Submitted by Automa??o e Estat?stica (sst@bczm.ufrn.br) on 2016-01-04T20:46:57Z No. of bitstreams: 1 LucioMauroSouzaBorges_DISSERT.pdf: 4799735 bytes, checksum: 79d871fbe0b0a5ebf018035ed6367963 (MD5) / Approved for entry into archive by Arlan Eloi Leite Silva (eloihistoriador@yahoo.com.br) on 2016-01-11T19:18:03Z (GMT) No. of bitstreams: 1 LucioMauroSouzaBorges_DISSERT.pdf: 4799735 bytes, checksum: 79d871fbe0b0a5ebf018035ed6367963 (MD5) / Made available in DSpace on 2016-01-11T19:18:03Z (GMT). No. of bitstreams: 1 LucioMauroSouzaBorges_DISSERT.pdf: 4799735 bytes, checksum: 79d871fbe0b0a5ebf018035ed6367963 (MD5) Previous issue date: 2014-01-24 / Este trabalho consiste na concep??o, desenvolvimento e implementa??o de um M?dulo Computacional CAE contendo algoritmos para a an?lise de tens?es e deforma??es integrado a um software acad?mico de visualiza??o denominado OrtoCAD. Os algoritmos de expans?o para a interface CAE que s?o frutos desse trabalho foram desenvolvidos na linguagem FORTRAN objetivando complementar e ampliar as potencialidades de dois trabalhos previamente desenvolvidos no ?mbito do PPGEM-UFRN, a saber: projeto e fabrica??o de um Leitor EletroMec?nico e o software OrtoCAD. O OrtoCAD ? uma interface CAD que, originalmente, inclui a visualiza??o 3D de cartuchos prot?ticos a partir de dados gerados por um equipamento (esp?cie de scanner tridimensional simplificado que utiliza engenharia reversa) dotado de um sistema de Leitura Eletro-Mec?nica (LEM). Inicialmente, a geometria de um coto (i.e. parte remanescente de uma perna amputada e onde a pr?tese se encaixa) ? obtida a partir dos dados produzidos pelo equipamento LEM, aplicando-se os conceitos da Engenharia Reversa. O n?cleo FEA proposto aplica os conceitos de teoria da casca, onde uma l?mina 2D ? gerada a partir de um pe?a s?lida 3D oriunda do OrtoCAD. O programa de an?lise de casca desenvolvido utiliza o M?todo dos Elementos Finitos (MEF) para a descri??o da geometria assim como a an?lise de comportamento do material, fazendo a utiliza??o de elementos de base Lagrangeana quadrangular de nove n?s e campo de deslocamento de ordem superior para melhor descri??o do campo de tens?es na espessura. Como resultado o novo m?dulo FEA oferece ?timas vantagens ao prover o OrtoCAD com novas funcionalidades, a saber: possibilitou a independ?ncia dos softwares comerciais de elevado custo; ampliou a biblioteca disponibilizando novas rotinas computacionais que tratam o problema de forma mais real?stica utilizando crit?rios de falhas de engenharia voltados para materiais comp?sitos; melhorou a performance da an?lise FEA ao utilizar um elemento de malha espec?fico que contempla um maior n?mero de n?s e, finalmente, possui a vantagem de ser aberto e customizado oferecendo versatilidade intr?nseca e amplas possibilidades de edi??o, ajuste e/ou otimiza??o que se fa?am necess?rias no futuro / This work consists of the conception, developing and implementation of a Computational Routine CAE which has algorithms suitable for the tension and deformation analysis. The system was integrated to an academic software named as OrtoCAD. The expansion algorithms for the interface CAE genereated by this work were developed in FORTRAN with the objective of increase the applications of two former works of PPGEM-UFRN: project and fabrication of a Electromechanincal reader and Software OrtoCAD. The software OrtoCAD is an interface that, orinally, includes the visualization of prothetic cartridges from the data obtained from a electromechanical reader (LEM). The LEM is basically a tridimensional scanner based on reverse engineering. First, the geometry of a residual limb (i.e., the remaining part of an amputee leg wherein the prothesis is fixed) is obtained from the data generated by LEM by the use of Reverse Engineering concepts. The proposed core FEA uses the Shell's Theory where a 2D surface is generated from a 3D piece form OrtoCAD. The shell's analysis program uses the well-known Finite Elements Method to describe the geometry and the behavior of the material. The program is based square-based Lagragean elements of nine nodes and displacement field of higher order to a better description of the tension field in the thickness. As a result, the new FEA routine provide excellent advantages by providing new features to OrtoCAD: independency of high cost commercial softwares; new routines were added to the OrtoCAD library for more realistic problems by using criteria of fault engineering of composites materials; enhanced the performance of the FEA analysis by using a specific grid element for a higher number of nodes; and finally, it has the advantage of open-source project and offering customized intrinsic versatility and wide possibilities of editing and/or optimization that may be necessary in the future

