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La thrombine, une protéase à sérine connue pour être l'acteur clé de la cascade de coagulation, a été décrite pour réguler les processus apoptotiques au niveau du côlon via l'activation de récepteurs activés par des protéases ou PARs (Protease-Activated Receptors). Cependant, les effets de la thrombine sur la cellule épithéliale colique n'ont été étudiés qu'en utilisant des lignées cellulaires. Les conséquences d'une exposition à différentes doses de thrombine sur un épithélium complexe, composés de différents types cellulaires plus ou moins différenciés sont inconnues à ce jour. Un nouveau modèle cellulaire, nommé organoïde, permet de reconstituer un épithélium colique fonctionnel en 3-dimensions (3D) à partir de résections ou de biopsies humaines, et ce, grâce aux capacités d'auto-renouvellement et de différenciation des cellules souches issues des cryptes coliques. Le 1er objectif de ma thèse a été d'évaluer les effets de la thrombine sur la survie, la prolifération, l'apoptose et la différenciation de l'épithélium colique humain, en utilisant le modèle organoïde. Puis, de déterminer l'implication des récepteurs PAR1 et PAR4 activés par la thrombine dans ces effets. Ainsi, l'ajout de thrombine (à faible dose : 10mU/mL et à forte dose : 50mU/mL) sur une culture d'organoïdes établis à partir de tissus colorectaux normaux entraîne une diminution de moitié de l'activité métabolique et de la prolifération cellulaire. Ces effets sont bloqués en présence d'un antagoniste de PAR1. Le processus apoptotique est, cependant, augmenté d'un facteur 8 en réponse à la thrombine (aux deux doses). Ce processus est inhibé en présence d'antagoniste de PAR1 ou de PAR4. Concernant la différenciation épithéliale, la thrombine diminue le nombre de colonosphères (structures immatures), au profit d'une augmentation du nombre de structures apoptotiques et de colonoïdes (structures plus matures présentant des néo-cryptes). Cet effet est dû à l'activation à la fois de de PAR1 et de PAR4 dans les cellules épithéliales coliques. Mes résultats démontrent que la thrombine exogène agit sur les processus d'apoptose, de prolifération et de différenciation sur un épithélium complexe, issu de la culture de tissus humains. L'utilisation de ce modèle ex vivo permet de comparer les organoïdes pathologiques et normaux, voire de tester les effets d'approches pharmacologiques et de nouveaux médicaments sur ces cultures. Ainsi, la 2nde partie de ce travail de thèse a été d'aborder la mise en place des conditions de culture et d'imagerie nécessaires pour réaliser un screening à haut débit robuste et reproductible, HCS (High-Content Screening), appliquée aux organoïdes. Les conditions de culture d'organoïdes en plaques 96-puits ont été mises au point de même que les conditions permettant d'acquérir des images répondant aux critères nécessaires pour une analyse via un système HCS. Le système Operetta HCS couplé au logiciel d'analyse Harmony (PerkinElmer) a été utilisé pour mettre en place une procédure d'analyse permettant de reconnaître les organoïdes, de les dénombrer, de les classer selon leur état de différenciation et de suivre leur croissance tout au long de la culture. Pour conclure, ces travaux de thèse ont permis de mettre en évidence les effets de la thrombine sur l'état métabolique, l'apoptose et la différenciation de l'épithélium colique humain, grâce au modèle 3D ex vivo d'organoïdes colorectaux. L'utilisation de ce modèle complète les approches jusque-là effectuées dans des modèles de lignées de cellules épithéliales, proposant une vision intégrée du comportement d'un épithélium complexe humain. L'approche HCS initiée lors de ces travaux de thèse pourrait permettre d'analyser de façon robuste et automatisée dans ce modèle, les effets d'autres composés et avoir ainsi un impact majeur sur notre compréhension des pathologies épithéliales et sur les tests de nouvelles approches thérapeutiques. / Thrombin, a serine protease known for its role in the coagulation cascade, was described for its effects on the induction of apoptosis in colonic epithelial cell lines, through the activation of Protease Activated Receptors (PARs). However, the effects of thrombin on complex epithelial structures such as the human intestinal epithelium composed of different cell types and cells at different stages of differentiation, has never been investigated. A new cellular model, named