This work deals with a basic question of modern science and it is its indefectibility. Quality of education is reduce to an evaluation of conformity to a common known knowledge and its quantity representation. Seeds of this long process go back to an ancient academia of Gondisapur established in an Arabic world. Author proclaims that the main goal of philosophy is to show, that this is not the only way of thinking and in the same time that the main goal and power of phenomenology is to apply the transcendental epoche to overcame the truth in its regularization shape. The hardcore of modern science is located in the world of mathematics and a lot of thinkers find the Math as a land of pure sureness - the core of this work in an opposite proofs, that in fact nowadays math is all, but the correct way of thinking. The two examples are explicit: the Pythagorean Theorem and the Sum of the geometric row. This work brings a quite new view on the mathematical problem of "the point" and "the nothing" as a border of things. In the second part uses as a frame of its topic the first 18 §§ of the work "Paradoxes of the infinite" by Czech mathematician of German mother tongue Bernard Bolzano. The important idea of this study is a new ontological view on the set of prime numbers.

El presente trabajo de investigación tiene como objetivo analizar cuáles son los impactos por la implementación de la NIC 16, y su influencia en los Estados Financieros y el Impuesto a la Renta en las empresas del sector construcción de edificios completos, en el Distrito de Miraflores, año 2018. Para la explicación de la investigación se ha tomado como referencia principalmente las NIC 16, los Estados Financieros y el Impuesto a la Renta. Asimismo, se ha hallado apropiado analizar el sector construcción, adquiriendo información de las características principales de este sector, debido a las actividades e información de las empresas que lo conforman. El trabajo de investigación se encuentra dividido en 5 capítulos, los cuales son: Capítulo I: Marco Teórico, donde se presenta las definiciones básicas relacionadas al tema principal. Luego, en el Capítulo II: Plan de Investigación, se describe el problema, así como la determinación de los objetivos e hipótesis generales y específicas. Seguidamente, en el Capítulo III: Metodología de Investigación, en donde se define el tipo de investigación a emplear, así como la determinación del tamaño de la muestra para el futuro análisis cuantitativo y cualitativo. Continuando con el Capítulo IV: Desarrollo de la Investigación, se desarrolla la aplicación de los instrumentos descritos previamente, a su vez, se ejecuta un caso práctico para evaluar la incidencia de la NIC 16 en los Estados Financieros y el Impuesto a la Renta. Por último, en el Capítulo V: Análisis de los Resultados, se realiza el análisis de los instrumentos y el caso práctico, brindando como últimos elementos, conclusiones y recomendaciones finales en relación a todo lo estudiado. Es por ello, que se ha concentrado el presente trabajo de investigación en el sector de la construcción, debido a es uno de los sectores en el país que poseen mayor inversión en activo fijo, principalmente en maquinarias y equipos que son utilizados para el progreso de sus actividades, donde se ha determinado que la NIC 16 tiene un impacto directamente en el rubro de Activo Fijo de las empresas del sector. / The purpose of this research work is to analyze the impacts of the adoption of IAS 16, and its influence on the Financial Statements and Income Tax on companies in the construction sector of complete buildings, in the District of Miraflores, 2018. For the development of the research, IAS 16, the Financial Statements and the Income Tax have been taken as reference. Likewise, it has been appropriate to analyze the construction sector, acquiring information on the main characteristics of this sector, due to the activities and information of the companies that comprise it. The research work is divided into 5 chapters, which are: Chapter I: Theoretical Framework, where the basic variables related to the main theme are presented. Then, in Chapter II: Research Plan, the problem is described, as well as the determination of the objectives and the general and specific conclusions. Then, in Chapter III: Research Methodology, where the type of research to be identified is defined, as well as the determination of the sample size for future quantitative and qualitative analysis. Continuing with Chapter IV: Research Development, the application of the previously processed instruments is developed, in turn, a practical case is executed to evaluate the incidence of IAS 16 in the Financial Statements and Income Tax. Finally, in Chapter V: Analysis of the Results, the analysis of the instruments and the case study is carried out, providing as final elements, conclusions and final recommendations in relation to everything studied. That is why, this research work has been concentrated in the construction sector, because it is one of the sectors in the country that has the greatest investment in fixed assets, mainly in machines and equipment that are used for progress of its activities, where it has been determined that IAS 16 has a direct impact on the Fixed Assets category of companies in the sector. / Tesis

La investigación del trabajo del presente busca enfatizar y mostrar los posibles impactos en los Estados Financieros y en el Impuesto a la Renta que la NIC 12 Impuesto a las ganancias prescribe y la forma en que estos son registrados contable y tributariamente de acuerdo a las normas fiscales actualizadas, y como afecta en los resultados financieros del periodo y los siguientes debido a los activos y pasivos diferidos y los impuestos declarados. La investigación se desarrolló en cinco partes: Capítulo I Marco teórico, el cual incluye los antecedentes, definiciones, nociones y las dimensiones de la Norma y la relevancia de nuestro tema de estudio respecto a la NIC 12 Impuesto a las Ganancias y el Impacto en los Estados Financieros y en el Impuesto a la Renta en el sector Inmobiliario en el distrito de Surco, año 2018. Capítulo II Plan de Investigación, se enuncia la problemática del contexto de la presente investigación, el problema, el objetivo y la hipótesis general y los específicos. Capítulo III Metodología de Investigación, se definió la población y muestra de la investigación, así como las herramientas a utilizar en la Investigación Cualitativa e Investigación Cuantitativa. Capitulo IV Desarrollo de la Investigación; se aplicó las herramientas de investigación como son la entrevista a profundidad y las encuestas, así como los posibles escenarios en el caso práctico. Capítulo V Análisis de Resultados, se