The dissertation describes Pd0-catalyzed formal 1,3-diaza-Claisen rearrangement and the design and development of cationic 1,3-diaza-Claisen rearrangement. Our previous work has shown that isocyanates react with azanorbornenes and azabicyclo[2.2.2]octenes under thermal conditions to afford zwitterionic intermediates that undergo a thermal 1,3-diaza-Claisen rearrangement to give both ureas and isoureas. However, some azanorbornenes and azabicyclooctenes failed to rearrange or proceeded in low yields. To address these challenging substrates for the thermal 1,3-diaza-Claisen rearrangement, we have developed a Pd0-catalyzed formal 1,3-diaza-Claisen rearrangement. Interestingly, under Pd0-catalyzed condition, both isocyanates with electron-withdrawing groups and isocyanates without electron-withdrawing groups react with azanorbornenes and azabicyclo[2.2.2]octenes to provide ureas as the only products in high yields. More importantly, the reactions that failed under thermal conditions were all successful under Pd0-catalysis. In addition to azanorbornenes and azabicyclo[2.2.2]octenes, other ring systems were also investigated. Pd0 catalysis has broadened the scope of tertiary allylic amines that react with isocyanates to afford 1,3-diaza-Claisen rearrangement products. In the presence of p-TsCl and NEt3, allylaminopropyl benzyl ureas were initially dehydrated to form protonated carbodiimides whose presence was confirmed by the infrared absorption frequency at 2100 cm-1 which is the characteristic band of -N=C=N-; then the in situ generated protonated carbodiimides were poised for further cationic 1,3-diaza-Claisen rearrangement to afford synthetically challenging guanidines. The effect of acid on the rearrangement was ascertained by the fact that no rearrangement product was observed by simply heating free base carbodiimide 3.10 in benzene at reflux. Other dehydration reagents, such as Tf2O, Ts2O, MsCl were also investigated, and none of them provide satisfactory results. A selection of allyamino benzyl ureas with different tether length, substituents, or in varied ring systems, were synthesized to explore the scope of this methodology. This methodology works best at allylaminopropyl benzyl ureas, and the substituents on the benzyl group does not seem to affect the reaction rate in a significant way.

1. The key glutarimides were obtained via facile [3+3] annulation. The method featured regioselective introduction of C-6 substituents in glutarimides, and application to the synthesis of natural products and pharmaceuticals. 2. The synthesis of a novel substituted aza-ticyclic compounds through the use of the intramolecular Diels-Alder reaction is present. Further aromaticzation in the present of BF3 to afford 2,3-dihydro-isoindolone.The use of method for the rapid preparation of a substituted isoindolone framework is described.

1. A new route towards the synthesis of drugs and alkaloids by using N-alkylsulfonylacetamide and unsaturated ester as starting materials via stepwise [3+3] annulation. 2. The application of regioselective nucleophilic addition of glutarimide which prepared via stepwise [3+3] annulation. 3. Synthesis of (E)-3-Substituted-N-Alkylacryl-amides and 3,4-Disubstituted Succinimides by using N-alkylsulfonyl-acetamide and alkyl halides as starting materials in the different reaction condition.

No description available.