organoid, enables to reconstitute a functional epithelium in 3-dimensions (3D), from human resections or biopsies, thanks to the self-renewal and differentiation properties of stem cells isolated from colonic crypts. The first objective of this thesis was to evaluate thrombin's effects on survival, proliferation, apoptosis and differentiation in human colonic epithelium, using the organoid model. Then, we aimed to determining the implication of PAR1 and PAR4 in the thrombin's effects. Thus, thrombin added (at low dose: 10mU/mL and higher dose: 50mU/mL) to organoid cultures from control patients, led to a decrease by half of metabolic activity and cell proliferation. These effects were blocked by the addition of a PAR1 antagonist. Apoptotic process was 8-fold higher in organoid cultures exposed to thrombin (both doses) and this effect was inhibited by the addition of a PAR1 or a PAR4 antagonist. As per epithelial differentiation, thrombin decreased the number of colonospheres (immature structures) favoring the increase of apoptotic structures and colonoids (budding structures considered as more mature). This effect was due to PAR1 and PAR4 activation as again, it was blocked both by PAR1 and PAR4 antagonist. Taken together, these results reveal that exogenous thrombin acts on apoptosis, proliferation and differentiation processes in complex human colonic epithelium. The use of this ex vivo model will allow to compare pathological versus normal organoid cultures, but also to test the effects of pharmacological approaches and new treatment options directly in cultured human tissues. Thus, the 2nd part of this thesis was to setup the best culture conditions and the best imaging conditions to perform a robust and reproducible screening approach, HCS (High-Content Screening), using organoid cultures. Culture conditions in 96-well plates were set up and allowed to acquire images with the HCS system. Operetta HCS coupled to an analysis software (Harmony, PerkinElmer) was used to develop a specific program enabling the recognition of organoids, their counting, their classification according to their differentiation status and enabling to follow organoid growth in cultures. To sum up, the work performed allowed to highlight the effects of thrombin on metabolic status, apoptosis and differentiation of human colon epithelium, using an ex vivo 3D organoid model. The use this model nicely completed epithelial cell line approaches, offering an integrated view of the complex behavior of human epithelium. The HCS approach initiated within this thesis should allow the automated analysis of a number of drugs and treatments. It should help our understanding of epithelial pathologies and the testing of new therapeutic approaches.

IEEE 802.11n Wireless Local Area Networks (WLANs) employ Multiple-Input-Multiple-Output (MIMO), which significantly boosts the raw data rate at the Physical layer (PHY). But the potential of enhancing Medium Access Control (MAC) layer efficiencies by MIMO is still in its early stage and is the aim of the research in this thesis. Many existing works in this field mainly employ distributed MIMO spatial multiplexing/Multi-User Detection (MUD) technique and stream sharing to enable multiple simultaneous transmissions. Most works require synchronization among multiple transmissions, split the channel, and aim for single-hop networks. In this thesis, a novel Hybrid Carrier Sense (HCS) framework is proposed, mainly at the MAC layer to exploit the power of MIMO. HCS senses the channel availability jointly by the virtual carrier sense and physical carrier sense. HCS does not require synchronization among nodes; each node independently and locally determines when to start its transmission. HCS not only shares the channel, but also exploits the bi-directional handshakes of the wireless transmissions and increases the number of simultaneous stream transmissions. For a network with M antennas in each node, HCS can accommodate 2x(M-1) streams instead of M streams achieved by all other existing works. Moreover, HCS is aimed for multi-hop wireless ad hoc networks, in which the hidden terminal, exposed terminal, and deafness problems greatly degrade network performance. The HCS framework incorporates solutions to these problems. HCS is implemented in an NS2 network simulator and the performance evaluation shows that HCS significantly outperforms MIMO-enabled IEEE 802.11 (in which MIMO is only used for enhancing the raw data rate in the physical layer), resulting in higher aggregate throughput, packet delivery ratio and fairness in multi-hop wireless ad hoc networks. The HCS framework will be in wide use in the future generation of wireless networks and opens up more research possibilities. Some ideas in the HCS framework can be applied not only for MIMO, but also for many other techniques surveyed in this thesis; or we may combine them with HCS to further boost the network performance. / Thesis (Ph.D, Electrical & Computer Engineering) -- Queen's University, 2013-10-15 21:46:15.983