realizó el análisis de la información obtenida de la aplicación de los instrumentos y el caso práctico concluyendo con la validación de las hipótesis. / The research in this paper seeks to emphasize and show the possible impacts on the Financial Statements and Income Taxes that IAS 12 Income Tax prescribes and the manner in which these are recorded for accounting and tax purposes in accordance with current tax standards, and how they affect financial results for the period and subsequent periods due to deferred assets and liabilities and declared taxes. The research was developed in five parts: Chapter I Theoretical framework, in which the background, dimensions and importance of our study topic were conceptualized, developed and defined with respect to IAS 12 Income Tax and Impact on Financial Statements and Income Tax in the Real Estate sector in the district of Surco, year 2018. Chapter II Research Plan, exposes the problems of the research scenario, the problem, the objective and the general hypothesis and the specific ones. Chapter III Research Methodology, the population and research sample were defined, as well as the tools to be used in Qualitative Research and Quantitative Research. Chapter IV Research Development; research tools such as in-depth interviews and surveys were applied, as well as possible scenarios in the practical case. Chapter V Analysis of Results, the analysis of the information obtained from the application of the instruments and the practical case was carried out, concluding with the validation of the hypotheses. / Tesis

La presente investigación fue elaborada con el fin de determinar el impacto financiero de la NIIF 11 Acuerdos Conjuntos en la toma de decisiones de las empresas constructoras del distrito de San Isidro en el año 2017. Para cumplir con lo anterior, la investigación se basará en la aplicación de la Norma Internacional de Información Financiera 11 “Acuerdos Conjuntos”, emitida el 12 de mayo del 2011, cuya aplicación inició a partir del 1 de enero del 2013. La norma mencionada tiene cambios sustanciales en la clasificación de los acuerdos conjuntos y será necesario para su correcta aplicación que esté soportada en un proceso adecuado de procesamiento y análisis de información. El presente trabajo se basará en empresas del sector construcción del distrito de San Isidro que cotizan en bolsa de valores que presentan información financiera al 31 de diciembre del 2017. El sector construcción conforme con el Instituto Nacional de Estadística e Informática (INEI) creció en 2.20% en el año 2017. Tras una caída considerable del PBI sector construcción en los años 2015 y 2016 experimenta un importante crecimiento al cierre del año 2017. Por otro lado, las empresas constructoras suelen recurrir al uso de alianzas estratégicas que implican una colaboración empresarial para proyectos específicos, lo cual requerirá un análisis según lo dispuesto por la IFRS 11 Acuerdos Conjuntos. Por todo ello en esta investigación se busca averiguar si el impacto financiero de la NIIF 11 Acuerdos Conjuntos influye negativamente en la toma de decisiones de las empresas constructoras de San Isidro. Para validar nuestras hipótesis, se realizó encuestas a empresas del sector construcción de San Isidro y, además, se recurrió a expertos en NIIF 11 y en el sector construcción para la realización de entrevistas a profundidad. Finalmente, se realizó un caso práctico para evaluar el impacto financiero de la presente investigación. Además, se realizó validaciones estadísticas para nuestras hipótesis tanto principal como secundarias mediante la herramienta denominada ji-cuadrado (o chi cuadrado) y para validar la confiabilidad de nuestra encuesta el estadístico de Alfa de Cronbach. En base a lo anteriormente mencionado se concluyó que el impacto financiero de la NIIF 11 Acuerdos Conjuntos influye negativamente en la toma de decisiones de las empresas constructoras de San Isidro en el año 2017. / The present investigation was elaborated in order to determine the financial impact of the IFRS 11 Joint Agreements in the decision making of the construction companies of San Isidro in the year 2017. To comply with the above, the investigation is based on the application of The International Financial Reporting Standard 11 "Joint Agreements", issued on May 12, 2011, whose application began on January 1, 2013. The aforementioned regulation has substantial changes in the classification of joint agreements and will be necessary for its Correct application is supported in an adequate process of information processing and analysis. This work will be based on companies in the construction sector of San Isidro that are listed on the stock exchange and are medium or large companies. The construction sector settled with the National Institute (INEI) grew by 2.20% in the year 2017. After a considerable decline in the GDP construction sector in 2015 and 2016 experienced an important growth at the end of 2017. On the other hand, the construction companies usually resort to the use of strategic alliances that imply a business collaboration for specific projects, which requires an analysis in accordance with the provisions of IFRS 11 Joint Agreements. For all this, this research seeks to find out the financial impact of IFRS 11 Joint Agreements negatively influence the decision making of the construction companies of San Isidro. To validate our hypothesis, it will be published to companies in the construction sector and, in addition, experts will be used to carry out in-depth interviews and, finally, a practical case will be made to evaluate the financial impact of the present investigation. In addition, statistical validations have been carried out for our hypotheses, both main and secondary, using the chi-square tool (or chi-square) and to validate the reliability of our survey the Cronbach's Alpha statistic. Based on the, it was concluded that the financial impact of IFRS 11 Joint Agreements negatively influences the decision making of the construction companies of San Isidro in 2017. / Tesis

