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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
171

Description multifractale unifiée du phénomène d'intermittence en turbulence Eulérienne et Lagrangienne

Chevillard, Laurent 21 September 2004 (has links) (PDF)
Le formalisme multifractal de Parisi et Frisch, ainsi que l'approche du propagateur de Castaing et collaborateurs, permettent de décrire de manière quantitative, dans le domaine inertiel, les statistiques des incréments de vitesse longitudinale en turbulence pleinement développée. Dans ce mémoire de doctorat, nous montrons que la physique liée aux effets dissipatifs, complètement pilotée par le nombre de Reynolds local, a des conséquences non triviales sur les statistiques des incréments de vitesse Eulérienne. A l'aide d'arguments dimensionnels simples, nous proposons une formalisation précise, dans le cadre du formalisme multifractal, de "l'accélération" du propagateur observée dans le domaine dissipatif intermédiaire, entre le domaine inertiel et le domaine dissipatif profond dans lequel les statistiques des incréments deviennent indépendantes de l'échelle. Nous montrons en particulier qu'il est possible, pour un nombre de Reynolds donné, de calculer la densité de probabilité des incréments de vitesse à toutes les échelles, moyennant une fonction paramétrable DE(h), qui sera assimilée au spectre des singularités dans la limite des nombres de Reynolds infiniment grands. Nous discutons aussi comment adapter notre formalisme pour rendre compte du phénomène de Skewness. Nous montrons qu'il est possible de généraliser notre approche à une description unifiée des fluctuations de vitesse Lagrangienne. Nous comparons nos prédictions théoriques avec des données expérimentales et numériques. Cette étude permet d'estimer le spectre DL(h) des singularités de la turbulence Lagrangienne et d'en démontrer le caractère universel. Nous évoquons ensuite la possibilité d'établir une transformation formelle entre les spectres des singularités de la turbulence Eulérienne DE(h) et de la turbulence Lagrangienne DL(h). Pour conclure, nous généralisons notre approche aux statistiques d'ordre supérieur afin de tester divers modèles de cascade sur des données expérimentales et numériques.
172

Early high Cascade silicic volcanism : analysis of the McKenzie Canyon and Lower Bridge tuff

Eungard, Daniel W. 31 July 2012 (has links)
Silicic volcanism in the central Oregon Cascade range has decreased in both the size and frequency of eruptions from its initiation at ~40 Ma to present. The reasons for this reduction in silicic volcanism are poorly constrained. Studies of the petrogenesis of these magmas have the potential for addressing this question by providing insight into the processes responsible for producing and erupting silicic magmas. This study focuses on two extensive and well-preserved ash-flow tuffs from within the ~4-8 Ma Deschutes Formation of central Oregon, which formed after the transition from Western Cascade volcanism to the modern High Cascade. Documentation of outcrop extent, outcrop thickness, clast properties, and samples provide the means to estimate a source location, minimum erupted volumes, and to constrain eruptive processes. Major and trace element chemistry of glass and minerals constrain the petrogenesis and chemical evolution of the system. The tuffs selected for this study, the Lower Bridge and McKenzie Canyon, are the first known silicic units originating from the Cascade Arc following the reorganization from Western Cascade to High Cascade Volcanism at ~8 Ma. These eruptions were significant in producing a minimum of ~5 km�� DRE each within a relatively short timeframe. These tuffs are sourced from some vent or edifices related to the Three Sisters Volcanic Complex, and capture an early phase of the volcanic history of that region. The chemical composition of the tuffs indicates that the Lower Bridge erupted predominately rhyolitic magma with dacitic magma occurring only in small quantities in the latest stage of the eruption while McKenzie Canyon Tuff erupted first as a rhyolite and transitioned to a basaltic andesite with co-mingling and incomplete mixing of the two magma types. Major and trace element concentrations in minerals and glass indicate that the basaltic andesite and rhyolite of the McKenzie Canyon Tuff were well convected and stored in separate chambers. Geothermometry of the magmas indicate that the rhyolites are considerably warmer (~850��) than typical arc rhyolites. Trace element compositions indicate that both the Lower Bridge and McKenzie Canyon Tuff experienced mixing between a mantle derived basaltic melt and a rhyolitic partial melt derived from gabbroic crust. Rhyolites of the Lower Bridge Tuff incorporate 30-50% partial melt following 0->60% fractionation of mantle derived melts. The McKenzie Canyon Tuff incorporates 50-100% of a partial melt of a mafic crust with up to 15% post mixing fractionation. The results of this study suggest that production of voluminous silicic magmas within the Cascade Arc crust requires both fractionation of incoming melts from the mantle together with mixing with partial melts of the crust. This provides a potential explanation for the decrease in silicic melt production rates from the Western Cascades to the High Cascades related to declining subduction rate. As convergence along the Cascade margin became more oblique during the Neogene, the consequent slowing rate of mantle melt production will result in a net cooling of the crust, inhibiting the production of rhyolitic partial melts. Without these partial melts to provide the rhyolitic end member to the system, the system will evolve to the mafic melt and fractionation dominated regime that has existed along Cascadia throughout the Quaternary. / Graduation date: 2013
173

