La presente tesis tiene como objetivo realizar una revisión histórico-filosófica del concepto de ridículo y de sus implicaciones como instrumento político. Primero, sin embargo, debe acotarse lo que se entiende por "ridículo" distinguiéndolo del fenómeno general de la risa: por una parte, aquello que singulariza una situación o un objeto ridículo que mueve a risa; por otra, el tipo específico de burla cómica que constituye la risa ridiculizadora. Una vez establecida esta distinción conceptual y delimitado el objeto de estudio, valiéndose para ello de los discursos filosóficos que han abordado la cuestión, es posible articular sus funciones y efectos en la conducta del sujeto individual y en la conducta de los sujetos sociales. El paso de la pesquisa ontológica y psicológica a la indagación sociológica permite apuntar una hipótesis sobre los usos políticos del ridículo en base a los conceptos de "poder" y "valor". Con vistas al esclarecimiento del concepto de lo ridículo se hace en las dos primeras partes de la tesis una crítica de los pensadores más destacados que se han ocupado del tema. En la tercera parte se aplican las categorías deducidas de esta revisión histórico-filosófica al mundo contemporáneo, analizando los usos de lo ridículo en la maquinaria política del Estado democrático. / The doctoral dissertation’s aim is to accomplish a historical - philosophical review of the concept of ridiculous and of his implications as political instrument. First of all it must be annotated what is understood for "ridiculous", distinguishing it from the general phenomenon of laughter. After the psychological and ontological investigation, the theoretical category of "ridiculous" is analyzed from a sociological perspective. In the first two parts of the dissertation there is carried out a critique of the most out-standing thinkers who have dealt with the topic. In the third part the deduced categories of this historical - philosophical review are applied to the contemporary world, studying the uses of the category of ridiculous on the democratic system.

La tesis parte del planteamiento del consumo de drogas como un fenómeno social, al ser una práctica antropológica histórica. Centramos la atención en el consumo de drogas que realizan los menores en edad escolar, proponiendo como objeto de estudio el proceso por el cual se legitima la intervención especializada en los centros educativos, ya que la hipótesis plantea si la llegada del especialista en materia de drogas a la escuela representa una estrategia de control ideológico. Para el abordaje de la misma se ha seguido una metodología descriptiva, con las siguientes fases: exploración (análisis documental), descripción (análisis de contenidos), interpretación y reflexión, desde donde establecer conclusiones y proponer nuevas líneas de investigación para el futuro, apostando por un posicionamiento socio-crítico. El fenómeno del consumo de drogas, es estudiado desde diferentes marcos de referencia: histórico, teórico, normativo-legislativo, ideológico, político y pedagógico, desde los cuales se establecen las indicaciones que determinan las prácticas preventivas en el marco escolar. El consumo de drogas, en edad escolar, está caracterizado por la baja edad de los consumidores, el aumento de la frecuencia de los consumos así como por un mayor acceso a más y diferentes sustancias alteradoras de la conciencia, la percepción de la realidad y los estados de ánimo y generadoras de dependencias y adicciones. Si la respuesta escolar ante estos consumos es la expulsión, entendemos que, en primer lugar, desaparece la pedagogía cuando más falta hace y que, también, aumentan las posibilidades de consumo de los alumnos expulsados, ya que estos permanecerán, durante las horas en que deberían estar en la escuela, solos en casa o en la calle. Por otro lado, si la respuesta escolar a los consumos es la demanda de intervención de especialistas, encontramos que: - los recursos, servicios y programas están subvencionados por órganos de decisión política, por lo tanto se produce un control político ideológico de los mismos .- los discursos oficiales, construidos desde los marcos de referencia, se centran en la difusión de perfiles y estereotipos de los consumidores de drogas como sujetos en riesgo, lo que dificulta que los menores que consumen drogas se identifiquen a si mismos como sujetos con problemas derivados de los consumos de drogas, aumentando el riesgo y obstaculizando la demanda de atención por su parte .