A histopatologia é considerada um dos recursos diagnósticos mais importantes na prática médica e caracteriza-se pelo estudo das alterações estruturais e morfológicas das células e dos tecidos causadas por doenças. Atualmente, o principal método utilizado no diagnóstico histopatológico de imagens microscópicas, obtidas por meio de amostras em exames convencionais, é a avaliação visual do patologista, a qual se baseia na experiência do mesmo. O uso de técnicas de processamento computacional de imagens possibilita a identificação de elementos estruturais e a determinação de características inerentes, subsidiando o estudo da organização estrutural das células e de suas variações patológicas. A utilização de métodos computacionais no auxílio ao diagnóstico visa diminuir a subjetividade do processo de avaliação e classificação realizado pelo médico. Diferentes características dos tecidos podem ser mapeadas por meio de métricas específicas que poderão ser utilizadas em sistemas de reconhecimento de padrões. Dentro desta perspectiva, o objetivo geral deste trabalho inclui a proposta, a implementação e a avaliação de um método para a identificação e a análise de estruturas histológicas, a ser utilizado para a análise de lesões neoplásicas do colo do útero (NICs) a partir de amostras histopatológicas. Este trabalho foi desenvolvido em colaboração com uma equipe de patologistas, especialistas do domínio. As imagens microscópicas digitalizadas foram adquiridas a partir de lâminas previamente fixadas, contendo amostras de biópsias. Para segmentação dos núcleos celulares, foi implementado um pipeline de operadores morfológicos. Métodos de segmentação baseados em cor também foram testados e comparados à abordagem morfológica. Foi proposta e implementada uma abordagem baseada em camadas para representação do tecido, adotando-se a Triangulação de Delaunay (TD) como modelo de grafo de vizinhança. A TD apresenta algumas propriedades particulares que permitem a extração de métricas específicas. Foram utilizados algoritmos de agrupamento e morfologia de grafos, adotando-se critérios de semelhança e relações de adjacência entre os triângulos da rede, a fim de se obter a fronteira entre as camadas histológicas do tecido epitelial de forma automática. As seguintes métricas foram extraídas dos agrupamentos resultantes: grau médio, entropia e taxa de ocupação dos triângulos da rede. Finalmente, foi projetado um classificador estatístico levando-se em consideração os diferentes agrupamentos que poderiam ser obtidos a partir das imagens de treinamento. Valores de acurácia, sensitividade e especificidade foram utilizadas para avaliação dos resultados obtidos. Foi implementada validação cruzada em todos os experimentos realizados e foi utilizado um total de 116 imagens. Primeiro, foi avaliado a acurácia da metodologia proposta na determinação correta da presença de anomalia no tecido, para isto, todas as imagens que apresentavam NICs foram agrupadas em uma mesma classe. A maior taxa de acurácia obtida neste experimento foi de 88%. Em uma segunda etapa, foram realizadas avaliações entre as seguintes classes: Normal e NIC-I; NIC-I e NIC-II, e, NIC-II e NIC-III, obtendo-se taxas de acurácia máximas de 73%, 77% e 86%, respectivamente. Além disso, foi verificada também, a acurácia na discriminação entre os três tipos de NICs e regiões normais, obtendo-se acurácia de 64%. As taxas de ocupação relativas aos agrupamentos representativos das camadas basais e superficiais, foram os atributos que levaram às maiores taxas de acurácia. Os resultados obtidos permitem verificar a adequação do método proposto na representação e análise do processo de evolução das NICs no tecido epitelial do colo uterino. / Histopathology is considered one of the most important diagnostic tools in medical routine and is characterized by the study of structural and morphological changes of the cells in biological tissues caused by diseases. Currently, the visual assessment of the pathologist is the main method used in the histopathological diagnosis of microscopic images obtained from biopsy samples. This diagnosis is usually based on the experience of the pathologist. The use of computational techniques in the processing of these images allows the identification of structural elements and the determination of inherent characteristics, supporting the study of the structural organization of tissues and their pathological changes. Also, the use of computational methods to improve diagnosis aims to reduce the subjectivity of the evaluation made by the physician. Besides, different tissue characteristics can be mapped through specific metrics that can be used in pattern recognition systems. Within this perspective, the overall objective of this work includes the proposal, the implementation and the evaluation of a methodology for the identification and analysis of histological structures. This methodology includes the specification of a method for the analysis of cervical intraepithelial neoplasias (CINs) from histopathological samples. This work was developed in collaboration with a team of pathologists. Microscopic images were acquired from blades previously stained, containing samples of biopsy examinations. For the segmentation of cell nuclei, a pipeline of morphological operators were implemented. Segmentation techniques based on color were also tested and compared to the morphological approach. For the representation of the tissue architecture an approach based on the tissue layers was proposed and implemented adopting the Delaunay Triangulation (DT) as neighborhood graph. The DT has some special properties that allow the extraction of specific metrics. Clustering algorithms and graph morphology were used in order to automatically obtain the boundary between the histological layers of the epithelial tissue. For this purpose, similarity criteria and adjacency relations between the triangles of the network were explored. The following metrics were extracted from the resulting clusters: mean degree, entropy and the occupation rate of the clusters. Finally, a statistical classifier was designed taking into account the different combinations of clusters that could be obtained from the training process. Values of accuracy, sensitivity and specificity were used to evaluate the results. All the experiments were taken in a cross-validation process (5-fold) and a total of 116 images were used. First, it was evaluated the accuracy in determining the correct presence of abnormalities in the tissue. For this, all images presenting CINs were grouped in the same class. The highest accuracy rate obtained for this evaluation was 88%. In a second step, the discrimination between the following classes were analyzed: Normal/CIN 1; CIN 1/CIN 2, and, CIN 2/CIN 3, which represents the histological grading of the CINs. In a similar way, the highest accuracy rates obtained were 73%, 77% and 86%, respectively. In addition, it was also calculated the accuracy rate in discriminating between the four classes analyzed in this work: the three types of CINs and the normal region. In this last case, it was obtained a rate of 64%.The occupation rate for the basal and superficial layers were the attributes that led to the highest accuracy rates. The results obtained shows the adequacy of the proposed method in the representation and classification of the CINs evolution in the cervical epithelial tissue.

