otra novedad resulta el estudio de caso en el ámbito pedagógico, pues en este caso es importante tener en cuenta a los participantes directos de la enseñanza musical, los maestros y los alumnos de música. En resumen, es una tesis que pretende la reflexión del profesorado de música sobre su materia y sobre cómo esta puede llegar a influir en el rendimiento académico general de sus alumnos. / The present Doctoral Thesis analyzes the effects of musical studies in the academic efficiency of elementary students. For that reason main factors in learning and musical teaching procedure have been investigated; these are the students of Music Conservatories/ Music Academies and music professionals. This Doctoral Thesis has been carried on the Comunidad Valenciana that is one of the best examples of musical tradition and international projection of its musicians and composers. Along this analysis questions affecting the academic study are developed, the study plan followed in Spain and in the Comunidad Valenciana, the definition of academic efficiency, students’ level using works about academic effectiveness and the extra knowledge achieved with musical studies. The thesis is based on two fundamental aspects. The first one is the data supported for several Public Elementary Schools of the Comunidad Valenciana. And the second one is the experience of the author of the present work in his career of a music teacher in an Elementary School. The departure point of the present Thesis are the pedagogical and clinic studies about the response of people towards the music, those studies have given rise to this work as is reflected in the introduction section. Quantitative and qualitative data provided by Elementary Schools and the class analysis have made possible this action research describing what most of teachers have ever noticed and what is exposed in a concise way with this study. Intrinsically the study of music creates connections with other areas contributing in student’s intelligence. The thesis is original due to its research is focused in a specific area neatly identifiable making easier to the professor the access to knowledge which could improve his pedagogical job and consequently could improve students’ learning abilities. Another original aspect in this Thesis is the class analysis in the pedagogical area, since in this case it is important to keep in mind the direct participants in musical teaching procedure, these are the music professors and music students.

Ulm, Univ., Diss., 2007.

L’insorgenza di fenomeni coinvolti nello sviluppo della farmacoresistenza costituisce al momento la principale causa di mancata risposta al trattamento chemioterapico nell’osteosarcoma. Questo è in parte dovuto ad una sovraespressione di diversi trasportatori ABC nelle cellule tumorali che causano un aumento dell’efflusso extracellulare del chemioterapico e pertanto una ridotta risposta al trattamento farmacologico. L'oncogene C-MYC è coinvolto nella resistenza al metothrexate, alla doxorubicina e al cisplatino ed è un fattore prognostico avverso, se sovraespresso al momento della diagnosi, in pazienti affetti da osteosarcoma. C-MYC è in grado di regolare l'espressione di diversi trasportatori ABC, probabilmente coinvolti nella resistenza ai farmaci nell’osteosarcoma, e questo potrebbe spiegare l’impatto prognostico avverso dell’oncogene in questo tumore. L’espressione genica di C-MYC e di 16 trasportatori ABC, regolati da C-MYC e / o responsabili dell'efflusso di diversi chemioterapici, è stata valutata su due diverse casistiche cliniche e su un pannello di linee cellulari di osteosarcoma umano mediante real-time PCR. L'espressione della proteina è stata valutata per i 9 trasportatori ABC risultati più rilevanti.Infine l'efficacia in vitro di un inibitore, specifico per ABCB1 e ABCC1, è stata valutata su linee cellulari di osteosarcoma. ABCB1 e ABCC1 sono i trasportatori più espressi nelle linee cellulari di osteosarcoma. ABCB1 è sovraespresso al momento della diagnosi in circa il 40-45% dei pazienti affetti da osteosarcoma e si conferma essere un fattore prognostico avverso se sovraespresso al momento della diagnosi. Pertanto ABCB1 diventa il bersaglio di elezione per lo sviluppo di strategie terapeutiche alternative, nel trattamento dell’osteosarcoma, atte al superamento della farmacoresistenza. L’inibizione dell'attività di tale trasportatore causa un aumento della sensibilità al trattamento chemioterapico nelle linee cellulari di osteosarcoma farmacoresistenti, indicando questo approccio come una possibile strategia per superare il problema della mancata risposta al trattamento farmacologico nei pazienti con osteosarcoma che sovraesprimono ABCB1. / Resistance to chemoterapeutic agents is a major obstacle for successful treatment of high grade osteosarcoma. This is in part caused by disregulation of the activity of ATP-binding cassette transporters (ABC) responsible for the efflux of chemotherapeutic agents in cancer cells. Studying how these transporters are regulated at transcription level is a crucial step to understanding multidrug resistance in cancer. The C-MYC oncogene has been identified to be related to resistance against methotrexate, doxorubicin and cisplatin and to be a prognostic factor for high grade osteosarcoma. C-MYC can regulate the expression of several ABC transporter genes, possibly related to drug resistance in osteosarcoma, and this may explain its adverse prognostic impact in this tumor. We have analyzed C-MYC and 16 ABC transporters, which are regulated by C-MYC and/or have been found to be responsible for the efflux of conventional drugs used in the treatment of human tumors on two different series of clinical samples and in a panel of human osteosarcoma cell lines by real-time PCR. The protein expression was evaluated for the 9 ABC transporters resulted as the most relevant from gene espression experiments. Finally the efficacy of a specific ABCB1 and ABCC1 inhibitor, was evaluated on osteosarcoma cell lines. ABCB1 and ABCC1 were the most expressed transporters in osteosarcoma cell lines. ABCB1 overexpression at diagnosis was found in about 40-45% of osteosarcoma patients and it was confirmed to be associated with adverse prognosis, being involved in drug resistance of osteosarcoma cells. Because of this, ABCB1 can be considered as a candidate therapeutic target for improving the treatment response of high-grade osteosarcoma patients. Inhibition of ABCB1 activity resulted to increase chemotherapeutics sensitivity of drug resistant human osteosarcoma cell lines, indicating this approach as a possible strategy to overcome treatment unresponsiveness in ABCB1-overexpressing osteosarcoma patients.

