The researcher of most varieties of Mixtec (Oto-Manguean) is faced with a high level of surface alternations whereby the tones of some words vary according to their context. Early researchers, such as Kenneth L Pike, accounted for these differences by assigning morphemes to different classes according to the effect morphemes have on the following morpheme. However a much more satisfactory explanation can be achieved by positing the presence of floating tones which are the result of one of three processes: right-ward shift of underlying tones, loss of CV segments, or the delinking of Low tones. The main focus of this thesis is to account for the tonal association patterns of Southeastern Nochixtlán Mixtec (MXY). As background we present a brief summary of the work of earlier researchers, including claims about the relationship between stress and High tone, (Chapters 2 and 3), and then in Chapter 4 we show how autosegmental phonology provides a more satisfactory account for these published data. In Chapter 5 we show that in spite of surface differences, when the surface tones of morphemes are compared across varieties, morphemes can be shown to belong to tonal categories which reflect a previous stage of Mixtec. Chapters 6 to 10 present unpublished data from MXY. In Chapter 6 we show that underlying tones of disyllabic morphemes usually align at the right edge of their sponsoring morpheme. We also demonstrate how tones are provided for the unspecified initial syllables. In this chapter we also present acoustic data to show that underlying Mid tones participate in phonological processes which default Mid tones do not. Chapter 7 presents more data to show MXY tonal association patterns, including the behaviour of floating High tones such as their tendency to align at the right edge of prosodic words. Chapter 8 describes the complex tonal association of floating High tones sponsored by four verbal prefixes. We show that the resulting surface forms depend not only on the underlying tones sponsored by the verb root, but the form of the verb stem with which it associates. In Chapter 9 we turn to examine whether there is any relationship between stressed syllables and High tone. We analyse acoustic data to show that initial syllables of roots show statistically significant increased duration. By examining the tonal association patterns, we conclude that in MXY, the association of High tones is governed by alignment rather than the locus of stress. Based on the findings of Chapter 9, in Chapter 10 we look at the locus of stress in two different contexts: one, stress found in compound words; and two, stress in verb roots which co-occur with prefixes. In all these contexts we see no predilection for High tones to associate with the stressed syllable. In this chapter we also look at contexts in which Low tone spreads. Chapter 11 pulls together the data presented in Chapters 6 to 10 and presents them against a theoretical background of the interaction between prosody and syntax.

La thérapie génique est une approche thérapeutique proposant d’utiliser des acides nucléiques (ADN,ARN, oligonucléotides) comme médicament. Les poly(éthylènimine)s linéaire (lPEI) et branchée (bPEI) sont des vecteurs de références pour le transfert de gènes, dans le domaines des polymères cationiques. L’objectif de ces travaux est de modifier la lPEI par des dérivés de la L-histidine-N-acryloyle, la L-arginine-Nacryloyleou le 1-adamantane méthylamine-N-acryloyle, en utilisant la réaction de Michaël. Les études physico-chimiques de ces polymères mettent en évidence le comportement de ces vecteurs en solution aqueuse et tamponnée, dont les effets peuvent avoir une influence non négligeable sur la complexation de l’ADN et le transfert de gène. La poly(éthylènimine-co-éthylènimine-N-éthylamide-N-2(3(3H-imidazol-4-yl) propionate de sodium) (lPEI-N-his) comportant 10 à 20% de greffons histidine a permis d’obtenir d’excellents résultats en transfection in vitro. Ces polymères ont montrés une très faible cytotoxicité sur les différentes lignées cellulaires utilisées pour cette étude. / Gene therapy is a therapeutic approach aiming at introducing corrective genetic materials into a cellin order to alleviate the symptoms of a disease. The linear (lPEI) and branched (bPEI) poly(ethylenimine) arethe gold standard among the polymeric vectors. The aim of this work is to modify the lPEI by N-acryloyl-Lhistidine,N-acryloyl-L-arginine and N-acryloyl-1 adamantane methylamine residue using the Michaelreaction to improve the transfection efficiency of cationic polymers. The physicochemical studies of thesepolymers are undertaken in aqueous and buffer solutions, and a higher buffering property of these polymersis emphasized. The polyplexes formation is found to be influenced by the behaviour of the macromolecules in the buffer solution. Transfection experiments are conducted in vitro, His-lPEI bearing 10 to 20% histidine residues allowed remarkable transfection efficiency (up to 95%) compared to unmodified lPEI. Moreremarkably, this new kind of cationic polymers showed very low cytotoxicity on cell lines.

No description available.

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.

No description available.

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.