N-acylethanolamines (NAEs) are family of lipid-derived signaling molecules in many organisms, which include an endocannabinoid N-arachidonoylethanolamide (anandamide, AEA, NAE 20:4). NAEs, specifically AEA plays pivotal role in mammalian neurological and physiological functions; however their metabolism and functional implications in plants are yet to be fully discovered. Unlike seed plants, bryophytes possess unique fatty acid composition that includes 20:4 and 20:5, which prompted our search for endocannabinods in moss Physcomitrella patens. To this extent, we used targeted lipidomic analyses and discovered long-chain NAEs and their corresponding N-acyl-phosphatidylethalamine (NAPE) precursors in an early land plant species. In protonemal tissues N-arachidonyl-PE and N-20:5-PE contributed to about 49% and 30%, respectively. Matured gametophytes on the other hand showed a 12% increase in N-20:4-PE and 20% decline in N-20:5-PE, relative to NAPE content in protonema. In all haploid developmental stages analyzed NAE 20:4 levels contributed to ~ 23% of the total NAE while NAE 20:5 remained as a minor component (5%). Interestingly, in Selaginella moellendorffi, an early vascular plant N-18:2-PE species was most abundant; although minor amounts of N-20:3-PE, N-20:4-PE and N-20:5-PE were present, only a small quantity of NAE 20:4 was identified among the 20C NAEs. Both AEA and it corresponding fatty acid, arachidonic acid have growth inhibitory effects in a dose dependent manner. Biological implications of anandamide and its metabolic pathway in moss are under investigation. Our data reveals an evolutionarily conserved occurrence of NAE metabolites in early land plants, with an exclusive report of AEA presence in a bryophyte.

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This doctoral dissertation work strived to contribute to the ever expanding knowledge about the mechanisms of polychlorinated biphenyl (PCB) toxicity using dietary strategies. PCBs are a family of persistent environmental pollutants with a wide range of toxicity. The toxicity of PCBs is largely dependent on the congener's chlorination pattern. Of particular interest to this work was 3,3',4,4',5-pentachlorobiphenyl (PCB 126), the most potent of the dioxin-like PCB congeners. I hypothesized that in vivo PCB 126 toxicity will be ameliorated by dietary selenium supplementation, lowered dietary copper, and dietary N-acetylcysteine (NAC) supplementation. Dioxin-like PCBs are known for diminishing hepatic selenium and selenium-dependent glutathione peroxidase (SeGPx), an antioxidant enzyme. In the first study, PCB 126 caused a dose-dependent decrease in hepatic selenium and SeGPx. Supplemental dietary selenium significantly increased hepatic selenium and SeGPx, and decreased incidence of apoptosis in these rats. The results from this study support that selenium plays a protective role, and differences in liver injuries of these rats may be reflected in their selenium status. The dose-dependent increase in hepatic copper caused by PCB 126 was a subject of interest and concern in the next study. Lowering dietary copper levels without negatively affecting the function of the essential antioxidant enzyme copper zinc superoxide dismutase did not result in reduction of PCB 126-induced toxicity. Copper metabolism was unlikely a main target of PCB 126 toxicity as increasing dietary copper did not significantly increase hepatic copper levels. Hepatic copper is highly regulated and likely does not play a significant role in PCB 126-induced toxicity. The effectiveness of NAC on restoring glutathione status and reducing PCB 126 toxicity was tested in the final study. While NAC did not restore glutathione status, NAC supplemented rats had significantly reduced severity of PCB 126-induced liver status. The results of this study are consistent with the theory that NAC has a glutathione-independent effect in improving mitochondrial energy metabolism. It also suggests that PCB 126-induced mitochondrial metabolic disruption of the liver is of greater concern than oxidative stress.