Submitted by Automa??o e Estat?stica (sst@bczm.ufrn.br) on 2016-04-08T23:17:04Z No. of bitstreams: 1 MarcondesMendesDeSouza_TESE.pdf: 3135857 bytes, checksum: 11e52ad3f92073cb71b4e3869890ab67 (MD5) / Approved for entry into archive by Arlan Eloi Leite Silva (eloihistoriador@yahoo.com.br) on 2016-04-11T23:07:06Z (GMT) No. of bitstreams: 1 MarcondesMendesDeSouza_TESE.pdf: 3135857 bytes, checksum: 11e52ad3f92073cb71b4e3869890ab67 (MD5) / Made available in DSpace on 2016-04-11T23:07:06Z (GMT). No. of bitstreams: 1 MarcondesMendesDeSouza_TESE.pdf: 3135857 bytes, checksum: 11e52ad3f92073cb71b4e3869890ab67 (MD5) Previous issue date: 2015-04-17 / Nos estados da Para?ba e Rio Grande do Norte, no Brasil, as jazidas mais expressivas na produ??o de minerais industriais n?o-met?licos s?o as dos pegmatitos, quartzitos e granitos, que est?o localizadas na regi?o do Serid?. Os munic?pios de V?rzea - PB, Ouro Branco - RN e Parelhas - RN s?o os principais respons?veis pela extra??o de argila, quartzo, micas e feldspato. As empresas de minera??o que atuam na extra??o e beneficiamento dos quartzitos geram grandes volumes de res?duos, constituindo cerca de 90% de SiO2 na sua composi??o qu?mica proveniente do quartzo, que ? um dos constituintes b?sicos nas formula??es das massas cer?micas para a produ??o de revestimento cer?micos. Para tanto, este trabalho avalia o estudo da adi??o de res?duos de quartzito para obten??o do gr?s porcelanato atrav?s da caracteriza??o das mat?rias-primas por FRX, DRX, MEV, AG, ATG e DSC, utilizando cinco formula??es contendo 57% de feldspato, 37% de argila e 6% de res?duos de quartzitos com colora??es diferentes (branco, dourado, rosa, verde e preto), que foram sinterizadas em tr?s temperaturas: 1150?C, 1200?C e 1250?C, com isoterma de 1 hora e taxa de aquecimento de 10? C/min. Ap?s a sinteriza??o, os corpos-de-prova foram submetidos a ensaios de caracteriza??o f?sica como: absor??o de ?gua, retra??o linear, porosidade aparente, massa espec?fica aparente, resist?ncia ? flex?o em tr?s pontos. Os resultados obtidos apontavam para a possibilidade da utiliza??o do res?duo de quartzito em um percentual de 6% de adi??o na massa cer?mica. A utiliza??o de res?duos de quartzito em massa cer?mica proporcionou um produto final com propriedades tecnol?gicas que atendem ?s normas t?cnicas para a produ??o de gr?s porcelanato, sendo a temperatura de 1200?Ca que apresentou melhores resultados. De acordo com os resultados obtidos verificou-se um alto teor de ?xido de ferro no quartzito preto, sendo descartada a utiliza??o do mesmo em gr?s porcelanato por quest?o estrutural, pois o material fundiu a 1250?C. Todas as formula??es dos quartzitos obtiveram baixa absor??o de ?gua quando sinterizadas a 1200?C, obtendo AA entre 0,1% a 0,36% sem terem passado pelo processo de atomiza??o. Nos ensaios de resist?ncia ? flex?o todos os quartzitos encontram-se nos limites de aceita??o, segundo a norma europeia EN 100, superando 27 MPa na sinteriza??o a 1200?C. Com isso, o uso de res?duo de quartzito em massas cer?micas se apresenta como excelente potencial para a produ??o de gr?s porcelanato. / In States of Para?ba (PB) and Rio Grande do Norte (RN), northeast of Brazil, the most significant deposits of non-metallic industrial minerals are pegmatites, quartzites and granites, which are located in Serid? region. Extraction of clay, quartz, micas and feldspars occurs mainly in the cities of V?rzea (PB), OuroBranco (RN) and Parelhas (RN). Mining companies working in the extraction and processing of quartzite generate large volumes of waste containing about 90% SiO2 in their chemical composition coming from quartz that is one of