Glioblastoma is the most malignant form of brain cancer. Due to its aggressive nature, extensive research has been performed, but little progress has been made in identifying effective treatment options. Glycogen synthase kinase-3 (GSK-3) is a ubiquitous, multifaceted protein kinase. Previous studies have shown that small molecule inhibitors of GSK-3 block the migration of glioblastoma cells and may prevent spread of tumor in the brain. However, these studies were performed using non-selective GSK-3 inhibitors (LiCl and an indirubin derivative, BIO); thus, it was unclear whether GSK-3 was the most important target. In this study, we used recently generated highly selective GSK-3 inhibitors (CHIR99021, AZD1080, and AZD2858, as well as BIO) to investigate these questions. These were applied to four glioblastoma cell lines: G30, G9, U251, and U1242, in three migration assays: transwell, spheroid, and wound healing (scratch) assay to further assess the suitability of GSK-3 as a target in glioblastoma. We also utilized the ATP Luciferase reporter assay for cell viability to assess the influence of our panel of drugs on cell migration versus viability. In addition, the TOPFlash Luciferase reporter assay was performed as an indicator of the level of GSK-3 inhibition. The TOPFlash assay showed that all GSK-3 inhibitors were able to increase luciferase levels. This indicates that GSK-3 was inhibited in our cells after drug treatment. The transwell assays showed us that the GSK-3 inhibitors were able to block migration significantly in all cell lines tested in a dose-dependent manner. The effectiveness of GSK-3 inhibition in the three-dimensional collagen spheroid assays was cell line-dependent, with the non-selective GSK-3 inhibitor BIO showing the most potent effects. Cell migration was not blocked by any of the three selective GSK-3 inhibitors in the wound healing scratch assay. Thus we have found that the three distinct highly selective inhibitors of GSK-3 block glioblastoma cell migration, but only work consistently in the transwell assay. Therefore, we conclude that GSK-3 might be important in the contraction and morphological changes necessary for glioblastoma cells to migrate through the 8 micron pores in the transwell. Further investigation into this observation is necessary. Though results were variable between assays, we conclude that the inhibition of GSK-3 is a promising potential therapeutic strategy for glioblastoma treatment.

The chaperone proteins designated 14-3-3 are expressed in all eukaryotic cells; they help to regulate signal transduction pathways controlling proliferation, differentiation, and survival. They associated directly or indirectly with proliferative signal-transducing proteins such as PKC, MEK kinases, PI3-kinase and Raf. In human, there are seven isotypes of 14-3-3 genes: £]¡]beta¡^¡B£^¡]gamma¡^¡B£`¡]epsilon¡^¡B£b¡]eta¡^¡B£m¡]sigma¡^¡B£n/£c¡]tau/theta¡^ and£a¡]zeta¡^, some of which would be pseudogenes, and yeast and plant each have two and fifteen genes. Althought these genes are diverse, all 14-3-3 isotypes share many conservation domains in amino acid sequences. The previous studies have suggested that 14-3-3 sigma is most directly linked to cancer because it is thought to function as a tumor suppressor by inhibiting cell-cycle progression. In tumor formation, inactivation of 14-3-3 sigma occurs with high frequency. More importantly, expression of 14-3-3 sigma is silenced in most breast cancer cells. The 14-3-3 sigma protein is associated with cyclin E-CDK2 complex as well as cyclin B-CDC2 complex and mediated their inactivation by cytoplasmic localization and causing cell-cycle arrest in G2 and G1. However, the roles of other 14-3-3 isotypes in the formation of breast cancer are controversial in published reference. The aim of this study was to determine the differential expressions of 14-3-3 gamma in non-tumor tissues and corresponding tumor tissues. Amplification and overexpression of 14-3-3 gamma in DNA, RNA, and protein of breast tumor tissues were found by experiments of RT-PCR, Western blot analysis, immunohistochemistry and Real-time PCR. However, the role of 14-3-3 gamma in the formation of breast cancer requires further study.