THE ROLE OF SHARKS IN MARINE ECOSYSTEMS: EVALUATING OVEREXPLOITED MARINE FISH COMMUNITIES TO DETECT LONG-TERM EFFECTS OF PREDATOR REMOVAL

Ferretti, Francesco 15 December 2010 (has links)
Elasmobranchs are among the oldest and most successful predators in the ocean, yet one of the most vulnerable to the direct and indirect effects of fishing. Many populations are rapidly declining around the world, and an increasing number is listed as threatened or endangered. The broader ecosystem consequences of these declines, and whether other marine predators can replace sharks, are open questions. In this thesis, I used a diverse set of data and modeling techniques to analyze long-term changes in elasmobranch populations in the Mediterranean Sea, and the consequences of shark declines on marine ecosystems. Because of its long history of fishing, the Mediterranean offers a unique perspective on the response of marine communities to exploitation over long time scales. Here, I reconstructed the history of elasmobranch exploitation over the past 200 years in pelagic, coastal and demersal communities. Results were combined meta-analytically to derive a general pattern of change for the entire region. Overall, I detected multiple cases of regional species extirpations, a strong correlation between historical intensity of exploitation and the stage of community degradation, and some cases of compensatory species increases. My results suggest that compared to other marine ecosystems worldwide, the Mediterranean Sea might be in an advanced stage of overexploitation. To gain more general conclusions about the patterns and consequences of shark declines in the ocean, I reviewed and reanalyzed documented changes in exploited elasmobranch communities around the world, and synthesized the effects of sharks on their prey and wider communities. This work revealed that sharks are abundant and diverse in little exploited or unexploited marine ecosystems but vulnerable to even light levels of fishing. The decline in large sharks has reduced natural mortality in a range of their prey, contributing to changes in abundance, distribution, and behaviour of marine megafauna that have few other predators. In some cases, this has resulted in cascading changes in prey populations and food-web structure. Overall, my thesis greatly enhanced our knowledge about the critical state of elasmobranchs in the Mediterranean Sea and the consequences of the declines of these important marine predators on marine ecosystems.
174

Synthèse et réactivité d'énamides, de la diversité moléculaire à la synthèse de molécules bioactives et/ou naturelles / Synthesis and reactivity of enamides, toward the molecular diversity and the synthesis of bioactive and/or natural compounds

Gigant, Nicolas 26 October 2012 (has links)
La nécessité grandissante de disposer d’une large librairie de diverses petites molécules pour le screening biologique constitue une puissante force motrice pour les chimistes organiciens et requiert en amont le développement de méthodologies rapides et efficaces. Dans ce cadre, nous nous sommes plus particulièrement intéressés à la fonctionnalisation d’énamides qui représentent des blocs moléculaires intéressants permettant d’introduire des fonctionnalités aminées dans des systèmes variés. Notre objectif a été de synthétiser des petites bibliothèques de molécules azotées à partir de substrats communs tout en mettant en oeuvre les différentes stratégies de la synthèse orientée vers la diversité et en s’attachant à respecter les règles suivantes : économie d’atomes, processus catalysés, synthèses rapides en peu d’étapes et contrôle de la stéréoselectivité. Dans un premier temps, nous avons principalement synthétisé divers énamides, nous permettant par la suite de développer des méthodologies innovantes et d’accéder à des « structures privilégiées » ou des fragments clés présents dans des produits naturels ou dans des substances potentiellement biologiquement actives en mettant en jeu des processus variés telles que des réactions d’aza-Michael, d’oxyamidation ou en cascade et la chimie du palladium avec de la CH insertion, des dioxoazoborocanes ou encore l’utilisation de l’auxiliaire chiral SAMP. / The continuing demand to synthesize new and original collections of small molecules for the biological screening is an attractive subject for organic chemists and requires upstream the development of fast and easy synthetic methods. In this context, we decided to focus particularly on the functionalization of enamides which represent valuable building blocks in order to introduce nitrogen based functionality into various organic systems. Our objective was to synthesize new nitrogen containing compound libraries starting from common substrates by applying Diversity-Oriented Synthesis strategy and following these rules: atom economy, catalyzed reactions, fast synthesis in few steps and control of stereoselectivity. Firstly we mainly synthesized enamides. Thereafter, we developped efficient methodologies giving access to motifs frequently found in “privileged structures” or key scaffolds present in natural products or potential bioactive compounds thanks to various processes like aza-Michael, oxyamidation or cascade reactions, palladium chemistry with CH activation, dioxoazoborocanes or chiral auxiliary SAMP.
175