the basic constituents of ceramic mass for the production of ceramic coating. Therefore, this work evaluates the utilization of these wastes on fabrication of high-quality ceramic products, such as porcelain stoneware, in industrial scale. Characterization of raw materials was based on XRF, XRD, GA, TGA and DSC analysis, on samples composed by 57% of feldspar, 37% of argil and 6% of quartzite residues, with 5 different colors (white, gold, pink, green and black). Samples were synthesized in three temperatures, 1150?C, 1200?C and 1250?C, with one hour isotherm and warming-up tax of 10?C/min. After synthesizing, the specimens were submit to physical characterization tests of water absorption, linear shrinkage, apparently porosity, density, flexural strain at three points. The addition of 6% of quartzite residue to ceramic mass provided a final product with technological properties attending technical norms for the production of porcelain stoneware; best results were observed at a temperature of 1200?C. According to the results there was a high iron oxide on black quartzite, being their use in porcelain stoneware discarded by ethic and structural question, because the material fused at 1250?C. All quartzite formulations had low water absorption when synthesized at 1200?C, getting 0.1% to 0.36% without having gone through the atomization process. Besides, flexural strain tests overcame 27 MPa reaching the acceptance limits of the European Directive EN 100, at 1200?C synthesizing. Thus, the use of quartzite residues in ceramic masses poses as great potential for the production of porcelain stoneware.

Este trabalho apresenta uma investigação experimental sobre o comportamento à fratura frágil de aços estruturais ferríticos, ASTM A285 Gr C e ASTM A515 Gr 65. Os resultados deste trabalho ampliam a base de dados de propriedades mecânicas utilizadas nas análises de integridade de estruturas pressurizadas tais como vasos de pressão e tanques de armazenamento construídos com esta classe de material. O trabalho tem por objetivo também avaliar a aplicabilidade de corpos de prova de dimensões reduzidas, PCVN, na determinação da temperatura de referência, T0, por meio da metodologia da Curva Mestra, a qual define a dependência da tenacidade à fratura do material em função da temperatura. Os ensaios de tenacidade à fratura foram conduzidos utilizando-se corpos de prova solicitados em flexão três pontos com geometria SE(B), PCVN e PCVN com entalhe lateral, extraídos de chapas laminadas. Os resultados dos ensaios foram obtidos em termos de integral J no momento da instabilidade, denotados por Jc. Dados adicionais de resistência à tração e de Impacto Charpy convencional também foram obtidos para caracterizar o comportamento mecânico dos aços utilizados. Os resultados mostraram uma forte influência da geometria dos corpos de prova sobre os valores de Jc, evidenciada pela grande variação nos valores de tenacidade à fratura. / This work presents an experimental investigation on the cleavage fracture behavior of structural ferritic steels, ASTM A285 Grade C and ASTM A515 Grade 65. One purpose of this study is to enlarge a previously reported work on mechanical and fracture properties for this class of steel to provide a more definite database for use in structural and defect analyses of pressurized components, including pressure vessels and storage tanks. Another purpose is to address the applicability of Precracked V-notch Charpy specimens to determine the reference temperature, T0, derived from the Master Curve Methodology which defines the dependence of fracture toughness with temperature for the tested material. Fracture toughness testing conducted on single edge bend specimens in three-point loading (SE(B), PCVN Plain Side and PCVN Side Grooved) extracted from laminated plates provides the cleavage fracture resistance data in terms of the J-integral at cleavage instability, Jc. Additional tensile and conventional Charpy tests produce further experimental data which serve to characterize the mechanical behavior of the tested materials. The results reveal a strong effect of specimen geometry on Jc values associated with large scatter in the measured values of cleavage fracture toughness.