Diese experimentelle Arbeit untersucht die Interaktionen diverser Substanzen (Succinat, Glutamat, Glutathion, Glycin, Cystein, Fumarat, N-Oxalyl-Glycin, Glycylglycin) mit dem Natrium-abhängigen Dicarboxylat-Transporter (hNaDC3). Bei den aufgezählten Substraten handelt es sich um Mono-und Dicarboxylate und Abkömmlinge dieser Substanzklassen. Um Wechselwirkungen und unter Umständen Überlappungen mit anderen Transportproteinen zu vermeiden, wurde Ribonuklein¬säure (cRNS) des hNaDC3-Transporters in Oozyten des südafrikanischen Krallenfrosches (Xenopus laevis) injiziert. Oozyten besitzen selbst sehr wenige endogene Transportproteine. Sie können fremde cRNS transkribieren und das fertige Protein, für das diese cRNS kodiert, in ihre Membran einbauen, welches dann z.B. mit der Zwei-Elektroden-Spannungsklemm-Methode (TEVC) untersucht werden kann. Das Dicarboxylat Succinat dient dabei jeweils als Test- und Referenzsubstrat, da es unter der TEVC die höchsten Substrat-mediierten Ströme induziert. Ströme vergleichbarer Amplitude wurden von Fumarat, solche von etwas niedriger Amplitude von N-Oxalyl-Glycin hervorgerufen. Im Gegensatz dazu waren unter Perfusion von Glutathion, Glutamat, Glycylglycin und Cystein sehr geringe oder keine Einwärtsströme mehr registrierbar. Aus diesen Versuchen lassen sich Struktur-Wirkungsbeziehungen ablesen: • Dicarboxylate mit einem Kohlenstoffgrundgerüst von 4 oder 5 C-Atomen, wie Succinat, Fumarat und N-Oxalyl-Glycin, interagieren mit dem hNaDC3 und induzieren Substrat-abhängige Ströme, • NH2-Gruppen, wie in Glutamat und Glutathion, erschweren die Interaktion mit dem hNaDC3, • SH-Guppen, wie in Cystein, erschweren ebenfalls die Interaktion mit dem hNaDC3.

No description available.

This dissertation investigates the challenges that Deaf adults encounter at the task of learning computer literacy skills. Deaf adults who communicate using South African Sign Language (SASL) come from poor socio-economic backgrounds are not familiar with the written form of English. They rely on interpreters and Deaf teachers to translate written text into SASL for them to learn computer literacy skill. We present our theme of support, in which Deaf people learn via an intermediary, a teacher or facilitator, in intermediated supported learning. We propose a shift from intermediated supported learning to multimedia supported learning which is most appropriate for the context. Using Community-based co-design we implement two systems: an authoring tool to support lesson content creation by the teacher and a mobile prototype that uses sign language videos to provide computer literacy instruction. We evaluate the two systems to evaluate if they support multimedia-supported learning. The authoring tool allowed the facilitator to create tailored lessons for the Deaf learners using pre-recorded SASL videos and images. The Deaf learners demonstrated ability to do self-paced learning while using the mobile system, better suited to Deaf learners with basic exposure to computer literacy skills.