Memoria para optar al t?tulo de Periodista / Autor no autoriza el acceso a texto completo de su documento. / Rapa Nui es una isla de Chile, ubicada en el v?rtice oriental del llamado Tri?ngulo Polinesio, cuyos otros dos v?rtices corresponden a Hawai y Nueva Zelanda. Administrativamente forma, junto a la isla de Sala y G?mez, la comuna de Isla de Pascua, perteneciente a la Regi?n de Valpara?so. M?s de 3.600 kilometros de mar la separan del continente. Seg?n cuenta la tradici?n oral, fue poblada hace m?s de mil a?os, cuando en la lejana y misteriosa tierra de Hiva ocurri? un cataclismo que oblig? a su pueblo a emigrar. Luego de enviar a siete emisarios que siguieron las orientaciones del consejero Haumaka, los poderosos navegantes polinesios, guiados por el rey Hotu Matu?a, se sumergieron en las profundidades del Pac?fico en busca de nuevas tierras para habitar. As? fueron poblando todos los territorios insulares de Polinesia, hasta desembarcar en una peque?a isla, situada al centro del Oc?ano Pac?fico Sur, que luego llamar?an ?Te Pito o te Henua?: El Ombligo del Mundo. Tras su asentamiento distribuyeron territorios, construyeron casas y centros ceremoniales. Crearon una espiritualidad propia materializada en colosales esculturas de piedra, as? como tambi?n un complejo sistema escritural denominado rongo-rongo, alcanzando un alto nivel de desarrollo y organizaci?n social. Al momento del primer contacto con occidente, en 1722, el crecimiento de la poblaci?n hab?a producido una fuerte presi?n sobre los recursos, generando conflictos internos que los llevaron a una inevitable decadencia. El cinco de abril de ese a?o, este peque?o trozo de tierra flotante aparec?a ante el mundo y se le dio nombre: Isla de Pascua, por pascua de resurrecci?n. En adelante su historia se ver?a plagada de dolorosos episodios. A mediados del siglo XIX, esclavistas peruanos se llevaron a sus sabios, ?nicos que pod?an interpretar las tablillas rongo-rongo, as? tambi?n perdieron parte importante de su lengua primal. M?s tarde, el empresario franc?s Dutrou Bornier convertir?a la isla en una estancia ovejera, confinando a los rapanui a habitar dentro de ciertos l?mites y castigando duramente a quienes se atrevieran a desautorizarlo. Mientras tanto, misioneros cat?licos bautizaban por doquier, sepultando creencias que a sus ojos constitu?an pr?cticas paganas. No hubo c?mo evitar el impacto.

Memoria para optar al t?tulo de Dise?adora Industrial

Memoria para optar al t?tulo de Ingeniero Civil Industrial / El objetivo de esta memoria es dise?ar un plan de negocio para un emprendimiento que se dedica a fabricar anteojos de sol de forma artesanal que, ocupando madera aut?ctona busca diferenciarse y generar un producto exclusivo. Este es un emprendimiento que ha tenido cierta inestabilidad debido a falta de experiencia, es as? que este plan busca estabilizar la empresa y consolidarla en el mercado local. En base a una metodolog?a probada que construye sobre una profunda investigaci?n de mercado, se estructura el an?lisis estrat?gico que entrega las base para plantear los requerimientos que la empresa necesitaba. Sobre un modelo de negocio establecido, se elaboraron los planes de marketing, operaciones y recursos humanos sobre los cuales se proyectaron resultados financieros. Con la investigaci?n de mercado se concluy? que aunque peque?o, s? exist?a un mercado para este producto. Por lo tanto es importante una buena estrategia de marketing y una gesti?n muy competente para llegar al consumidor final. Se desarroll? el plan en base de tres modelos diferentes, retail tradicional, una asociaci?n con operadores tur?sticos en el sur de Chile y establecerse con ventas en internet en un portal masivo como lo es Amazon.com El plan de marketing se desarroll? con la idea de expandir los puntos de ventas de 9 a 24 que, en conjunto con el desarrollo de otros canales de venta, significa aumentar las ventas de 530 anteojos en el segundo semestre del 2014 a casi 2500 en todo el 2016. Para que el emprendimiento tenga una mayor rentabilidad, se hizo una reestructuraci?n organizacional, donde el principal cambio se vio en la creaci?n de una sociedad externa de artesanos que manufacturan el producto a un precio fijo por unidad. Esto transform? un costo fijo en un costo variable, lo que signific? una mayor contribuci?n para la empresa. En conjunto con una disminuci?n de los gastos fijos, se logr? crear un plan rentable que proyecta ingresos para el 2016 sobre los $250 millones y proyecta un VAN hasta el 2016 de $56 millones. Se concluy? que un emprendimiento requiere de un plan de negocio ?ntegro y completo y que una buena investigaci?n de mercado es fundamental para establecer las bases sobre el cual construir el negocio.