Stall Flutter of a Cascade of Blades at Low Reynolds Number

Jha, Sourabh Kumar January 2013 (has links) (PDF)
Due to the requirements for high blade loading, modern turbo‐machine blades operate very close to the stall regime. This can lead to flow separation with periodic shedding of vortices, which could lead to self induced oscillations or stall flutter of the blades. Previous studies on stall flutter have focused on flows at high Reynolds number (Re ~ 106). The Reynolds numbers for fans/propellers of Micro Aerial Vehicles (MAVs), high altitude turbofans and small wind turbines are substantially lower (Re < 105). Aerodynamic characteristics of flows at such low Re is significantly different from those at high Re, due in part to the early separation of the flow and possible formation of laminar separation bubbles (LSB). The present study is targeted towards study of stall flutter in a cascade of blades at low Re. We experimentally study stall flutter of a cascade of symmetric NACA 0012 blades at low Reynolds number (Re ~ 30, 000) through forced sinusoidal pitching of the blades about mean angles of incidences close to stall. The experimental arrangement permits variations of the inter‐blade phase (σ) in addition to the oscillation frequency (f) and amplitude; the inter‐blade phase angle (σ) being the phase difference between the motions of adjacent blades in the cascade. The unsteady moments on the central blade in the cascade are directly measured, and used to calculate the energy transfer from the flow to the blade. This energy transfer is used to predict the propensity of the blades to undergo self‐induced oscillations or stall flutter. Experiments are also conducted on an isolated blade in addition to the cascade. A variety of parameters can influence stall flutter in a cascade, namely the oscillation frequency (f), the mean angle of incidence, and the inter‐blade phase angle (σ). The measurements show that there exists a range of reduced frequencies, k (=πfc/U, c being the chord length of the blade and U being the free stream velocity), where the energy transfer from the flow to the blade is positive, which indicates that the flow can excite the blade. Above and below this range, the energy transfer is negative indicating that blade excitations, if any, will get damped. This range of excitation is found to depend upon the mean angle of incidence, with shifts towards higher values of k as the mean angle of incidence increases. An important parameter for cascades, which is absent in the isolated blade case is the inter‐blade phase angle (σ). An excitation regime is observed only for σ values between ‐450 and 900, with the value of excitation being maximum for σ of 900. Time traces of the measured moment were found to be non‐sinusoidal in the excitation regime, whereas they appear to be sinusoidal in the damping regime. Stall flutter in a cascade has differences when compared with an isolated blade. For the cascade, the maximum value of excitation (positive energy transfer) is found to be an order of magnitude lower compared to the isolated blade case. Further, for similar values of mean incidence angle, the range of excitation is at lower reduced frequencies for a cascade when compared with an isolated blade. A comparison with un‐stalled or classical flutter in a cascade at high Re, shows that the inter‐blade phase angle is a major factor governing flutter in both cases. Some differences are observed as well, which appear to be due to stalled flow and low Re.
176

Contributions à la modélisation des données financières à hautes fréquences / No English title available

Fauth, Alexis 26 May 2014 (has links)
Cette thèse a été réalisée au sein de l’entreprise Invivoo. L’objectif principal était de trouver des stratégies d’investissement : avoir un gain important et un risque faible. Les travaux de recherche ont été principalement portés par ce dernier point. Dans ce sens, nous avons voulu généraliser un modèle fidèle à la réalité des marchés financiers, que ce soit pour des données à basse comme à haute fréquence et, à très haute fréquence, variation par variation. / No English summary available.
177