L’augmentation de la moyenne de vie a modifié le spectre des maladies cardiaques vers l'insuffisance cardiaque, un désordre progressif incurable, marqué par une perte massive de cardiomyocytes. En raison de la rareté des donneurs, la transplantation cardiaque, devient de plus en plus difficile. En 2003, la découverte des cellules souches cardiaques humaines (hCSC) pouvant supporter la réparation du myocarde après un infarctus a soulevé l’espoir d’approches thérapeutiques plus prometteuses. La transplantation des cellules autologues (issues du patient) a montré une efficacité limitée en raison de la mauvaise qualité des cellules après infarctus. De ce fait, l’utilisation des CPC allogéniques provenant de donneurs sains semble aujourd’hui le choix le plus réaliste et représente un potentiel produit thérapeutique abordable et disponible pour tous. Cependant les cellules allogéniques soulèvent des problèmes immunologiques importants qu’il faut résoudre avant leur utilisation clinique. Concernant la réponse immune innée, nos résultats indiquent que les hCPC allogéniques ont une susceptibilité modeste à la lyse NK et pourraient même être protégées contre cette lyse en contexte inflammatoire. Contrairement à la réponse immunitaire innée favorable contre les hCPC allogéniques, la présence des alloanticorps anti-HLA peut être néfaste. Nos résultats ont montré que les DSA-HLA I spécifiques de l’haplotype des hCPC peuvent induire leur lyse par CDC et ADCC et cette lyse est fortement augmentée par les conditions inflammatoires. L’ensemble de ces résultats indique que les hCPC allogéniques sont des cellules à faible risque immunologique en ce qui concerne la réponse immune innée, par contre une élimination rapide par CDC ou tardive par ADCC des hCPC pourrait se produire chez les patients ayant des DSA-HLA I spécifiques de l’allèle(s) exprimé(s) par les hCPC incitant ainsi le dépistage des DSA-HLA avant l’infusion thérapeutique des hCPC. / The increase in average life changed the spectrum of heart disease to heart failure, a progressive incurable disorder, characterized by a massive loss of cardiomyocytes. Due to the scarcity of donors, cardiac transplantation, only effective treatment known to date is becoming increasingly difficult. In 2003, the discovery of human cardiac stem cells (HCS/PC) can support the repair of the myocardium after myocardial raised hopes of promising therapeutic approaches. Transplantation of autologous (from the patient) showed limited efficiency because of the poor quality of the cells after infarction. Therefore, the use of stem / progenitor heart (CPC) from allogeneic healthy donors seems today the most realistic choiceand represents a potential therapeutic product available to all. However allogeneic cells raise significant immunological problems that must be resolved before clinical use. Regarding the innate immune response, our results indicate that allogeneic HCPC have a modest susceptibility to NK lysis and could even be protected against this lysis in the inflammatory context. In addition, allogeneic HCPC seem able to inhibit the activity of NK cells. Unlike the favorable innate immune response against the allogeneic HCPC, the presence of anti-HLA alloantibodies can be harmful. Our results showed that the DSA-specific HLA class I haplotype of the HCPC can induce their lysis by CDC and ADCC and this lysis is greatly increased by inflammatory conditions. However, the DSA-specific HLA II do not induce HCPC lysis. All these results indicate that allogeneic HCPC are cells with low immunological risk regarding the innate immune response. On the contrary, rapid elimination by CDC or ADCC of HCPC may occurs in patients with DSA- HLA class I specific allele (s) expressed by the HCPC thus prompting the screening of HLA-DSA prior to therapeutic infusion of HCPC.