Im Neuroblastom ist die Amplifikation des MYCN-Gens, das für den Transkriptionsfaktor N-Myc kodiert, der klinisch bedeutendste Faktor für eine schlechte Prognose. Als Mitglied der onkogenen Myc-Familie induziert N-Myc die Expression von Genen, die in vielen biologischen Prozessen wie Metabolismus, Zellzyklusprogression, Zellwachstum und Apoptose eine wichtige Rolle spielen. Die Deregulation der MYCN-Expression führt zu einem charakteristischen Genexpressionsprofil und einem aggressiven Phenotyp in den Tumorzellen. In normalen neuronalen Vorläuferzellen wird N-Myc gewöhnlich sehr schnell proteasomal abgebaut. Während der Mitose wird N-Myc an Serin 62 phosphoryliert. Diese Phosphorylierung dient als Erkennungssignal für die Kinase GSK3β, die die Phosphorylierung an Threonin 58 katalysiert. Das Phosphodegron wird von Fbxw7, einer Komponente des E3-Ubiquitinligase-Komplex SCFFbxw7, erkannt. Die anschließende Ubiquitinierung induziert den proteasomalen Abbau des Proteins. Die Reduktion der N-Myc–Proteinlevel ermöglicht den neuronalen Vorläuferzellen den Austritt aus dem Zellzyklus und führt zu einer terminalen Differenzierung. In einem shRNA Screen konnte AURKA als essentielles Gen für die Proliferation MYCN-amplifizierter Neuroblastomzellen identifiziert werden. Eine Aurora-A–Depletion hatte jedoch keinen Einfluss auf das Wachstum nicht-amplifizierter Zellen. Während dieser Doktorarbeit konnte gezeigt werden, dass Aurora-A speziell den Fbxw7-vermittelten Abbau verhindert und dadurch N-Myc stabilisiert. Für die Stabilisierung ist zwar die Interaktion der beiden Proteine von entscheidender Bedeutung, überraschenderweise spielt die Kinaseaktivität von Aurora-A jedoch keine Rolle. Zwei spezifische Aurora-A–Inhibitoren, MLN8054 und MLN8237, sind allerdings in der Lage, nicht nur die Kinaseaktivität zu hemmen, sondern auch die N-Myc-Proteinlevel zu reduzieren. Beide Moleküle induzieren eine Konformationsänderung in der Kinasedomäne von Aurora-A. Diese ungewöhnliche strukturelle Veränderung hat zur Folge, dass der N-Myc/Aurora-A–Komplex dissoziiert und N-Myc mit Hilfe von Fbxw7 proteasomal abgebaut werden kann. In MYCN-amplifizierten Zellen führt diese Reduktion an N-Myc zu einem Zellzyklusarrest in der G1-Phase. Die in vitro Daten konnten in einem transgenen Maus-Modell für das MYCN-amplifizierte Neuroblastom bestätigt werden. Die Behandlung mit MLN8054 und MLN8237 führte in den Tumoren ebenfalls zu einer N-Myc-Reduktion. Darüber hinaus konnte ein prozentualer Anstieg an differenzierten Zellen, die vollständige Tumorregression in der Mehrzahl der Neuroblastome und eine gesteigerte Lebenserwartung beobachtet werden. Insgesamt zeigen die in vitro und in vivo Daten, dass die spezifischen Aurora-A–Inhibitoren ein hohes therapeutisches Potential gegen das MYCN-amplifizierte Neuroblastom besitzen. / Amplification of MYCN, encoding the transcription factor N-Myc, is one of the strongest clinical predictors of poor prognosis in neuroblastoma. As a member of the oncogenic Myc family, N-Myc activates genes that are involved in several biological processes like metabolism, cell cycle progression, cell growth and apoptosis. Deregulation of MYCN expression leads to a distinct gene expression profile and an aggressive phenotype in neuroblastoma cells. In normal neuronal progenitor cells, N-Myc is rapidly degraded by the ubiquitin-proteasome system. N-Myc degradation is controlled by two phospho-sites. During mitosis, Cyclin B/Cdk1 phosphorylates N-Myc at serine 62, which primes the protein for a second phosphorylation at threonine 58 via GSK3β. This phospho-degron provides a recognition site for Fbxw7, an F-box protein of the E3-Ligase complex SCFFbxw7, leading to destabilisation of the N-Myc protein. Mitotic degradation of the N-Myc protein allows progenitor cells to exit the cell cycle and enables terminal differentiation. Our group had previously identified AURKA as a gene that is required for cell growth in MYCN-amplified neuroblastoma cells but not essential for cells lacking MYCN. Here, we show that Aurora-A counteracts the Fbxw7-mediated degradation, and that the interaction between Aurora-A and N-Myc is cruical for N-Myc stabilization. Surprisingly, Aurora-A stabilizes the transcription factor in a kinase-independent manner. Interestingly, two Aurora-A-Inhibitors, MLN8054 and MLN8237, inhibit the kinase activity but also destabilize the N-Myc protein. These inhibitors induce an unusual conformation of the kinase domain and resulting in the dissociation of the N-Myc/Aurora-A complex. We demonstrate that the disruption of the complex promotes Fbxw7-mediated degradation of N-Myc. Inhibitor treatment in neuroblastoma cells leads to a cell cycle arrest in G1-phase. In a transgenic mouse model of MYCN-driven neuroblastoma, treatment causes downregulation of N-Myc protein levels, differentiation of the tumor cells and complete tumor regression in the majority of tumors. Consistent with the tumor reduction, treatment with MLN8054 and MLN8234 results in an extension of survival of the transgenic mice. Collectively, these results demonstrate that the Aurora-A–Inhibitors MLN8054 and MLN8237 are potential therapeutics against MYCN-amplified Neuroblastoma.