Ultra-high-energy cosmic-ray nuclei and neutrinos in models of gamma-ray bursts and extragalactic propagation

Heinze, Jonas 08 June 2020 (has links)
The propagation code PriNCe, which is discussed in Chapter 4 of this thesis, has since been published. The open-source code is available at https://github.com/joheinze/PriNCe. / Utrahochenergetische kosmische Strahlung (ultra-high-energy cosmic rays -- UHECR) besteht aus ionisierten Atomkernen mit den höchsten Teilchenergien, die je gemessen wurden. Zwar wurden die Quellen von UHECRs noch nicht eindeutig identifiziert, doch gibt es deutliche Anzeichen, dass sie extragalaktisch sind. Um die Beobachtungen zu interpretieren, wird ein Modell der Wechselwirkungen mit Photofeldern sowohl in der Quelle als auch während der extragalaktischen Propagation benötigt. Bei diesen Wechselwirkungen werden sekundäre Neutrinos erzeugt. Diese Dissertation behandelt Modelle der Quellen von UHECRs und die damit verbundene Produktion von Neutrinos sowohl in den Quellen als auch während der Propagation. Dafür wurde ein neuer Code, PriNCe, für die Propagation von UHECRs entwickelt. Dieser Code wird in einem umfangreichen Parameterscan für ein generisches Quellenmodell angewendet, welches mit dem Spektralindex, der maximalen Rigidität, der kosmologischen Quellenverteilung und der chemischen Komposition als freie Parameter definiert ist. Dabei wird der Einfluss von verschiedenen Photodisintegrations- und Luftschauermodellen auf die erwarteten Eigenschaften der Quellen demonstriert. Der Fluss kosmogenischer Neutrinos, der sich daraus robust vorhersagen lässt, liegt außerhalb der Reichweite aller derzeit geplanten Neutrinodetektoren. GRBs als mögliche Quellen von UHECRs werden im Multi-Collision Internal-Shock Modell simuliert, welches die Abhängigkeit der Strahlungsprozesse von den verschiedenen Dissipationsradien im Plasmajet berücksichtigt. Für dieses Modell wird der Effekt demonstriert, den verschiedene Annahmen über die anfängliche Verteilung des Plasmajets und das hydrodynamische Modell auf die resultierende UHECR- und Neutrinosstrahlung haben. Für den Gammastrahlenblitz GRB170817A, welcher zusammen mit einem Gravitationswellensignal beobachtet wurde, werden Vorhersagen für den Neutrinofluss und ihre Abhängigkeit vom Beobachtungswinkel gemacht. / Ultra-high-energy cosmic rays (UHECRs) are the most energetic particles observed in the Universe. While the astrophysical sources of UHECRs have not yet been uniquely identified, there are strong indications for an extragalactic origin. The interpretation of the observations requires both simulations of UHECR acceleration and energy losses inside the source environment as well as interactions during extragalactic propagation. Due to their extreme energies, UHECR will interact with photons in these environments, producing a flux of secondary neutrinos. This dissertation deals with models of UHECR sources and the accompanying neutrino production in the source environment and during extragalactic propagation. We have developed a new, computationally efficient code, PriNCe, for the extragalactic propagation of UHECR nuclei. The PriNCe code is applied for an extensive parameter scan of a generic source model that is described by the spectral index, the maximal rigidity, the cosmological source evolution and the injected mass composition. In this scan, we demonstrate the impact of different disintegration and air-shower models on the inferred source properties. A prediction for the expected flux of cosmogenic neutrinos is also derived. GRBs are discussed as specific UHECR source candidates in the multi-collision internal-shock model. This model takes the radiation from different radii in the GRB outflow into account. We demonstrate how different assumptions about the initial setup of the jet and the hydrodynamic collision model impact the production of UHECRs and neutrinos. Motivated by the multi-messenger observation of GRB170817A, we discuss the expected neutrino production from this GRB and its dependence on the observation angle. We show that the neutrino flux for this event is at least four orders of magnitude below the detection limit for different geometries of the plasma jet.
178

Nuclear Cascades and Neutrino Production in the Sources of Ultra-High Energy Cosmic Ray Nuclei