Submitted by Alex Sandro R?go (alex@ifpb.edu.br) on 2016-11-23T14:27:36Z No. of bitstreams: 1 Aplica??o da Transformada Wavelet em An?lise de Texturas de Gr?ficos de Recorr?ncia.pdf: 3275892 bytes, checksum: 62518c9066cc2060f2785d053b661ff7 (MD5) / Approved for entry into archive by Alex Sandro R?go (alex@ifpb.edu.br) on 2016-11-23T14:29:16Z (GMT) No. of bitstreams: 1 Aplica??o da Transformada Wavelet em An?lise de Texturas de Gr?ficos de Recorr?ncia.pdf: 3275892 bytes, checksum: 62518c9066cc2060f2785d053b661ff7 (MD5) / Made available in DSpace on 2016-11-23T14:29:16Z (GMT). No. of bitstreams: 1 Aplica??o da Transformada Wavelet em An?lise de Texturas de Gr?ficos de Recorr?ncia.pdf: 3275892 bytes, checksum: 62518c9066cc2060f2785d053b661ff7 (MD5) Previous issue date: 2016-11-23 / A an?lise ac?stica do sinal de voz, devido ? sua natureza n?o invasiva e ao baixo custo, tem se mostrado uma eficiente ferramenta para aux?lio ao diagn?stico das desordens vocais provocadas por patologias na laringe. Os gr?ficos apresentam padr?es de larga e pequena escala, cujas varia??es em sua textura representam o comportamento do sinal de voz, proporcionando informa??es acerca do estado de normalidade ou de altera??o na qualidade vocal. Os padr?es de pequena escala podem ser vistos como caracter?sticas de textura e servem como base para uma an?lise quantitativa dos gr?ficos de recorr?ncia. T?cnicas de Processamento Digital de Imagens s?o empregadas para a an?lise da textura contida nos gr?ficos de recorr?ncia, baseada na transformada wavelet bidimensional. A fim de discriminar sinais saud?veis de sinais patol?gicos, s?o extra?dos diversos descritores de texturas dos coeficientes de cada sub-banda obtida pela decomposi??o wavelet bidimensional. Nesta pesquisa, duas abordagens foram aplicadas, as quais se diferenciam pela forma de extra??o dos padr?es representativos dos sinais: extra??o dos descritores de textura diretamente das sub-bandas da transformada wavelet; e extra??o dos descritores de Haralick, a partir da matriz de co-ocorr?ncia. Os sinais de voz foram classificados como saud?veis ou patol?gicos, como tamb?m foi realizada a discrimina??o entre patologias. Paralisia, edema de Reinke e n?dulos nas pregas vocais foram as patologias lar?ngeas consideradas na pesquisa. Os melhores resultados foram obtidos com os descritores de Haralick, empregando redes neurais MLP (Multilayer Perceptron) na classifica??o, em conjunto com o algoritmo de otimiza??o por enxame de part?culas PSO (Particle Swarm Optimization) empregado na sele??o das caracter?sticas mais representativas. O sistema proposto melhorou significativamente a acur?cia na discrimina??o entre patologias, com resultados superiores aos encontrados na literatura, que empregam a an?lise de recorr?ncia.

Glucocorticoids have long been used in the treatment of acute lymphoblastic leukaemia due to their ability to cause cell cycle arrest and apoptosis of lymphoid cells. However, some patients do not respond to glucocorticoid treatment and the majority, who initially respond, may relapse upon prolonged hormone treatment. The inefficiency of the treatment is mainly attributed to the gradual loss of the cellular sensitivity to glucocorticoid-induced apoptosis. Therefore, the need to understand the molecular mechanisms of resistance/ sensitivity of acute lymphoblastic leukaemia cells to glucocorticoid-induced apoptosis is of vital importance, as this will help to develop better prognostic outcomes and improve glucocorticoids therapy. Several mechanisms have been proposed to explain the evasion of glucocorticoid mediated apoptosis in resistant cells. These include post-translational modifications of GR especially phosphorylation which modulates the GR transcriptional activity, and GR mediated signalling thereby affecting gene expression and hence the balance between pro- and anti-apoptotic Bcl-2 family members. In addition the concentration of components of the energy metabolism pathways (i.e. oxidative phosphorylation and glycolysis) and ROS generation are altered in the acute lymphoblastic leukaemia cells. The hypothesis that differentially phosphorylated GR in the resistant versus sensitive ALL cells modulate GR transcriptional activity and target selectively resulting in diverse pro- or anti-apoptotic Bcl-2 family members' gene expression in the two cell lines was tested. Furthermore, in a similar manner, the possibility that differential GR phosphorylation diversely affected gene expression of GR transcriptional target genes that are components of cellular energy production pathways in resistant versus sensitive cells, altering energy and ROS production levels in distinct ways in the two cell lines was explored. GR was found to be predominantly phosphorylated at S211 in the glucocorticoid-sensitive CEM C7-14, and at S226 in the glucocorticoid-resistant CEM C1-15 cells. Differential GR phosphorylation is presumably an indication of dominant p38 MAPK activity in CEM C7-14 and JNK kinase activity in CEM C1-15, which could lead to adverse gene expression of some pro- and anti-apoptotic Bcl-2 family members and particularly