- la intervención de los especialistas queda legitimada por las carencias formativas de los docentes en materia de drogas, que se observan tanto en la formación básica del magisterio como en los máster de profesorado de secundaria. La tesis llega a la conclusión de la necesidad de que la educación sobre drogas sea reivindicada desde la pedagogía y deje de pertenecer al ámbito de la política / The thesis of the approach of drugs use as a social phenomenon, being a historical anthropological practice. We focus attention on drug use carried out by school-age children, proposing as an exploration of the process by which specialist intervention is legitimized in the schools, since the hypothesis is whether the arrival of specialist drugs school represents a strategy of ideological control. For the same approach was followed a descriptive methodology, with the following phases: exploration (document analysis), description (content analysis), interpretation and reflection, from which to draw conclusions and propose new lines of research for the future, betting a socio-critical position. The drug phenomenon is studied from different frames of reference: historical, theoretical, normative-legal, ideological, political and pedagogical, from which one can detect signs that determine the preventive practices in school settings. Drugs use, school age, is characterized by the low age of consumers, the increased frequency of consumption as well as greater access to more and different consciousness-altering substances, perception of reality and moods and creates dependency and addiction. If the answer to these consumptions school expulsion, we understand that, first, disappears when most needed education and also increase the consumption possibilities of expelled students, as these remain, during the hours should be in school, alone at home or on the street. On the other hand, if the school response is consumption demand intervention specialists, found that: . - Resources, services and programs are supported by policy making bodies, therefore there is a political and ideological control of the same . - Official speeches, built from the frames of reference, focus on the dissemination of profiles and stereotypes of drug users as subjects at risk, making it difficult for children who use drugs to identify themselves as individuals with problems derived from drug consumption, increasing the risk and hampering the demand for care on their part . - Specialist intervention is legitimized by the deficiencies of teachers training on drugs, which are observed both in the basic training of teachers and masters in secondary school teachers. The thesis concludes that the need for drug education to be claimed from the pedagogy ceases to belong to the realm of politics.

Cancer is one of the leading causes of death. There have been many investigations into therapeutic ways to prevent and reverse cancerous growth. We report a new approach in this thesis, which is to investigate the functions of Vitamin B1 (thiamine) in cancerous cells and their regulation. A number of thiamine analogs were synthesized to carry out the structure-activity relationship (SAR) studies with two transporters THTR1 and THTR2. Initial results show that the modifications of thiazole reduced the uptake of thiamine.

Studien omfattar 19 elever i år 6. Syftet var att undersöka om det går att se och utvärdera några förändringar i elevernas resultat i läsförståelse efter att de systematiskt tränats i denna färdighet under sex veckor. Eleverna fördelades på en test- och kontrollgrupp. Elevernas prestationer mättes före och efter insatserna med material från nationella prov. Därefter gjordes en intervention av övningar för att stärka läsförståelsen hos eleverna i testgruppen. Eleverna i testgruppen följs upp och arbetet beskrivs mer ingående av mig som deltagande observatör. Övningarna genomfördes 3-4 gånger i veckan med 20min vid varje tillfälle och under sex veckor. Testresultaten redovisas i tabellform och arbetsprocessen följs upp och beskrivs. I resultaten kan man utläsa en förändring i positivriktning hos testgruppen och i klassens resultat.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most insidious forms of cancer whose incidence nearly equals its death rate. Despite extensive research studies, no effective therapeutic approaches for diminishing the morbidity associated with this disease are available. PDAC is characterized by activating Kras mutations and inactivation of Ink4a and the p53-Arf pathway in virtually all cases, while SMAD4¡Xa central regulator of Transforming growth factor-beta (TGF-£]) signaling¡Xis inactivated in 55% of PDAC. Our overall goal is to understand how perturbations in the inactivation of SMAD4 pathway contribute to the late stages of PDAC pathogenesis, and to elucidate the role of SMAD4 inactivation on the conversion of a benign form of the cancer to a more aggressive metastatic form. To address this important topic in cancer biology, we have devised a strategy to develop model cell lines to dissect the role of SMAD4 defect in PDAC cell lines and the potential synergistic effects of hypoxia and/or TGF-£]1 upon SMAD4 inactivation in their metastatic properties. Experiment results showed SMAD4 restored in PDAC model cell lines were down regulate HIF-1£\, VEGF, FGF10 and FGFR2 genes expression level, and also inhibited migration, chemoresistance and angiogenesis of cancer cells. We hypothesize that these effects are due to SMAD4 suppresses some cancer genes in PDAC. Further detailed investigations are also needed to fully elucidate the detail mechanisms for our findings here therefore, the future works of this study will go step on looking for those important downstream effect genes regulated by Smad4 protein in PDAC cells and try to find out the connection of all the dependence proteins.