The topic of this thesis is knowledge discovery and artificial intelligence based knowledge discovery algorithms. The knowledge discovery process and associated problems are discussed, followed by an overview of three classes of artificial intelligence based knowledge discovery algorithms. Typical representatives of each of these classes are presented and discussed in greater detail. Then a new knowledge discovery algorithm, called Hybrid Classifier System (HCS), is presented. The guiding concept behind the new algorithm was simplicity. The new knowledge discovery algorithm is loosely based on schemata theory. It is evaluated against one of the discussed algorithms from each class, namely: CN2; C4.5, BRAINNE and BGP. Results are discussed and compared. A comparison was done using a benchmark of classification problems. These results show that the new knowledge discovery algorithm performs satisfactory, yielding accurate, crisp rule sets. Probably the main strength of the HCS algorithm is its simplicity, so it can be the foundation for many possible future extensions. Some of the possible extensions of the new proposed algorithm are suggested in the final part of this thesis. / Dissertation (MSc)--University of Pretoria, 2007. / Computer Science / unrestricted

The natural resources offer a unique opportunity for the discovery of active compounds, due to the complexity and biodiversity of their chemical structures. Natural resources have been used as medicines throughout human history. Saudi Arabia’s natural resources, for instance its terrestrial medicinal plants and the Red Sea sponges, have not been extensively investigated with regard to their biological activities. To better identify the diversity of compounds with bioactive potential, new techniques are also necessary in order to improve the drug discovery path. This study comprises three sections. The first section examines Juniperus phoenicea (Arar), Anastatica hierochuntica (Kaff Maryam) and Citrullus colocynthis (Hanzal); these herbal plants were screened for potential bioactivity using a newly developed pipeline based on a high-content screening technique. We report a new cell-based high-throughput phenotypic screening for the bio-prospecting of unknown natural products from Saudi Arabian plants, in order to reveal their biological activities. The second section investigates Avicennia marina plants, screened for reverse transcriptase anti-HIV bioactivity using biochemical assay. Image-based high-content screening with a set of cellular stains was used to investigate the phenotypic results of toxicity and cell cycle arrest. The third section considers the isolation of Actinomycetes from Red Sea Sponges. Actinomycetes bacterial isolates were tested for bioactivity against West Nile Virus NS3 Protease. Analytical chemical techniques such as liquid chromatography–mass spectrometry (LC-MS), gas chromatography–mass spectrometry (GC-MS) and nuclear magnetic resonance (NMR) were used to gain more understanding of the possible chemical compounds responsible for this bioactivity. Overall, the aim of this work is to investigate the potential bioactive effect of several Saudi Arabian plants and Red Sea sponges against cancer cells and viral infections. Our study demonstrates the efficiency of the newly developed pipeline using cell-based phenotypic screening. Anti-cancer potential activity was detected in Juniperus phoenicea. Bioactive potential against the reverse transcriptase enzyme of HIV virus was confirmed in Avicennia marina leaves. The organic extracts of Actinomycetes bacterial isolates were found active against West Nile Virus NS3 Protease. Here, promising starting point for the potential of drug discovery of plants and marine organism of Saudi Arabia.

Data were analyzed from the 1998-2004 Uniform Data System (UDS) to identify trends and predictors of financial performance (costs, productivity, and overall financial health) for health centers (HCs). Several differences were noted regarding revenues, self-sufficiency, service offerings, and urban/rural setting. Urban centers with larger numbers of clients, centers that treated high numbers of patients with chronic diseases, and centers with large numbers of prenatal care users were the most fiscally sound. Positive financial performance can be targeted through strategies that generate positive revenue, strive to decrease costs, and target services that are in demand.

Yes / In this work, the effect of the nanosized CZA2 (cerium-zirconium-aluminium) on the performance and emissions in a two- cylinder indirect injection (IDI) diesel engine, was studied. CZA2 was dispersed in diesel (D100) and waste cooking oil and tallow origin biodiesel-diesel blends (B10, B20, B30) and tested at different engine loads and constant speed. The nanocatalyst (CZA2) increased the brake specific fuel consumption (BSFC) and decreased the brake thermal efficiency (BTE, %) of all tested fuels, at all loads, except B20 at the lowest load. CZA2 reduced nitrogen oxides (NOx) from D100 at low and high engine loads, as well as carbon monoxide (CO) and unburned hydrocarbons (HC) at medium and high tested loads. The dispersion of CZA2 promoted the combustion of the biodiesel blends by almost eliminating HC while reducing NOx and CO emissions at various loads. Thermogravimetric analysis (TGA) coupled with Attenuated Total Reflectance- Fourier Transform Infrared (ATR-FTIR) spectroscopy revealed that the addition of CZA2 in diesel and biodiesel under pyrolysis and oxidation conditions resulted in the presence of saturated species like ketones and final oxidation products such as CO2, supporting their improved combustion and emissions’ reduction in the engine tests.