Mcl-1, in the two cell lines. Furthermore, differential GR phosphorylation at S211 and S226 in CEM C7-14 and CEM C1-15 affected the gene expression of the Cytochrome C Oxidase assembly factors Surf-1 and SCO2 as well as the nuclear encoded Cytochrome C Oxidase subunit COX-Va and the mitochondrial encoded COX-I, COX-II and COX-III. This effect was more pronounced in the glucocorticoid-sensitive CEM C7-14 cells, probably due to the fact that GR was predominantly phosphorylated at S211 and hence transcriptionally active in these cells. Moreover, in comparison to the resistant CEM C1-15 cells, the CEM C7-14 cells exhibited higher levels of ROS, increased number of active mitochondria and up-regulated glycolysis upon inhibition of oxidative phosphorylation. Glucocorticoids further reduced ROS levels in the CEM C1-15 cells, and increased the NADH/ NAD+ ratio. In conclusion results presented in this thesis provide evidence that differential GR phosphorylation in resistant versus sensitive to glucocorticoid induced apoptosis cells plays essential role in the regulation of programmed cell death and energy metabolism pathways, offering a potential explanation for the molecular events that determine resistance/sensitivity to glucocorticoid-induced apoptosis in ALL cells.

Globally, the importance of teaching mathematics to young children has rapidly increased. The concepts of space and shape are one of the mathematical content areas of mathematics that young children should explore, and Grade R teachers ought to understand and implement. Numerous theorists, researchers and authors have provided valuable insights and research on why Grade R teachers should be effectively teaching the mathematical content of knowledge of space and shape in their classrooms. In South Africa, several influences and contributing factors make it a challenge for Grade R teachers to implement the mathematical content knowledge of space and shape. This study sought to gain an insight in how Grade R teachers understand and implement the mathematical content knowledge of space and shape. The conceptual framework was developed from existing theories and research literature. A constructivist approach was followed. The framework comprised six levels to explain how Grade R teachers’ mathematical and pedagogical knowledge develops. The framework assisted in formulating questions and methods for the data collection process. The collected data was organised, transcribed and analysed. The study employed a qualitative case study design to generate data from five Grade R teachers’ experiences, views, ideas, opinions and perceptions on teaching the mathematical concepts of space and shape. Data were collected from the five teachers through participant observations, semi-structured interviews, documents and keeping a journal. The data analyses and findings support the themes and subthemes to answer the research questions. The findings from the research revealed that teachers should implement various innovative teaching approaches to facilitate active participation, so that the children could make their own meaning and understanding of the mathematical content of space and shape. Age-appropriate content and materials that scaffolds on children’s prior knowledge were found to be important strategies for effective teaching and learning. Teachers and their schools have a responsibility to establish positive learning environments as well as positive learning experiences for the children. The teachers in the study raised their concerns about the Curriculum and Assessment Policy Statements as they felt that they lacked creativity and guidance. Various factors with a negative impact on teaching and learning were identified and recommendations were made for improvement. The study concludes that Grade R teachers would benefit from gaining an in-depth understanding of the effective implementation of the mathematical content knowledge of space and shape. / Dissertation (MEd)--University of Pretoria, 2018. / Early Childhood Education / MEd / Unrestricted

We report on some experience with a parallel version of the Gröbner basis algorithm with factorization, implemented in the REDUCE package CALI [4]. It is based on a coarse grain parallel master-slave model with distributed memory. This model was realized on an HP workstation cluster both with a disk remote connection based on (ordinary) REDUCE [9] and the special PVM-based parallel REDUCE version of H. Melenk and W. Neun [7]. Our considerations focus on a detailed study of the practical time behaviour of the parallelized improved Gröbner factorization algorithm [5]. For well splitting examples, where the number of intermediate subproblems is large compared to the number of parallel processes available on the system (only for such examples this approach makes sense), we've got almost always a good load balance. Since even for the relative slow disk remote connection the results are encouraging, we conclude that with a fast and stable communication hard- and software one will obtain a serious speed up on such problems compared to the serial implementation.