A histopatologia é considerada um dos recursos diagnósticos mais importantes na prática médica e caracteriza-se pelo estudo das alterações estruturais e morfológicas das células e dos tecidos causadas por doenças. Atualmente, o principal método utilizado no diagnóstico histopatológico de imagens microscópicas, obtidas por meio de amostras em exames convencionais, é a avaliação visual do patologista, a qual se baseia na experiência do mesmo. O uso de técnicas de processamento computacional de imagens possibilita a identificação de elementos estruturais e a determinação de características inerentes, subsidiando o estudo da organização estrutural das células e de suas variações patológicas. A utilização de métodos computacionais no auxílio ao diagnóstico visa diminuir a subjetividade do processo de avaliação e classificação realizado pelo médico. Diferentes características dos tecidos podem ser mapeadas por meio de métricas específicas que poderão ser utilizadas em sistemas de reconhecimento de padrões. Dentro desta perspectiva, o objetivo geral deste trabalho inclui a proposta, a implementação e a avaliação de um método para a identificação e a análise de estruturas histológicas, a ser utilizado para a análise de lesões neoplásicas do colo do útero (NICs) a partir de amostras histopatológicas. Este trabalho foi desenvolvido em colaboração com uma equipe de patologistas, especialistas do domínio. As imagens microscópicas digitalizadas foram adquiridas a partir de lâminas previamente fixadas, contendo amostras de biópsias. Para segmentação dos núcleos celulares, foi implementado um pipeline de operadores morfológicos. Métodos de segmentação baseados em cor também foram testados e comparados à abordagem morfológica. Foi proposta e implementada uma abordagem baseada em camadas para representação do tecido, adotando-se a Triangulação de Delaunay (TD) como modelo de grafo de vizinhança. A TD apresenta algumas propriedades particulares que permitem a extração de métricas específicas. Foram utilizados algoritmos de agrupamento e morfologia de grafos, adotando-se critérios de semelhança e relações de adjacência entre os triângulos da rede, a fim de se obter a fronteira entre as camadas histológicas do tecido epitelial de forma automática. As seguintes métricas foram extraídas dos agrupamentos resultantes: grau médio, entropia e taxa de ocupação dos triângulos da rede. Finalmente, foi projetado um classificador estatístico levando-se em consideração os diferentes agrupamentos que poderiam ser obtidos a partir das imagens de treinamento. Valores de acurácia, sensitividade e especificidade foram utilizadas para avaliação dos resultados obtidos. Foi implementada validação cruzada em todos os experimentos realizados e foi utilizado um total de 116 imagens. Primeiro, foi avaliado a acurácia da metodologia proposta na determinação correta da presença de anomalia no tecido, para isto, todas as imagens que apresentavam NICs foram agrupadas em uma mesma classe. A maior taxa de acurácia obtida neste experimento foi de 88%. Em uma segunda etapa, foram realizadas avaliações entre as seguintes classes: Normal e NIC-I; NIC-I e NIC-II, e, NIC-II e NIC-III, obtendo-se taxas de acurácia máximas de 73%, 77% e 86%, respectivamente. Além disso, foi verificada também, a acurácia na discriminação entre os três tipos de NICs e regiões normais, obtendo-se acurácia de 64%. As taxas de ocupação relativas aos agrupamentos representativos das camadas basais e superficiais, foram os atributos que levaram às maiores taxas de acurácia. Os resultados obtidos permitem verificar a adequação do método proposto na representação e análise do processo de evolução das NICs no tecido epitelial do colo uterino. / Histopathology is considered one of the most important diagnostic tools in medical routine and is characterized by the study of structural and morphological changes of the cells in biological tissues caused by diseases. Currently, the visual assessment of the pathologist is the main method used in the histopathological diagnosis of microscopic images obtained from biopsy samples. This diagnosis is usually based on the experience of the pathologist. The use of computational techniques in the processing of these images allows the identification of structural elements and the determination of inherent characteristics, supporting the study of the structural organization of tissues and their pathological changes. Also, the use of computational methods to improve diagnosis aims to reduce the subjectivity of the evaluation made by the physician. Besides, different tissue characteristics can be mapped through specific metrics that can be used in pattern recognition systems. Within this perspective, the overall objective of this work includes the proposal, the implementation and the evaluation of a methodology for the identification and analysis of histological structures. This methodology includes the specification of a method for the analysis of cervical intraepithelial neoplasias (CINs) from histopathological samples. This work was developed in collaboration with a team of pathologists. Microscopic