According to science, food allergy is a growing health problem. In home- and consumer studies (HCS), food and meals are central parts. According to the Education Act, teachers must be given professional development to create a safe environment for students.   The purpose of this study was to examine how teachers in home economics and consumer studies experienced the conditions for teaching students with food allergies. The focus was on the classroom, routines, allocated budget, and professional development.   Qualitative method was used. Nine qualified home economics teachers were interviewed based on a semi-structured question guide. The interviews were transcribed and analyzed with a qualitative content analysis.   The results showed that the classroom and the economic conditions limited the teaching. The teachers felt confident in their current knowledge but were positive about continuing education. Routine improvements regarding information management and action plan are desired.     The study showed that the classroom was important for the teaching and that the few students with food allergies did not affect the budget in general. Routines around these students should be reconsidered. Basic education needs to be strengthened and teachers need to be given the opportunity for further training.

[EN] Several efforts have been made in experimental and theoretical research about shear to understand all the variables that influence the phenomenon. Nowadays, however, due to its complexity, the shear performance of structural concrete elements, especially those without any traditional transversal reinforcement, continue with no clear explanation of the problem. Uncertainty about the problem grows when new variables like fibres are incorporated into the shear study. Research works have demonstrated the effectiveness of steel fibre in improving the mechanical properties of concrete elements. Experimental results reveal that steel fibres have proven effective in improving shear resistance, and they confer some concrete elements more ductility. In adequate amounts, steel fibres can completely or partially substitute traditional shear reinforcements. This is why international codes have included some requirements to take into account the action of fibres on the shear response of concrete elements. However, most recommendations and requirements for steel fibre-reinforced concrete (SFRC) were originally created. New fibres with different materials properties and shapes, such as macrosynthetic fibres, are now available on the market. These fibres, some of which are made of polypropylene, are an alternative in the construction industry given their properties and final cost. Initially, polypropylene fibres were used to control shrinkage cracking. Nevertheless, in the last decade the chemical industry has created larger fibres with better surface shapes, which allows polypropylene fibres to meet the requirements of international codes so they can be used in structural elements. Within this framework, the present PhD thesis aims to contribute to knowledge about fibre reinforced concrete (FRC), especially to study the effectiveness of polypropylene fibres when used as shear reinforcement. For this purpose, a literature review of the material, polypropylene fibre-reinforced concrete (PFRC) and its structural applications is first carried out. This study also discusses the parameters that affect the shear behaviour of traditional concrete and FRC. In order to evaluate the effectiveness of polypropylene fibres in shear, three experimental campaigns are presented. Each campaign represents a different level of study. The first corresponds to the material level, where the shear behaviour of PFRC is evaluated by push-off specimens. The second level involves studying shear in real scale elements. For this purpose, shear critical slender beams were manufactured and tested. The last level corresponds to real application of polypropylene fibres to act as shear reinforcement. In this campaign, deep hollow core slabs, with real sections and supports conditions, were tested. At each level, the shear behaviour of PFRC was evaluated against control reinforced concrete specimens, which were also tested during each campaign. / [ES] Varias investigaciones experimentales y teóricas han sido realizadas para entender el comportamiento a cortante de elementos de hormigón y sus variables. Sin embargo, hoy en día debido a la complejidad del tema, el comportamiento a cortante de elementos de hormigón armado y en especial aquellos que no tienen refuerzo transversal, continúan sin tener una explicación clara. Por otro lado, esta complejidad del cortante aumenta cuando nuevas variables, como las fibras, se incorporan al estudio. Investigaciones han demostrado la efectividad de las fibras de acero para mejorar las propiedades mecánicas de hormigón. Según resultados experimentales, la fibra de acero mejora la resistencia cortante y ductilidad de ciertos elementos. Y en cantidades adecuadas, la fibra puede sustituir total o parcialmente los refuerzos tradicionales de cortante. Es así que varios códigos internacionales han incluido requisitos