[ES] Nuestra investigación se centra en comprender los mecanismos moleculares que median las acciones de los glucocorticoides (GCs) en la fisiopatología de la piel mediante el análisis funcional del receptor de GCs (GR) y el receptor de mineralocorticoides (MR), dos proteínas altamente relacionadas estructural y funcionalmente, que actúan como factores de transcripción dependientes de ligando. Nuestros datos previos demuestran que GR juega un papel central en el desarrollo de la piel; en la edad adulta, tanto GR como MR actúan como mediadores anti-inflamatorios en enfermedades cutáneas (Sevilla et al. 2013; Boix et al. 2016). No obstante, desconocíamos si los receptores ejercían funciones cooperativas o antagónicas en la epidermis. Esta tesis doctoral se ha centrado en la generación y caracterización de ratones con inactivación específica en la epidermis de GR y MR (ratones double knock-out o DKO). Al nacer, los DKO mostraron un fenotipo cutáneo con diferenciación epidérmica defectuosa y un estado inflamatorio único caracterizado por infiltrados inmunes epiteliales y alteraciones en la expresión génica, similar a las lesiones psoriáticas. Este fenotipo fue mucho más severo que el de los KO individuales (ratones GR epidermal KO o GREKO y MR epidermal KO o MREKO), pero se resolvió espontáneamente a partir del día post-natal 3. En la edad adulta, la piel DKO mostró un aumento en el grosor epidérmico, similar al de los KO individuales. Todos los ratones KO mostraron una mayor susceptibilidad a la inflamación aguda respecto a los controles (CO), que no se contrarrestó de forma efectiva por un tratamiento tópico con GCs. Además, los ratones DKO mostraron una mayor susceptibilidad a la psoriasis inducida por imiquimod respecto a los KO individuales. El aumento de la respuesta inflamatoria en los DKO era consistente con un aumento significativo de la actividad de AP-1 y NF-kappaB en queratinocitos DKO respecto a los CO o KO individuales. En conjunto, nuestros datos demuestran que GR y MR epidérmicos actúan de manera cooperativa para contrarrestar la inflamación de la piel, durante el desarrollo y la edad adulta, y que ambos son necesarios para una respuesta transcripcional óptima y una actividad terapéutica de los GCs. Los tratamientos prolongados con dosis farmacológicas de GCs producen defectos como la atrofia cutánea, similar a la que tiene lugar durante el envejecimiento cronológico, que correlaciona con un aumento de los niveles locales endógenos de GCs. Este trabajo ha abordado las consecuencias fenotípicas de la pérdida epidérmica de MR durante el envejecimiento cronológico y los mecanismos involucrados. Los ratones MREKO de 13 meses de edad fueron resistentes a la atrofia epidérmica pero mostraron un menor grosor dérmico y depósito de colágeno, en parte debido a una disminución de la actividad SMAD2/3 respecto a la piel de ratones CO. Además, el tejido adiposo subcutáneo (dWAT) se engrosó 2.5 veces en MREKO vs CO a los 13 meses, con hiperplasia e hipertrofia de adipocitos. Estos cambios se desencadenaron, al menos en parte, a través de alteraciones en la señalización mediada por GCs, y la activación de WNT/beta-catenina inducida por señales paracrinas epidérmicas que condujeron al aumento de expresión de Pparg. Estos resultados demuestran un papel crucial de MR epidérmico en la regulación del cross-talk entre compartimientos durante el envejecimiento cronológico de la piel. / [CA] La nostra investigació se centra en comprendre els mecanismes moleculars que regulen les accions dels glucocorticoides (GCs) en la fisiopatologia de la pell mitjançant l'anàlisi funcional del receptor de GCs (GR) i el receptor de mineralocorticoides (MR), dues proteïnes altament relacionades estructural i funcionalment, que actuen com a factors de transcripció dependents de lligant. Els nostres resultats previs demostren que GR juga un paper central en el desenvolupament de la pell; en l'edat adulta, tant GR com MR actuen com a mediadors antiinflamatoris en malalties cutànies (Sevilla et al. 2013; Boix et al. 2016). No obstant, desconeixíem si els receptors exercien funcions cooperatives o antagòniques en l'epidermis. Aquesta tesi doctoral s'ha centrat en la generació i caracterització de ratolins amb inactivació específica en l'epidermis de GR i MR (ratolins double knock-out o DKO). En néixer, els DKO van mostrar un fenotip cutani amb diferenciació epidèrmica defectuosa i un estat inflamatori únic caracteritzat per infiltrats immunes epitelials i alteracions en l'expressió gènica, similar a les lesions psoriàtiques. Aquest fenotip va ser molt més sever que el dels KO individuals (ratolins GR epidermal KO o GREKO i MR epidermal KO o