The transcribed ultraconserved regions (T-UCRs) are a group of long non-coding RNAs involved in human carcinogenesis. The factors regulating the expression of T-UCRs and their mechanism of action in human cancers are unknown. In this work it was shown that high expression of uc.339 associates with lower survival in 204 non-small cell lung cancer (NSCLC) patients. Moreover, it was shown that uc.339 found up-regulated in archival NSCLC samples, acts as a decoy RNA for miR-339-3p, -663-3p and -95-5p. So, Cyclin E2, a direct target of three microRNAs is up-regulated, inducing cancer growth and migration. Evidence of this mechanism was provided from cell lines and primary samples confirming that TP53 directly regulates uc.339. These results support a key role for uc.339 in lung cancer.

The physicochemical interactions between water, sediment and soil deeply influence the formation and development of the ecosystem. In this research, different freshwater, brackish and saline subaqueous environments of Northern Italy were chosen as study area to investigate the physicochemical processes which occur at the interface between water and sediments, as well as the effects of soil submergence on ecosystem development. In the freshwater system of the Reno river basin, the main purpose was to define the heavy metals hazard in water and sediments of natural and artificial water courses. Heavy metals partitioning and speciation allowed to assess the environmental risk linked to the critical action of dredging canal sediments, for the maintenance of the hydraulic safety of plain lands. In addition, some bioremediation techniques were experimented for protecting sediments from heavy metals contamination, and for giving an answer to the problem of sediments management. In the brackish system of S. Vitale park, the development of hydromorphic and subaqueous soils was investigated. The study of soil profiles highlighted the presence of a soil continuum among pedons subjected to different saturation degrees. This investigation allowed to the identification of both morphological and physicochemical indicators, which characterize the formation of subaqueous soils and describe the soil hydromorphism in transitional soil systems. In the saline system of Grado lagoon, an ecosystem approach was used to define the role of water oscillation in soil characterization and plants colonization. This study highlighted the close relationship and the mutual influence of soil submergence and aeration, tide oscillation and vegetation cover, on the soil development. In view of climate change, this study contribute to understand and suppose how soil and landscape could evolve. However, a complete evaluation of hydromorphic soil functionality will be achieved only involving physiological and biochemical expertise in these kind of studies.

Autism Spectrum Disorder (ASD) is a range of early-onset conditions classified as neurodevelopmental disorders, characterized by deficits in social interactions and communication, as well as by restricted interest and repetitive behaviors. Among the proteins associated with this spectrum of disease there are Caspr2, α-NRXN1, NLGN1-4. Caspr2 is involved in the clustering of K+ channels at the juxtaparanodes, where it is proposed to bind TAG-1. Recent works reported a synaptic localization of Caspr2, but little is know on its role in this compartment. NRXNs and their ligand NLGNs, instead, have a well-defined role in the formation and maintenance of synapses. Among the neuroligins, NLGN2 binds NRXNs with the lowest affinity, suggesting that it could have other not yet characterized ligands. The aim of this work was to better characterize the binding of Caspr2 to TAG-1 and to identify new potential binding partner for Caspr2 and NLGN2. Unexpectedly, using Isothermal Titration Calorimetry and co-immunoprecipitation experiments the direct association of the first two proteins could not be verified and the results indicate that the first evidences reporting it were biased by false-positive artifacts. These findings, together with the uncharacterized synaptic localization of Caspr2, made the identification of new potential binding partners for this protein necessary. To find new proteins that associate with Caspr2 and NLGN2, affinity chromatography in tandem with mass spectrometry experiments were performed. Interestingly, about 25 new potential partners were found for these two proteins and NLGN1, that was originally included as a control: 5 of those, namely SFRP1, CLU, APOE, CNTN1 and TNR, were selected for further investigations. Only the association of CLU to NLGN2 was confirmed. In the future, screenings of the remaining candidates have to be carried out and the functional role for the proposed NLGN2-CLU complex has to be studied.