para tener a las fibras en la respuesta estructural de elementos de hormigón. Sin embargo, estos requerimientos se han creado originalmente para el hormigón reforzado con fibra de acero (Steel fibre-reinforced concrete -SFRC). Nuevas fibras con diferentes materiales y formas, como las fibras macro-sintéticas, han sido introducidas en el mercado. Estas fibras, también llamadas fibras de polipropileno o poliolefina, son una alternativa en la construcción debido a su propiedades y costo final. Inicialmente, las fibras de polipropileno eran usadas únicamente en el hormigón para controlar la fisuración por retracción. Sin embargo, en la última década la industria química ha desarrollado fibras más grandes y con mejores prestaciones de adherencia, que permiten a estas fibras cumplir con requisitos para ser utilizadas estructuralmente. En este contexto, la presente tesis pretende ser una contribución al conocimiento sobre el hormigón reforzado con fibras (Fibre-reinforced concrete - FRC), especialmente en la efectividad de las fibras de polipropileno como refuerzo a cortante. Para esto, primero se realiza un estudio bibliográfico del hormigón reforzado con fibra de polipropileno (PFRC) como material y sus aplicaciones estructurales. Este estudio también tratará sobre los parámetros que afectan el comportamiento a cortante del hormigón tradicional y hormigón reforzado con fibras. Para evaluar la efectividad de las fibras de polipropileno en el cortante, se realizarán tres campañas experimentales. Cada campaña representa un nivel de estudio diferente. El primero es a nivel material en donde se evalúa el comportamiento a cortante a través de especímenes tipo Push-off. El segundo nivel, corresponde al estudio del cortante en elementos a escala real. Para esto se fabrican y ensayan vigas esbeltas críticas a cortante. El último nivel corresponde a una aplicación real de fibras de polipropileno actuando como refuerzo cortante. En esta campaña, se fabrican y ensayan placas alveolares de gran canto con secciones y condiciones de apoyos reales. / [CA] Diverses investigacions experimentals i teòriques han estat realitzades per entendre el comportament a tallant d'elements de formigó i les seues variables. No obstant això, hui en dia a causa de la complexitat del tema, el comportament a tallant d'elements de formigó armat i especialment aquells que no tenen reforç transversal, continuen sense tindre una explicació clara. D'altra banda, aquesta complexitat del tallant augmenta quan noves variables, com les fibres, s'incorporen a l'estudi. Investigacions han demostrat l'efectivitat de les fibres d'acer per a millorar les propietats mecàniques del formigó. Segons resultats experimentals, les fibres d'acer milloren la resistència a tallant i la ductilitat de certs elements. A més, en quantitats adequades, les fibres poden substituir total o parcialment els reforços tradicionals de tallant. És així que diversos codis internacionals han inclòs requisits per a tindre amb compte la resposta estructural de les fibres en els elements de formigó. No obstant això, aquests requeriments s'han creat originalment per al formigó reforçat amb fibres d'acer (Steel fibre-reinforced concrete -SFRC). Noves fibres amb diferents materials i formes, com les fibres macro-sintètiques, han estat introduïdes al mercat. Aquestes fibres, també anomenades fibres de polipropilè o poliolefina, són una alternativa a la construcció a causa de les seues propietats i cost final. Inicialment, les fibres de polipropilè eren usades únicament en el formigó per controlar la fissuració per retracció. No obstant això, en l'última dècada, la industria química ha desenvolupat fibres més grans i amb millors prestacions d'adherència, que permeten a aquestes fibres complir amb requisits per a ser utilitzades estructuralment. En aquest context, la present tesi pretén ser una contribució al coneixement sobre el formigó reforçat amb fibres (Fibre-reinforced concrete - FRC), especialment en l'efectivitat de les fibres de polipropilè com a reforç a tallant. Per això, primer es realitza un estudi bibliogràfic del formigó reforçat amb fibres de polipropilè (PFRC) com a material i les seues plicacions estructurals. Aquest estudi també tractarà sobre els paràmetres que afecten el comportament a tallant del formigó tradicional i del formigó reforçat amb fibres. Per avaluar l'efectivitat de les fibres de polipropilè en el tallant, es realitzaran tres campanyes experimentals. Cada campanya representa un nivell d'estudi diferent. El primer és a nivell material on s'avalua el comportament a tallant a través d'espècimens tipus Push-off. El segon nivell, correspon a l'estudi del tallant en elements a escala real. Per això es fabriquen i assagen bigues esveltes crítiques a tallant. L'últim nivell correspon a una aplicació real de fibres de polipropilè actuant com a reforç a tallant. En aquesta campanya, es fabriquen i assagen plaques alveolars de gran cantell amb seccions i condicions de suports reals. / Ortiz Navas, FR. (2020). Effectiveness of polypropylene fibres as shear reinforcement in structural elements [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/153147 / TESIS