MREKO), però es va resoldre espontàniament a partir del dia post-natal 3. En l'edat adulta, la pell DKO va mostrar un augment en el gruix epidèrmic, similar al dels KO individuals. Tots els ratolins KO van mostrar una major susceptibilitat a la inflamació aguda en comparació als controls (CO), que no va ser contrarestada de manera efectiva per un tractament tòpic amb GCs. A més, els ratolins DKO van mostrar una major susceptibilitat a la psoriasis induïda per imiquimod respecte als KO individuals. L'augment de la resposta inflamatòria en els DKO era consistent amb un augment significatiu de l'activitat d'AP-1 i NF-kappaB en queratinòcits DKO respecte als CO o KO individuals. En conjunt, les nostres dades demostren que GR i MR epidèrmics actuen de manera cooperativa per contrarestar la inflamació de la pell, durant el desenvolupament i l'edat adulta, i que tots dos són necessaris per a una resposta transcripcional òptima i una activitat terapèutica dels GCs. Els tractaments prolongats amb dosis farmacològiques de GCs produeixen defectes com l'atròfia cutània, similar a la que té lloc durant l'envelliment cronològic, que correlaciona amb un augment dels nivells locals endògens de GCs. Aquest treball ha abordat les conseqüències fenotípiques de la pèrdua epidèrmica de MR durant l'envelliment cronològic i els mecanismes involucrats. Els ratolins MREKO de 13 mesos d'edat van ser resistents a l'atròfia epidèrmica però van mostrar un menor gruix dèrmic i dipòsit de col¿lagen, en part a causa d'una disminució de l'activitat SMAD2/3 respecte a la pell de ratolins CO. A més, el teixit adipós subcutani (dWAT) es va engrossir 2.5 vegades en MREKO vs CO als 13 mesos, amb hiperplàsia i hipertròfia d'adipòcits. Aquests canvis es van desencadenar, almenys en part, a través d'alteracions en la senyalització mediada per GCs, i l'activació de WNT/beta-catenina induïda per senyals paracrines epidèrmiques que van conduir a l'augment d'expressió de Pparg. Aquests resultats demostren un paper crucial de MR epidèrmic en la regulació del cross-talk entre compartiments durant l'envelliment cronològic de la pell. / [EN] Our research focuses on understanding the molecular mechanisms that mediate the actions of glucocorticoids (GCs) in skin pathophysiology through functional analysis of the GC receptor (GR) and the mineralocorticoid receptor (MR), two highly related structural and functionally proteins, which act as ligand-dependent transcription factors. Our previous data show that GR plays a central role in skin development; in adulthood, both GR and MR act as anti-inflammatory mediators in skin diseases (Sevilla et al. 2013; Boix et al. 2016). However, we did not know if the receptors exerted cooperative or antagonistic functions in the epidermis. This doctoral thesis has focused on the generation and characterization of mice with specific inactivation in the epidermis of GR and MR (double knock-out or DKO mice). At birth, DKO show a skin phenotype with defective epidermal differentiation and a unique inflammatory state characterized by epithelial immune infiltrates and alterations in gene expression, similar to psoriatic lesions. This phenotype was much more severe than that of individual KO (GR epidermal KO or GREKO and MR epidermal KO or MREKO mice), but resolved spontaneously from postnatal day 3. In adulthood, DKO skin showed an increase in epidermal thickness, similar to that of individual KO. All KO mice showed greater susceptibility to acute inflammation compared to controls (CO), which was not effectively counteracted by topical treatment with GCs. Furthermore, DKO mice show a greater susceptibility to imiquimod-induced psoriasis relative to individual KO. The increased inflammatory response in DKO was consistent with a significant increase in AP-1 and NF-kappaB activity in DKO keratinocytes relative to CO or individual KO. Taken together, our data show that epidermal GR and MR act cooperatively to counteract skin inflammation, during development and adulthood, and that both are required for optimal transcriptional response and therapeutic activity of GCs. Prolonged treatments with pharmacological doses of GCs produce defects such as cutaneous atrophy, similar to that which occurs during chronological aging, which correlates with an increase in endogenous local levels of GCs. This work has addressed the phenotypic consequences of epidermal loss of MR during chronological aging and the mechanisms involved. The 13-month-old MREKO mice were resistant to epidermal atrophy but displayed reduced dermal thickness and collagen deposition, in part due to a decrease in SMAD2 3 activity relative to the skin of CO mice. In addition, the subcutaneous