VCAM-1 (CD106) is a transmembrane glycoprotein and involved in many pathological inflammatory processes. VCAM-1 plays an important role in leukocyte adhesion, leukocyte transendothelial migration and cell activation by binding to integrin VLA-1 (£\4£]1). In our preliminary data, we observed 2-3 fold increase in the expression of VCAM-1 in the side population of ovarian cancer, which exhibits stem cell-like properties in ovarian cancer. In addition, we have also found VCAM-1 is upregulated in many breast cancer epithelial cells and directly correlated with breast tumor progression; however, its mechanism of action in tumor biology remains unknown. Here, we describe the establishment and use of breast cancer cell line model systems to dissect the functional roles of VCAM-1 activation in the manifestation of malignant phenotype of human breast cancer. We show that VCAM-1 overexpression in the NMuMG breast epithelial cells increase cell motility rates and chemoresistance to doxorubicin and cisplatin in vitro, conversely, in an established metastatic breast cancer cell line, MDAMB231, we find that knockdown endogenous VCAM-1 expression by small interfering RNA reduced the migration rate . Furthermore, we also demonstrated that knockdown endogenous VCAM-1 expression in MDAMB231 cells reduced the tumor formation in SCID xenograft mouse model. In conclusion, our findings are consistent with the hypothesis that overexpression of VCAM-1 facilitates breast cancer progression by enhancing the malignant properties of breast cancer cells and suggests that targeting of VCAM-1 induced pathways are attractive strategies for therapeutic intervention.

Chemokines are important mediators of leukocyte migration. Chemokines bind to G protein–coupled receptors (GPCR) and cause conformational changes that trigger intracellular signaling pathways involved in inflammation, injury healing, cancer, metastasis, and HIV infections. No direct structural information about any chemokine receptor is available, but the structure of chemokines has been well studied. Structural studies of chemokines coupled with cell-biological investigations may lead to a better understanding of the mechanisms of chemokine-receptor interactions. In this Ph.D. project, I studied the structural and functional relationship between chemokines and chemokine receptors using NMR, X-ray crystallography, and mutagenesis approaches, coupled with several different cell-biology assays. We found that the conserved “chemokine fold” can support different dimerization types in the chemokines family, although changing the dimers from CC- to CXC-type fold is not readily accomplished. I also used an engineered covalently-bound dimer of the MIP-1β mutant, MIP-1β-A10C, to study the relationship between dimerization of chemokines and their interaction with the CCR5 receptor. My results suggest that MIP-1β dimer neither bind nor activate the CCR5 receptor. I also studied the biophysical properties of one N-terminal awkward mutant of P2-RANTES, which was originally selected by others from a phage display using CCR5-expressing cells. Although the NMR and X-ray crystal studies revealed that the wild type RANTES is a tight homodimer, analytical ultracentrifugation reveals that P2-RANTES is a monomer in solution, the 1.7 Å resolution X-ray crystal structure of P2-RANTES was found to be a packed tetramer. The mutated N-terminal residues play a very important role in the tetramerization in the X-ray crystal structure. Finally I used the HIV-1 env mediated cell-cell fusion assay to study the combination of chemokines or chemokine variants with anti-HIV peptides C37 or/and T-20. A surprisingly synergistic effect was found between P2-RANTES and C37 or T-20. This combination stratagem may lead to further useful drug combinations or drug delivery for more potent anti-HIV treatments.