images were acquired from blades previously stained, containing samples of biopsy examinations. For the segmentation of cell nuclei, a pipeline of morphological operators were implemented. Segmentation techniques based on color were also tested and compared to the morphological approach. For the representation of the tissue architecture an approach based on the tissue layers was proposed and implemented adopting the Delaunay Triangulation (DT) as neighborhood graph. The DT has some special properties that allow the extraction of specific metrics. Clustering algorithms and graph morphology were used in order to automatically obtain the boundary between the histological layers of the epithelial tissue. For this purpose, similarity criteria and adjacency relations between the triangles of the network were explored. The following metrics were extracted from the resulting clusters: mean degree, entropy and the occupation rate of the clusters. Finally, a statistical classifier was designed taking into account the different combinations of clusters that could be obtained from the training process. Values of accuracy, sensitivity and specificity were used to evaluate the results. All the experiments were taken in a cross-validation process (5-fold) and a total of 116 images were used. First, it was evaluated the accuracy in determining the correct presence of abnormalities in the tissue. For this, all images presenting CINs were grouped in the same class. The highest accuracy rate obtained for this evaluation was 88%. In a second step, the discrimination between the following classes were analyzed: Normal/CIN 1; CIN 1/CIN 2, and, CIN 2/CIN 3, which represents the histological grading of the CINs. In a similar way, the highest accuracy rates obtained were 73%, 77% and 86%, respectively. In addition, it was also calculated the accuracy rate in discriminating between the four classes analyzed in this work: the three types of CINs and the normal region. In this last case, it was obtained a rate of 64%.The occupation rate for the basal and superficial layers were the attributes that led to the highest accuracy rates. The results obtained shows the adequacy of the proposed method in the representation and classification of the CINs evolution in the cervical epithelial tissue.

Notch receptors and ligands are type I transmembrane proteins that regulate development and differentiation during cell-cell contact. There are four Notch receptor homologues and five notch ligands, identified in humans till date. Upon ligand activation, Notch1 intracellular domain (NIC-1) is released into the cytoplasm, which binds to several proteins as well as translocates into the nucleus to effect the Notch signaling. In the absence of the activated Notch signaling, the Notch target genes are kept repressed by the transcriptional repressor C protein binding factor 1 (CBF1) also known as RBPjk or CSL for CBF1/Su(H)/Lag1. RBPjk binds to the sequence “CGTGGGAA” and acts as a constitutive repressor. Upon ligand dependent activation, NIC-1 enters into the nucler and converts RBPjk from transcriptional repressor to an activator. Notch binding to CSL replaces the SMRT corepressor complex with a coactivator complex including SKIP, Mastermind like 1 (MAML1) (Mastermind in Drosophila), and histone acetyl transferases PCAF, GCN5 and p300 activating the transcription of target genes. Mastermind-like (MAML), a family of transcriptional activator proteins comprising of 3 members 1 to 3, has been shown to be required for Notch signaling. MAML forms a ternary complex with RBPjk-NIC by directly interacting with NIC. In turn, MAML recruits the histone acetyl transferase p300/CBP, which acetylates the histones, thereby altering the structure of chromatin amenable for transcription. Activation of Notch pathway induces oncogenesis, which can be divided into two categories including 1) Inhibition of Apoptosis and 2) Induction of proliferation. In T cells, activation of Notch1 protects cells from T cell receptor, dexamethasone and etoposide-mediated apoptosis, Fas receptor-mediated signaling by up regulating IAP (Inhibitor of Apoptosis) and Bcl-2 families, as well as FLIP (FLICE-like inhibitor protein). Notch signaling also promotes the survival of T cells through maintenance of cell size as well as through the promotion of glucose uptake and metabolism. Notch-1 has been shown to protect against anoikis (apoptosis induced by matrix withdrawal) or p53-mediated apoptosis in immortalized epithelial cells, T cell receptor-induced apoptosis in mature cells and dexamethasone-mediated apoptosis in thymocytes. This study was carried out to functionally characterize NIC-1 (human Notch1-intracellular domain) as an inhibitor of apoptosis and to evaluate the therapeutic potential of reversal of this apoptosis inhibition. The main objectives of this study are 1. Construction of recombinant adenovirus expressing human Notch1-intracellular domain (Ad-NIC-1) and characterization of NIC-1 as an inhibitor of chemotherapy and p53-induced cytotoxicity and apoptosis. 2. Role of PI3 kinase -Akt/PKB -mTOR pathway in NIC-1-mediated inhibition of p53-induced apoptosis. 