adipose tissue (dWAT) thickened 2.5 times in MREKO vs CO at 13 months, with hyperplasia and hypertrophy of adipocytes. These changes were triggered, at least in part, through alterations in GC-mediated signaling, and the activation of WNT/beta-catenin induced by epidermal paracrine signals that led to increased expression of Pparg. These results show a crucial role for epidermal MR in the regulation of the cross-talk between compartments during chronological skin aging. / Este trabajo ha sido realizado con el apoyo económico de los proyectos de investigación que se enumeran a continuación: SAF2014-59474-R, SAF2017-88046-R. Judit Bigas Corominas ha disfrutado de una beca predoctoral FPI (BES2015-072722) otorgada por el Ministerio de Economía y Competitividad, asociada al proyecto SAF2014-59474-R. Agradecemos el apoyo de COST ADMIRE BM-1301 y NuRCaMeIn (SAF2015-71878-REDT y SAF2017-90604-REDT). / Bigas Corominas, J. (2020). Contribuciones relativas de los receptores de glucocorticoides y mineralocorticoides en la biología cutánea [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/156214 / TESIS

We consider a recent approach to the construction of gauge-invariant relational observables in gravity in the context of cosmological perturbation theory. These observables are constructed using a field-dependent coordinate system, which we take to be geodesic lightcone coordinates. We show that the observables are gauge-independent in the fully nonlinear theory, and that they have the expected form when one adopts the geodesic lightcone gauge for the metric. We give explicit expressions for the Sasaki-Mukhanov variable at linear order, and the Hubble rate — as measured both by geodesic observers and by observers co-moving with the inflaton — to second order. Moreover, we show that the well-known linearised equations of motion for the Sasaki-Mukhanov variable and the scalar constraint variables follow from the gauge-invariant Einstein’s equations

Предметом диссертации является частно-государственное партнерство в сфере высшего образования как специфическая GR -технология. Особое внимание автор уделяет изучению коммуникативных механизмов, обеспечивающих эффективное взаимодействие между бизнес-структурами и органами власти. Диссертант подробно рассматривает новые коммуникативные механизмы данной технологии, особенности их применения в системе российского и зарубежного высшего образования. Анализ предмета статьи доказывает, что частно-государственные проекты являются самыми эффективными площадками открытого диалога бизнеса и власти для решения проблем высшего образования РФ. Для характеристики функционирования субъектов и коммуникативных механизмов GR-технологий используются структурно-функциональный и сравнительный метод. Для получения доказательной базы применен метод case-study. Основные результаты: 1.Частно-государственное партнерство является GR-технологией, выражающейся в применении специфических методов взаимодействия бизнеса и власти с целью решения социальных проблем.2.Изучение коммуникативных механизмов ЧГП как GR-технологии определило ее эффективные формы: ассоциации выпускников, эндаумент-фонды, академический фандрайзинг, частно-государственные проекты. 3.Метод Сase-study позволил определить частно-государственные проекты в системе высшего образования, как самый эффективный механизм GR-деятельности в РФ. / The subject of this research is the public-private partnership in the sphere of higher education as a specific GR-technology. The author pay particular attention to the study of communication mechanisms that ensure the productive interaction between businesses and government authorities. The work carefully examines the new communication mechanisms of such technology, as well as specificities of its application in the system of the Russian and foreign higher education. Analysis of the subject of research confirms that the public-private projects manifest as the most efficient platforms for the open dialogue between business and government for resolution of the issues of higher education in the Russian Federation. The author made the following conclusions: 1) public-private partnership is the GR-technology, which manifests in application of specific methods of interaction between business and government to address the social issues; 2) examination of the communication mechanisms of public-private partnership as a GR-technology defined its efficient forms: alumni association ,endowment funds, fundraising, and public-private projects; 3) the case-study method allowed identifying the public-private projects within the system of higher education as the most effective mechanism for GR-activity in the Russian Federation.