Successful synaptic transmission at the neuromuscular junction depends on the precise alignment of the nerve terminals with the postsynaptic specialization of the muscle fiber. It is increasingly apparent that this precision is achieved during development and maintained in the adult through signals exchanged between motoneurons and their target muscle fibers that serve to coordinate their spatial and temporal differentiation. Several aspects of neuronal differentiation appear to be dependent on retrograde signals from the target and studies about synaptic modulation have now focused attention on the characterization of proteins that mediate retrograde signals regulating the organization and function of nerve terminals. According to the published evidences, we find Insulin-like growth factor-I (IGF-I ) might be one of these potential factors. The acute application of IGF-I, a factor which has been addressed to widely express in developing myocyte, dose-dependently enhances the spontaneous acetylcholine secretion at developing neuromuscular synapses in Xenopus cell culture using whole-cell patch clamp recording. The IGF-I-induced potentiating effect is not abolished when calcium is eliminated from culture medium or bath application of pharmacological calcium channel blocker cadmium, indicating calcium influx through voltage-activated calcium channels are not required. We further define the roles of intracellular Ca2+ stores in IGF-I-induced synaptic potentiation. To approach this problem, Ca2+-ATPase inhibitor thapsigargin were initially used to deplete internal Ca2+ stores. IGF-I no longer elicited any changes in SSC frequency in thapsigargin-treated synapses suggesting that an increase in [Ca2+]i due to Ca2+ release from intracellular Ca2+ stores may contribute to the facilitation of transmitter release induced by IGF-I. Application of membrane-permeable inhibitors of IP3-induced Ca2+ release 2-aminoethoxydiphenyl borate (2-APB) or Xestospongin C (XeC) effectively occluded the increase of SSC frequency elicited by IGF-I. Furthermore, pretreatment of the cultures with ryanodine receptor antagonist 8-(dethylamino) octyl 3, 4, 5-trimethoxybenzoate (TMB-8) also blocked the IGF-I effects indicating that IGF-I activates IP3 and/or ryanodine pathway to initiate calcium release from intracellular stores which subsequently potentiate transmitter release. Treating cells with inhibitors of phosphoinositide-3 kinase (wortmannin and LY294002) and Phospholipase C-g (U73122), but not inhibitor of MAP kinase (PD98059) abolishes IGF-1-induced potentiation of synaptic transmission. Inhibition of Ca2+/calmodulin-dependent protein kinase II (CaMKII) by KN-62 effectively blocks the effect of IGF-I. Taken collectively, our results obtained suggest that IGF-I potentiates neurotransmitter secretion by stimulating Ca2+ release from IP3 and ryanodine sensitive intracellular calcium stores via activate PI3 and/or PLC-g signaling cascades, which leading to an activation of CaMKII-dependent transmitter release.

17β-Estradiol induces E2F-1 gene expression in ZR-75 and MCF-7 human breast cancer cells. Analysis of the E2F-1 gene promoter in MCF-7 cells previously showed that hormone-induced transactivation required interactions between estrogen receptor α (ERα)/Sp1 bound to upstream GC-rich sites and NFYA bound to downstream CCAAT sites within the -169 to -54 promoter region. This promoter region was also E2-responsive in ERα-positive ZR-75 cells; however, further analysis of the promoter showed that cooperative ERα/Sp1/NFY interactions were not necessary for hormone-induced transactivation in ZR-75 cells. The upstream GC-rich motifs are activated independently by ERα/Sp1 in ZR-75 but not MCF-7 cells, and the downstream CCAAT sites were also E2-responsive. E2 also induced reporter gene activity in ZR-75 cells transfected with an expression plasmid containing the yeast GAL4 DNA binding domain fused to pM-NFYA and a construct containing five tandem GAL4 response elements. Subsequent studies showed that hormonal activation of pE2F-1jm1 and pM-NFYA are dependent on non-genomic pathways in which E2 activates cAMP/protein kinase A. Hormone-dependent regulation of E2F-1 gene expression in ZR-75 and MCF-7 involves different mechanisms, demonstrating the importance of cell context on transactivation pathways, even among ER-positive breast cancer cell lines. TCDD inhibited ERα-mediated responses in MCF-7 and ZR-75 cells. E2- induced E2F-1protein and mRNA levels in MCF-7 and ZR-75 cells and this response was inhibited by TCDD. Constructs containing GC-rich sites alone or in combination with the downstream NFY sites were used in transactivation studies to investigate the mechanism of inhibitory AhR-ERα crosstalk. Although TCDD inhibited E2-induced mRNA, protein and reporter gene actitivity, it was not possible to determine if the inhibitory response was due to limiting ERα protein levels due to proteasome degradation since proteaome inhibitors alone blocke hormone-dependent responses. TCDD also inhibited the cAMP/PKA pathway by inhibiting adenyl cyclase activity. In Drosophila SL-2 cells cotransfected with the GC-rich -169 to -54 region, ERα and Sp1 plasmids E2 induced transactivation in cells cotransfected with AhR/Arnt expression plasmids suggesting that the AhR complex suppressed ERα/Sp1 action. These results demonstrate that TCDD inhibits E2-dependent activation of both non-genomic and genomic pathways of ER-mediated E2F-1 gene expression. 