3. Essential role of association between mTOR and NIC-1 and the dependent NIC-1 phosphorylation in Notch1-mediated transcription and survival signaling. 4. Identification of NIC-1 as an inhibitor of E1A-induced apoptosis and the role of mTOR in NIC-1-mediated inhibition of E1A-induced apoptosis. Activated Notch1 was first linked to tumorigenesis through identification of a recurrent t(7;9)(q34;q34.3) chromosomal translocation involving the human Notch1 gene that is found in a subset of human pre-T-cell acute lymphoblastic leukemia’s (T-ALL). Deregulated Notch signaling is oncogenic, inhibits apoptosis and promotes survival. In order to understand survival signaling induced by Notch1 and its possible role in chemoresistance, we have generated a replication deficient recombinant adenovirus expressing human Notch1-intracellular domain (Ad-NIC-1) and shown that it produces functional NIC-1 protein. Using this overexpression system, we characterized that activated Notch1-inhibits chemotherapy and in particular p53 induced apoptosis. Notch1-mediated inhibition of p53-induced apoptosis does not include coactivator squelching. p53 was inefficient in binding to its DNA in NIC-1 overexpressing cells. The levels of phosphorylation at Ser15, Ser20, and Ser392 of p53 expressed from Ad-p53 significantly reduced in NIC-1 preinfected cells. These results suggest that NIC-1-mediated inhibition of p53-mediated apoptosis involves reduced DNA binding, reduced nuclear localization and reduced post translational modifications and thus reduced transactivation of its target genes. Notch1-mediated inhibition of p53 was found to occur mainly through mammalian target of rapamycin (mTOR) using PI3 kinase-Akt/PKB pathway, as the mTOR inhibitor; rapamycin treatment was able to reverse Notch-1 mediated inhibition of p53 and chemoresistance. Consistent with this, rapamycin failed to reverse NIC-1 induced chemoresistance in cells expressing rapamycin resistant mTOR. Our results also suggest that the N-terminal HEAT repeat and the kinase function of mTOR are essential for Notch mediated inhibition of p53. Further, ectopic expression of eIF4E, a translational regulator that acts downstream of mTOR, inhibited p53-induced apoptosis and conferred protection against p53-mediated cytotoxicity to similar extent as that of NIC-1 overexpression, but was not reversed by rapamycin, which indicates that eIF4E is the major target of mTOR in Notch1-mediated survival signaling. Notch1-intracellular domain (NIC-1), following proteolytic cleavage, binds to RBPjk and regulates transcription. Active NIC-1 located in the nucleus is phosphorylated, which makes it more stable and bind better to RBPjk. NIC-1 was also shown to bind to Deltex1 in the cytoplasm. Next, we studied the requirement of components of Notch1 signaling pathway for this function. By using variety of approaches, we found that both RBPjk and Maml1 and hence transcription activation is required for NIC-1-mediated survival signaling and inhibition of p53 functions. Interestingly, while we found the other Notch1 effector, Deltex1 is also required for above functions, Notch1 failed to activate PI3 kinase -Akt/PKB -mTOR pathway in Deltex1, but not in RBPjk silenced cells. Our results suggest that Notch-Deltex1 pathway activates PI3 kinase. Previous studies show that NIC-1 interacts with Deltex1 and Grb2 interacts with PI3 kinase. Our data shows that Deltex1 interacts with SH3 domain of Grb2. Since Notch1-Deltex1 and PI3 kinase-Grb2 interactions are known, we conclude that Notch1 activation of PI3 kinase involves Deltex1 and Grb2. We found activated mTOR was able to binds to NIC-1 and regulates its phosphorylation. Inhibition of mTOR either by PI3 kinase inhibitors or mTOR inhibitor treatment or silencing of Akt/PKB or mTOR reduced the phosphorylation of NIC-1 with the concomitant reduction in NIC-1-mediated transcription. Further, endogenous Notch1 receptor activated by the DSL ligand failed to activate transcription efficiently in rapamycin treated cells, implying a positive role for mTOR in mammalian Notch signaling. These studies reveal that Notch1 activates PI3 kinase -Akt/PKB -mTOR signaling through Deltex1 and subsequently activated mTOR modulates Notch1 signaling by direct binding and possibly thorough phosphorylation of the intracellular domain of Notch. Adenoviral E1A, in the absence of cooperating oncogene, suppresses primary tumor growth and reverses the transformed phenotype of human tumor cells by inducing apoptosis. E1A requires p53 for efficient induction of apoptosis and was shown to induce apoptosis by down regulating Akt and the activation of pro apoptotic factor p38 MAP kinase. Since our results suggest Notch1 inhibits chemotherapy and p53-induced apoptosis, we analyzed the ability of Notch1 to protect cells from E1A-induced apoptosis. Here we show that NIC-1 suppresses the ability of E1A to induce apoptosis. NIC-1 requires mTOR-dependent signal to inhibit E1A-mediated apoptosis, as the rapamycin, an mTOR inhibitor was able to completely reverse the ability of Notch1 to