Biehl, Daniel 13 September 2019 (has links)
Der Ursprung ultra-hochenergetischer kosmischer Strahlung (UHECRs) ist eine der wichtigsten offenen Fragen der Astrophysik. Gammastrahlenblitze (GRBs) galten als potentielle Quellen, da sie zu den energetischsten Ereignissen im Universum zählen. Konventionelle Szenarien sind jedoch durch Neutrinodaten stark eingeschränkt. Außerdem weisen Messungen der chemischen Zusammensetzung kosmischer Strahlen auf schwere Kerne hin, welche in zu dichten Strahlungsfeldern disintegrieren würden. Um dieses Dilemma zu umgehen deuten neue Studien auf versteckte Beschleuniger hin, welche schwer zu detektieren sind. In dieser Dissertation präsentieren wir neue Ansätze um nukleare Prozesse in astrophysikalischen Quellen effizient und selbstkonsistent zu berechnen. Wir quantifizieren diese Wechselwirkungen anhand der nuklearen Kaskade, welche die Disintegration schwerer Kerne in leichtere Fragmente beschreibt. Auch in umfassenden Modellen, wie sie in dieser Arbeit entwickelt werden, sind GRBs durch Neutrinodaten unter Druck. Dennoch zeigen wir, dass eine Population von GRBs niedriger Luminosität konsistent mit derzeitigen Messungen ist und zugleich auch das Spektrum und die Zusammensetzung kosmischer Strahlung über den Knöchel hinweg sowie Neutrinodaten beschreiben kann. Aus unserer Prozedur können wir zusätzlich weitere Quelleneigenschaften wie die baryonische Ladung oder die Ereignisrate bestimmen. Wir zeigen weiter, dass auch von schwarzen Löchern zerrissene Sterne mögliche Kandidaten eines gemeinsamen Ursprungs der gemessenen kosmischen Strahlung und PeV-Neutrinos sind. Sie können jedoch durch kosmogenische Neutrinos von LLGRBs abgegrenzt werden. Schließlich wenden wir unser Modell auf das Gravitationswellenereignis GW170817 an. Wir zeigen für verschiedene Jet-Szenarien, dass der erwartete Neutrinofluss weit unter der Sensitivität derzeitiger Instrumente liegt. Dennoch könnten verschmelzende Neutronensterne die kosmische Strahlung unterhalb des Knöchels erklären. / The origin of Ultra-High Energy Cosmic Rays (UHECRs) is still one of the most important open questions in astrophysics. Gamma-Ray Bursts (GRBs) were considered as potential sources as they are among the most energetic events known in the Universe. However, conventional GRB scenarios are strongly constrained by astrophysical neutrino data. In addition, cosmic ray composition measurements indicate the presence of heavy nuclei, which would disintegrate if the radiation fields in the source were too dense. In order to circumvent this dilemma, recent studies point towards hidden accelerators, which are intrinsically hard to detect. In this dissertation, we present novel approaches to efficiently and self-consistently calculate the nuclear processes in astrophysical sources. We quantify these interactions by means of the nuclear cascade, which describes the subsequent disintegration of heavy nuclei into lighter fragments. Even in sophisticated source-propagation models, as the ones developed in this thesis, conventional GRBs are in tension with neutrino data. However, we demonstrate that a population of low-luminosity GRBs is not only consistent with current constraints, but can even describe the UHECR spectrum and composition across the ankle as well as neutrino data simultaneously. From our fitting procedure we can further constrain certain source properties, such as the baryonic loading and the event rate. Furthermore, we show that stars disrupted by black holes are viable candidates for a simultaneous description of cosmic ray and PeV neutrino data too. However, they can be discriminated from LLGRBs by cosmogenic neutrinos. Finally, we apply our model to GW170817. We show for different jet scenarios that the expected neutrino flux is orders of magnitude below the sensitivity of current instruments. Nevertheless, binary neutron star mergers could in principle support cosmic rays below the ankle.
179

Perturbation Analysis of Colorectal Cancer Cell Plasticity and Therapy Resistance at Single Cell Resolution