17β-Estradiol induces E2F-1 gene expression in ZR-75 and MCF-7 human breast cancer cells. Analysis of the E2F-1 gene promoter in MCF-7 cells previously showed that hormone-induced transactivation required interactions between estrogen receptor α (ERα)/Sp1 bound to upstream GC-rich sites and NFYA bound to downstream CCAAT sites within the -169 to -54 promoter region. This promoter region was also E2-responsive in ERα-positive ZR-75 cells; however, further analysis of the promoter showed that cooperative ERα/Sp1/NFY interactions were not necessary for hormone-induced transactivation in ZR-75 cells. The upstream GC-rich motifs are activated independently by ERα/Sp1 in ZR-75 but not MCF-7 cells, and the downstream CCAAT sites were also E2-responsive. E2 also induced reporter gene activity in ZR-75 cells transfected with an expression plasmid containing the yeast GAL4 DNA binding domain fused to pM-NFYA and a construct containing five tandem GAL4 response elements. Subsequent studies showed that hormonal activation of pE2F-1jm1 and pM-NFYA are dependent on non-genomic pathways in which E2 activates cAMP/protein kinase A. Hormone-dependent regulation of E2F-1 gene expression in ZR-75 and MCF-7 involves different mechanisms, demonstrating the importance of cell context on transactivation pathways, even among ER-positive breast cancer cell lines. TCDD inhibited ERα-mediated responses in MCF-7 and ZR-75 cells. E2- induced E2F-1protein and mRNA levels in MCF-7 and ZR-75 cells and this response was inhibited by TCDD. Constructs containing GC-rich sites alone or in combination with the downstream NFY sites were used in transactivation studies to investigate the mechanism of inhibitory AhR-ERα crosstalk. Although TCDD inhibited E2-induced mRNA, protein and reporter gene actitivity, it was not possible to determine if the inhibitory response was due to limiting ERα protein levels due to proteasome degradation since proteaome inhibitors alone blocke hormone-dependent responses. TCDD also inhibited the cAMP/PKA pathway by inhibiting adenyl cyclase activity. In Drosophila SL-2 cells cotransfected with the GC-rich -169 to -54 region, ERα and Sp1 plasmids E2 induced transactivation in cells cotransfected with AhR/Arnt expression plasmids suggesting that the AhR complex suppressed ERα/Sp1 action. These results demonstrate that TCDD inhibits E2-dependent activation of both non-genomic and genomic pathways of ER-mediated E2F-1 gene expression.

Zeolites are crystalline, microporous aluminosilicates that have been extensively used in heterogeneous catalysis, separations, and ion-exchange operations. It has long been understood that particle size and morphology play a central role in the successful application of zeolites. This dissertation reports on controlling the morphology of all-silica zeolite, silicalite-1, made in nonionic/ionic microemulsions under conventional synthesis conditions. Silicalite-1 materials formed in microemulsion-mediated syntheses possess different morphological properties as compared to samples grown using the same synthesis mixture in the absence of the microemulsion. The work presented here is a systematic study showing how parameters such as synthesis temperature, microemulsion composition, silica precursor, alkali content, presence of salt, and the surfactant identity impact the material properties, most notably crystal morphology. In the nonionic microemulsion mediated synthesis, the work demonstrates the possibility of using microemulsions to manipulate the shape and size of silicalite-1 materials, growing both spheres and high-aspect ratio platelets. In both cases these large particles are robust aggregates of small submicron particles. Based on the results presented, a mechanism is proposed illustrating the role of both the confined space presented by the microemulsion as well as the importance of the surfactant-silicate interactions leading to the formation of the large aggregates. In the cationic microemulsion mediated synthesis, it is concluded that the surfactant??silicate interactions are primarily responsible for the modulation of crystal morphology observed. The results indicate that surfactant adsorption on the growing crystal surface, not the confined space afforded by the microemulsion, is essential. The results suggest that this may be a versatile and useful approach to controlling zeolite crystal morphology and growth of crystals obtained from conventional high-silica zeolite synthesis procedures.