Il presente studio si concentra sull’analisi degli aspetti traslazionali nella ricerca farmacologica applicata alla Gastroenterologia. La trattazione si articola in due parti: una prima elaborazione teorica, che permette di inquadrare nel contesto della ricerca traslazionale il razionale scientifico ed etico alla base delle attività sperimentali eseguite durante il triennio; una seconda parte, nella quale si riportano i metodi, i risultati e le osservazioni conclusive derivanti dallo studio sperimentale. Nella prima parte vengono analizzate alcune caratteristiche delle procedure, adottate nella ricerca in ambito farmacologico gastrointestinale, che permettono di ottenere un dato verosimile derivabile da modelli diversi rispetto all’organismo umano. Sono inclusi nella trattazione gli aspetti etici dell’utilizzo di alcuni modelli animali di patologie intestinali organiche e funzionali in relazione al loro grado di predittività rispetto alla realtà sperimentale clinica. Nella seconda parte della trattazione, viene presentato uno studio esplorativo tissutale multicentrico sul ruolo del sistema oppioide e cannabinoide nella sindrome dell’intestino irritabile (IBS). Obiettivo dello studio è la valutazione dell’espressione e la localizzazione del recettore oppioide µ (µOR), del suo ligando β endorfina (β-END) e del recettore cannabinoide 2 (CB2) nei pazienti con IBS ad alvo costipato (IBS-C) e diarroico (IBS-D), ed in soggetti sani (HC). I dati ottenuti indicano un’implicazione del sistema oppioide e cannabinoide nella risposta immune alterata riscontrata nei pazienti con IBS ed in particolare nel sottogruppo IBS-C. La presente trattazione suggerisce come la creazione di nuovi sistemi di indagine sempre più validi da un punto di vista traslazionale possa dipendere, almeno in parte, dalla capacità di integrare realtà disciplinari, tecnologie ed esperienze metodologiche diverse nel contesto della ricerca in campo biomedico e farmacologico ed in particolare tramite un mutuo scambio di informazioni tra realtà clinica e ricerca di base / The present study focuses on the analysis of translational issues of pharmacological research applied to Gastroenterology. The dissertation is divided in two parts: the first one consists in a theroethical elaboration allowing to contextualize - within the framework of translational research - the scientific and ethical rationale underlying the experimental activity carried out over the last three years. The second part deals with the methods, the results and the conclusive observations deriving from the experimental study presented. In the first part some features of the procedures adopted in the field of pharmacology applied to gastroenterology are presented. These allow to obtain a reliable data deriving from models other than human one. This section also addresses the ethical issues concerning the use of animal models of both organic and functional intestinal pathologies. Such issues are put in relation to the level of predicitivity peculiar to the model and related to the research. In the second part of the dissertation the author presents a multicenter study about the role of the opioid and cannabinoid system in the irritable bowel syndrome (IBS). The aim of the study is the assessment of the expression of µ opioid receptor (µOR), of its ligand β-endorphin (β-END) and the cannabinoid receptor 2 (CB2) in IBS patients with either constipation (IBS-C) or diarrhea (IBS-D) compared to healthy controls (HC). The data obtained suggest that the opioid and cannabinoid systems contribute to the abnormal immune response detected in IBS patients, particularly in IBS-C. The present dissertation suggests how the creation of innovative research methodologies ever more effective from a translational standpoint may depend, at least in part, from the ability to integrate different research areas, technologies and methodological expertise in the context of biomedical and pharmacological research, especially through the mutual exchange of information between clinical and basic research.

Nanotechnology promises huge benefits for society and capital invested in this new technology is steadily increasing, therefore there is a growing number of nanotechnology products on the market and inevitably engineered nanomaterials will be released in the atmosphere with potential risks to humans and environment. This study set out to extend the comprehension of the impact of metal (Ag, Co, Ni) and metal oxide (CeO2, Fe3O4, SnO2, TiO2) nanoparticles (NPs) on one of the most important environmental compartments potentially contaminated by NPs, the soil system, through the use of chemical and biological tools. For this purpose experiments were carried out to simulate realistic environmental conditions of wet and dry deposition of NPs, considering ecologically relevant endpoints. In detail, this thesis involved the study of three model systems and the evaluation of related issues: (i) NPs and bare soil, to assess the influence of NPs on the functions of soil microbial communities; (ii) NPs and plants, to evaluate the chronic toxicity and accumulation of NPs in edible tissues; (iii) NPs and invertebrates, to verify the effects of NPs on earthworms and the damaging of their functionality. The study highlighted that NP toxicity is generally influenced by NP core elements and the impact of NPs on organisms is specie-specific; moreover experiments conducted in media closer to real conditions showed a decrease in toxicity with respect to in vitro test or hydroponic tests. However, only a multidisciplinary approach, involving physical, chemical and biological skills, together with the use of advanced techniques, such as X-ray absorption fine structure spectroscopy, could pave the way to draw the right conclusions and accomplish a deeper comprehension of the effects of NPs on soil and soil inhabitants.