This thesis introduces a " new " international relations theorist who is also, in fact, one of the oldest of international relations theorists. Mencius (Meng Zi 371-289 BCE) is well known to students of Chinese culture as a key figure in the history of Confucianism and in the history of China: the second sage no less. Yet modern scholars usually study him, if he is studied at all, for an idea of how " Chinese" think rather than as a thinker worth studying for his own sake. I decided to study Mencius as an international relations theorist in response to the common criticism that international relations, the academic discipline, is too &quote; eurocentric". This criticism has been made many times. My goal however was not to repeat the criticism but to find a major thinker outside the euro-centric world. Such a thinker could be presented as an international relations theorist and thus demonstrate that we should indeed heed the critics of euro-centrism and make studies outside the euro-centric framework rather than simply announce that international relations is euro-centric and proceed to make another euro-centric study. This study of Mencius, qua international relations theorist, illustrates that point. Mencius lived in a world of warring states and tried to bring peace and order to that world. In the course of doing so he developed a sophisticated international relations theory which can be used to analyse events in the contemporary world. In this thesis I offer a comparison of Mencius and Kenneth N Waltz, a famous contemporary international relations theorist, to show the strength of Mencius’ theory. Mencius argues that an anarchical system of states can become an ordered one if the order is legitimised by what he calls " benevolence" , an ethic based on universal values. Waltz argues that values can never underpin an order that runs contrary to states’ interests. Once an anarchical international system has commenced balance of power formations will rise to stop it moving towards order. The disagreement between Mencius and Waltz is profound; it is not simply about the patterns of international relations ii systems but whether a policy of reform based on values can succeed in the international arena. Waltz, and the vast majority of international relations theorists, answer that question in the negative. This " ruling out" of progress distinguishes the study of international politics from the study of domestic politics. Mencius does not rule it out; he offers hope for progress and reform in the international arena. Thus the attempt to address one problem, euro-centrism, led me to approach the greatest problem, the denial of a role for values in the international world. The thesis sets out to show that Mencius’ international relations theory has greater explanatory power than the theory of Waltz, the arch positivist. The thesis also seeks to demonstrate that it is a mistake to rule values out of international politics.

Biofertilisers are rhizosphere microorganisms inoculated to reduce the need for N or P fertiliser application and maximise plant growth and nutrition, resulting in greater grain yield and N or P content. This study aimed to evaluate the effectiveness of diazotrophic bacteria isolated from the rhizosphere of wheat in Victoria, Australia. This thesis shows that N2-fixing Burkholderia species have great potential as biofertilisers on wheat productivity. In Chapter 2, strains of bacteria were isolated from wheat-growing soils in main Victoria wheat belt at Horsham and Birchip in North West Victoria. Strains were identified as Burkholderia spp. by their closest matches in the 16S DNA and by morphology and physiology. In Chapter 3, one selected strain from each of Birchip and Horsham were used to inoculate wheat in a pot trial in a glasshouse during winter-spring. Soil was collected on site from wheat fields. Pots were inoculated with these strains to evaluate the effects of Burkholderia inoculum as biofertiliser on the plant growth and yield. Different nitrogen sources (urea 46% N and ammonium sulphate 21% N) were used as fertiliser at one of four levels (0, 50, 100 and 150 kg N/ ha). There was a greater effect in Birchip than in Horsham soil and with ammonium sulphate than with urea due to waterlogying in Horsham soil. In Chapter 4, field-grown wheat was inoculated with the same strains of Burkholderia. Three experiments were carried out in plots at two sites, dryland and irrigated fields at Horsham and a dryland field at Birchip, during the winter wheat season of 2006, to evaluate the effect of Burkholderia species inoculum and different types of nitrogen source at one of four levels of added N (0, 50, 100 and 150 kg N/ha) on wheat growth and yield. The effects of both bacterial inoculation and N fertiliser on growth promotion and grain yield. Since 2006 was a year of drought, dry land crops were unsuccessful. Grain %N as well as total N content in grain per area in the Horsham irrigated field increased with increasing N fertiliser levels up to 100 kg N/ha. In Chapter 5, acetylene reduction (ARA) activity was measured in the pots for both inoculated and uninoculated plants at various growth stages and populations of nitrogen-fixing bacteria associated with the wheat roots and bulk soil were measured in addition to biomass and N content of plants and grain. Molecular tracing using specific primers showed that the inoculum was present only in inoculated treatments. Up to 60% of the increased N content of the grain in inoculated plants was potentially derived from nitrogen fixed by the inoculum in the rhizosphere. It was concluded that the most significant result due to inoculation was the consistent maximal increase of N content in grain in inoculated treatments with ammonium sulphate fertiliser at 100 kg N/ha. Inoculation with Burkholderia consistently increased %N in wheat grain, with the potential benefit of decreasing the production cost and reducing use of chemical fertilisers.

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