protect cells against E1A-induced apoptosis. The role of mTOR in NIC-1-mediated survival signaling was further confirmed by using the cells stably expressing rapamycin resistant mTOR. Rapamycin was able to reverse Notch1-mediated protection in cells expressing wild type mTOR but not in rapamycin resistant mTOR expressing cells. We also found that E1A was able to induce apoptosis in cells silenced for the pro apoptotic factor p38 and NIC-1 continued to inhibit E1A-induced apoptosis in these cells. These results confirm that Notch1 requires the activation of mTOR signaling but not p38 MAP kinase for inhibition of E1A-induced apoptosis. These results also suggest that the combination therapy utilizing E1A-mediated gene delivery in combination with inhibition of mTOR pathway may prove successful in treating Notch overexpressing cancers. Chemotherapy remains a major treatment modality for human cancers. Chemoresistance is a clinical problem that severely limits treatment success. It can be divided into two forms: intrinsic and acquired. Intrinsic resistance is the essence of oncogenic transformation, resulting from activation of oncogenes and the loss of tumor suppressors, and manifests itself as alterations in cell cycle checkpoints and apoptotic pathways. It is now widely accepted that the apoptotic capacity of the cancer cell is crucial in determining the response to chemotherapeutic agents. Indeed, several gene products that regulate apoptosis, i.e., p53, Akt and PI3K are frequently altered in cancer cells. In this study, we identified that cells with aberrant Notch1 signaling are chemoresistant. Activated Notch1 overexpression makes cells resistant to chemotherapy in a wild type p53 dependent manner. Notch protected p53 wild type cells but not p53 mutated or p53 deleted cells against chemotherapy induced cytotoxicity. Further, inactivation of p53 by specific silencing abrogated the ability of NIC-1 to protect H460 cells against adriamycin induced cytotoxicity. Most importantly, NIC-1 mediated chemoresistance can be reversed by blocking PI3 kinase -Akt/PKB -mTOR pathway. Collectively, these results suggest that cancers with activated Notch1 signaling are chemoresistant and provide basis for the reversal of chemoresistance.

Pour faire cohabiter les nombreuses technologies radios, les terminaux mobiles nécessitent une miniaturisation de plus en plus poussée des antennes. Toutefois, les performances d'antennes ont des limites fondamentales liées à leurs dimensions physiques. La littérature met en évidence que les réseaux superdirectifs permettent de dépasser la limite de Harrington sur la directivité et que des antennes adaptées par des circuits non-Foster peuvent dépasser la limite de Bode-Fano sur la bande passante. Les contributions essentielles de ce travail de thèse consistent en la conception deréseaux d'antennes superdirectifs et d'antennes adaptées par des circuits non-Foster comme solutions possibles pour l'amélioration des performances des Antennes Electriquement Petites (AEP). Dans une première partie, un convertisseur d'impédance négative est réalisé pour obtenir des condensateurs de valeurs négatives de façon à adapter des antennes miniatures sur une large bande de fréquence. Dans la deuxième partie de ces travaux, les limites théoriques des réseaux d'antennes superdirectifs sont évaluées et une approche simple et pratique permettant la conception de ces réseaux à partir d'éléments parasites est proposée. L'intégration des AEP superdirectives sur des cartes de circuit imprimé est étudiée et les difficultés de mesure de ce type d'antenne sont évaluées. A partir de ces résultats, une nouvelle stratégie pour réaliser des réseaux compactes 3D ou planaires à polarisation linéaire ou circulaire en utilisant des éléments superdirectifs est présentée. / For supporting different wireless technologies, mobile terminals require significant miniaturization of antennas. However, antennas performance has some fundamental limits related to their physical dimensions. The available theory shows that superdirective arrays can exceed Harrington’s limit on antenna directivity and non-Foter matched antennas can surpass Bode-Fano limit on antenna bandwidth. Therefore, this work focuses on the design of superdirective antenna arrays and non-Foster matched antennas as possible solutions for improving the performance of Electrically Small Antennas (ESAs). In the first part: a Negative Impedance Converter (NIC) is designed to have a very small negative capacitor. The circuit is evaluated in terms of gain, stability and linearity. Then, the circuit is used to match several small antennas in the UHF band. In the second part: the theoretical limits of superdirective antenna arrays are studied. A simple and practical approach to design parasitic antenna arrays is proposed. The integration of superdirective ESAs in Printed Circuit Boards (PCBs) is studied and the difficulties of measuring this type of antennasare evaluated. A new strategy for the design of 3D or planar compact arrays, with linear or circular-polarization, using superdirective elements is presented.