Aquesta tesi doctoral -en format d'articles i amb esment de “Doctorat Internacional”- es basa en una recerca realitzada entre Barcelona (Espanya) i Santo Domingo (República Dominicana), des de 2010 fins a 2012. L'objectiu general de l'estudi és analitzar com els estigmes de la condició immigrant i de la negritud repercuteixen en les trajectòries escolars i en la construcció de les identitats de la joventut d'origen dominicà en la perifèria de Barcelona. El context clau de l'estudi és l'escola secundària, investigada a partir de la teoria de la reproducció social: les escoles no serien institucions basades en la igualtat d'oportunitats, sinó mecanismes per a la perpetuació de les desigualtats. La metodologia de la recerca és etnogràfica, amb un enfocament transnacional. El treball de camp es va realitzar tant en la societat d'acollida, com en la societat d'origen. Les tècniques clau van ser l'observació participant -dins i fora de les aules- i la recollida de fonts orals. Es van construir 25 biografies de joves dominicans; a més, entre els dos contextos etnogràfics es van entrevistar –a nivell individual o grupal- 160 actors socials que participen en les trajectòries vitals d'aquests joves: a) professionals educatius; b) altres professionals; c) familiars; d) altres joves. Els resultats de l'estudi detecten les contradiccions de l'escola espanyola en relació a la presència immigrant. A més, exploren els processos de fracàs escolar generalitzat de la població dominicana, indagant sobre els dispositius -oficials i ocults- que s'implementen a l'escola. Al mateix temps, s'analitzen les representacions racials que es construeixen mitjançant el procés migratori –com per exemple el descobriment de la negritud en la societat d'arribada-, que fan visible la variabilitat de la línia del color. Finalment, es reflexiona sobre les formes d'agència, detectant algunes tàctiques –com les que es vinculen als grups juvenils- que els actors socials estudiats utilitzen per gestionar l'estigma. Les conclusions finals estan pensades en termes de policy recommendations. / Esta tesis doctoral -en formato de artículos y con mención de “Doctorado Internacional”- se basa en una investigación realizada entre la periferia de Barcelona (España) y Santo Domingo (República Dominicana), desde 2010 hasta 2012. El objetivo general del estudio es analizar cómo los estigmas de la condición inmigrante y de la negritud repercuten en las trayectorias escolares y en la construcción de las identidades de la juventud de origen dominicano. El contexto clave del estudio es la escuela secundaria, investigada a partir de la teoría de la reproducción social: las escuelas no serían instituciones basadas en la igualdad de oportunidades, sino mecanismos para la perpetuación de las desigualdades. La metodología de la investigación es etnográfica, con un enfoque transnacional. El trabajo de campo se ha realizado tanto en la sociedad de acogida, como en la sociedad de origen. Las técnicas clave han sido la observación participante -dentro y fuera de las aulas- y la recogida de fuentes orales. Se han construido 25 biografías de jóvenes dominicanos; además, entre los dos contextos etnográficos se han entrevistado -a nivel individual o grupal- 160 actores sociales que participan en las trayectorias vitales de estos jóvenes: a) profesionales educativos; b) otros profesionales; c) familiares; d) otros jóvenes. Los resultados del estudio detectan las contradicciones de la escuela española en relación a la presencia inmigrante. Además, los resultados exploran los procesos de fracaso escolar generalizado de la población dominicana, indagando sobre los dispositivos -oficiales y ocultos- que se implementan en la escuela. Al mismo tiempo, se analizan las representaciones raciales que se construyen a través del proceso migratorio –como por ejemplo el descubrimiento de la negritud en la sociedad de llegada-, que visibilizan la variabilidad de la línea del color. Por último, se reflexiona sobre las formas de agencia, detectando algunas tácticas -como las que se vinculan a los grupos juveniles- que los actores sociales estudiados utilizan para gestionar el estigma. Las conclusiones finales están pensadas en términos de policy recommendations. / This PhD dissertation -by articles and with a "International PhD" mention- is based on research carried out between the suburbs of Barcelona (Spain) and Santo Domingo (Dominican Republic), from 2010 to 2012. The overall objective of the study is to analyze how the stigma of the immigrant status and the stigma of blackness impact school careers and the construction of identities by the youth of Dominican origin. The key context of the study is the High School, investigated from the theory of social reproduction: schools would not be institutions based on equality of opportunity but mechanisms for perpetuating inequalities. The research methodology is ethnographic, with a transnational approach. The fieldwork has been carried out both in the host society, and in the society of origin. Key techniques are participant observation -inside and outside the classroom- and the collection of oral sources. 25 biographies of young Dominicans have been constructed. In addition, in two ethnographic contexts 160 social actors involved in the life trajectories of these young people, have been interviewed -individually or at group level-: a) educational professionals b) other professionals; c) family; d) peers. Study results detect contradictions of the Spanish school in relation to the immigrant presence. Also, study results explore the widespread school failure processes of the Dominican population, inquiring about mechanisms -official or hidden practices- that are implemented in school. At the same time, the investigation analyzes the racial representations that are constructed through the migration process -such as, for example, the discovery of blackness in the host society-, which makes the variability of the color line more visible. Finally, a reflection on the forms of agency has been made, detecting some tactics -such as those linked to youth groups- that the social actors of this study use to manage stigma. The final conclusions are designed in terms of policy recommendations.