El presente trabajo de investigación “Efecto de la NIC 16 en la valuación de los activos fijos y su impacto financiero en las empresas del sector transporte (de carga) fluvial en la Ciudad de Iquitos en el 2017” se enfoca en determinar el impacto financiero realizar correctamente aplicación de las Normas Internacionales de Información Financiera. Asimismo, se encofará en el análisis del método de revaluación bajo los criterios indicados en la NIC 16. La técnica de investigación utilizada fue cualitativa que consiste en aplicar entrevistas y encuestas a una muestra seleccionada bajo el método no probabilístico, con el fin de conocer y analizar la situación actual de las empresas del sector transporte fluvial con respecto a sus activos fijos. El trabajo de investigación se encuentra dividido en cinco capítulos, como siguen: Capítulo I. Marco Teórico, se definen los conceptos básicos en base a las Normas Internacionales de Información Financiera, así como relacionadas al sector transporte fluvial en la Ciudad de Iquitos. Capítulo II. Plan de investigación, se define el problema, los objetivos e hipótesis para la investigación. Capítulo III. Metodología de la investigación se emplearán los siguientes: investigación exploratoria, descriptiva y explicativa con un enfoque de investigación mixta. Capítulo IV. Desarrollo de la investigación, en este capítulo se mostrarán las encuestas y entrevistas realizadas a una muestra de empresas. Además de desarrollarse un caso práctico en base a la valuación posterior de activos fijos y ver el impacto financiero producido. Capítulo V. Análisis de los resultados, se analizarán las respuestas de las encuestas y entrevistas aplicadas, asimismo se analizará el resultado del caso práctico desarrollado. En el último Capítulo VI, se concluirá en base a las hipótesis planteadas en el Capítulo II. / The present research work "Effect of IAS 16 on the valuation of fixed assets and their financial impact on companies in the fluvial transportation (cargo) sector in the City of Iquitos in 2017" focuses on determining the impact financially by having a correct application of the International Financial Reporting Standards. Likewise, will be focused in the analysis of the revaluation method under the criteria indicated in IAS 16. Qualitative research techniques were used, which consists of applying interviews and surveys to a sample selected under the non-probabilistic method, in order to know and analyze the current situation of companies in the fluvial transport sector respect to its accounting treatment with fixed assets. The research work is divided into five chapters, as follows: Chapter I. Theorical Framework, where is developed to define the basic concepts based on the International Financial Reporting Standards establishes, also definitions in order to describe the fluvial transportation in the City of Iquitos. Chapter II. Research plan, where the problem, the objectives and hypothesis were defined for the investigation. Chapter III. Research methodology, the three types of research; exploratory, descriptive will be used. Chapter IV. Development of the investigation, in this chapter the surveys and interviews made to the sample of companies of fluvial transport will be shown. Likewise, a case of study will be developed. Chapter V. Analysis of the results, the answers obtained in the surveys and interviews applied to the companies will be analyzed. Also we are going to analyze the results of the case of study. In the last Chapter VI, Conclusions, it will be concluded based on the hypotheses set forth in Chapter II on the financial impact with the correct valuation of assets. / Tesis

Este trabajo de investigación tiene como objetivo determinar cómo la NIC 19: Beneficios a los empleados impactó financieramente en las empresas comercializadoras de muebles del distrito de Villa El Salvador, en 2019, cuya metodología fue de enfoque mixto, nivel exploratorio, descriptivo y explicativo. Respecto a su diseño, fue no experimental y de corte transversal. Con base en las investigaciones, la de tipo cualitativo se realizó a 3 especialistas de Normas Internacionales de Información Financiera (NIIF); mientras que, la cuantitativa se aplicó en 15 entidades del comercio de muebles del distrito mencionado. El trabajo consta de 5 capítulos, en donde el capítulo i presenta diversas fuentes que brindan información para sustentar la investigación. En el capítulo ii, se expone el plan de investigación, en el que se plantea la situación del problema, la justificación, objetivos, hipótesis y limitaciones. En el capítulo iii, se describe la metodología, la cual corresponde a una investigación mixta, es decir, cualitativa y cuantitativa. Además, se explican los instrumentos que han sido utilizados para el desarrollo de la investigación, la determinación de la población y la muestra. En el capítulo iv, se procedió al desarrollo de la investigación, donde se detalla la aplicación de los instrumentos y un caso práctico aplicando la NIC 19 para determinar su impacto financiero. En el capítulo v, se llevó a cabo el análisis de los resultados del estudio, de la entrevista a profundidad y del cuestionario. Finalmente, se presentan las conclusiones y recomendaciones considerando las hipótesis postuladas, las cuales permitieron confirmar que la NIC 19: Beneficios a los empleados, impacta financieramente en las empresas comercializadoras de muebles de Villa El Salvador, 2019. / The objective of this research work was to determine how IAS 19: Employee benefits financially impacts furniture trading companies in the Villa El Salvador district, year 2019. The methodology was of a mixed, approach explanatory, descriptive and explanatory level. Regarding the design, it was non-experimental, cross-sectional. Likewise, the qualitative research was inquired to three specialists from International Financial Reporting Standards (IFRS) and the quantitative research were carried out with 15 furniture trading companies from the Villa El Salvador district, in the year 2019, in which a study will be carried out on the linkage of IAS 19 Employee Benefits and the Impact. The work consists of five chapters; being chapter I, the theoretical framework, where various sources are presented that provide information to support the research. In chapter II, you will find the Research Plan, where the problematic situation, the problem, the justification, objectives, hypotheses, and limitations are presented. In chapter III, the methodology is described, which corresponds to a mixed investigation, such as qualitative and quantitative. In addition, the instruments that have been used for the development of the research, the determination of the population and the sample are explained. In chapter IV proceeded to the development of the investigation, where the application of the instruments is detailed, and also a practical case applying IAS 19, to determine their financial impact. In chapter V, the analysis of the study results, the in-depth interview and the questionnaire were carried out. Finally, the conclusions and recommendations were presented considering the hypotheses postulated, which allowed to confirm that IAS 19: Employee benefits, has a financial impact on furniture trading companies in the district of Villa El Salvador, year 2019. / Tesis