Lüthen, Mareen 21 November 2023 (has links)
Das normale Kolonepithel weist eine strenge Zellhierarchie auf, die aus bekannten Zelltypen besteht. Bei Darmkrebs (CRC) ist die Struktur weniger konserviert und nicht gut verstanden. Krebsauslösende Mutationen können die Prävalenz von Zelltypen verändern, und Zellen können sich auch dedifferenzieren, um einer gezielten Krebstherapie zu entgehen. Mein Ziel ist es, die Existenz heterogener Zelltypen in Organoiden zu bestätigen und Signalnetzwerke in CRC zu untersuchen, indem ich mit pharmakologischen Eingriffen spezifische Signalwege inhibiere, die Zellhierarchien im normalen Darm kontrollieren. Strategisch ausgewählte Medikamente wurden eingesetzt, um Knotenpunkte in verschiedenen Signalwegen zu hemmen, die für das Fortschreiten von Darmkrebs relevant sind. Ich untersuchte, ob die Inhibition von Signalwegen die Zusammensetzung der Zelltypen und den Differenzierungszustand verändert oder welche Kombinationen von Inhibitoren Plastizität oder Apoptose auslösen könnten. Von Patienten stammende Organoide mit verschiedenen onkogenen Treibermutationen wurden kultiviert und 48 Stunden lang mit einer Reihe von Inhibitoren und Inhibitorkombinationen behandelt. Diese Organoide wurden hauptsächlich auf zwei Ebenen untersucht: durch scRNA seq zur Ermittlung ihres Transkriptoms und durch CyTOF, das die Proteinhäufigkeit pro Zelle misst, um die Aktivität von Signaltransduktionskaskaden zu beurteilen. Beide Methoden wurden eingesetzt, um die Heterogenität des CRC zu quantifizieren. Ich konnte feststellen, dass sich Organoide mit denselben Treibermutationen ähnlicher verhalten und dass die molekularen Grundlagen der verschiedenen Linien Unterschiede im Therapieerfolg bedingen. Heterogene Transkriptome und Proteinexpression wurden durch einen Differenzierungsgradienten beeinflusst und konnten durch die Zugabe von Inhibitoren verändert werden. Die MAPK-Aktivität folgt diesem Differenzierungsgradienten und eine MAPK-Inhibition verringerte die Zellheterogenität und führte zu Plastizität. Darüber hinaus stellte ich fest, dass ein Teil der Zellen in Apoptose geht und die verbleibenden Zellen einen nicht-proliferativen Stammzellzustand annehmen, der es den Zellen ermöglicht, sich nach Aussetzung der Behandlung zu erholen. Es wurden in silico und in vitro Analysen durchgeführt, um neuartige Inhibitorkombinationen zur Maximierung der Apoptose in CRC-Organoiden zu finden, um die Entstehung therapieresistenter Subpopulationen weiter zu reduzieren. Wirksame Behandlungskombinationen bleiben jedoch zelllinienabhängig. Durch die getrennte Analyse des Zelldifferenzierungszustands und des Zellsignalisierungszustands habe ich dazu beigetragen zu verstehen, wie Tumorzellen einer gezielten Therapie durch nicht-genetische Resistenzmechanismen entgehen können. Die MAPK-Inhibition zur Verringerung der Zellheterogenität in Kombination mit anderen Inhibitoren könnte in Zukunft zur Optimierung des Therapieerfolgs eingesetzt werden. / Normal colon epithelium has a strict cell hierarchy consisting of well-known cell types. In colorectal cancer (CRC) the structure is less conserved and poorly understood. Cancer driver mutations may modulate the prevalence of cell types, and cells may also dedifferentiate to overcome targeted cancer therapy. My aim is to confirm the existence of heterogeneous cell types in organoids and investigate signaling networks in CRC by targeting specific signaling pathways with pharmacological intervention, which control cell hierarchies in the normal intestine. Strategically selected drugs were used to inhibit nodes in different signaling pathways relevant to the progression of CRC. I explored whether signaling inhibition changes cell type composition and differentiation state, or which inhibitor combinations might induce plasticity or apoptosis. Patient-derived organoids with different oncogenic diver mutations were cultured and treated with a panel of inhibitors and inhibitor combinations for 48 hours. These organoids were mainly examined on two levels: by scRNA seq to assess their transcriptome and by CyTOF, which measures protein abundance to assess the activity of pathways. Both methods were used to quantify CRC heterogeneity. I was able to see that organoids with the same driver mutations behave more similarly and that the molecular underpinnings of the different lines drive differences in therapy response. Heterogeneous transcriptomes and protein expression were affected by a differentiation gradient and could be altered by inhibitor addition. MAPK activity was graded along this differentiation gradient, and MAPK inhibition reduced cell heterogeneity and induced plasticity. Additionally, I found that a fraction of cells undergo apoptosis, and the remaining cells adopt a non-proliferative stem cell state, which allows cells to recover after suspension of treatment. \textit{In silico} and \textit{in vitro} analyses were performed to find novel inhibitor combinations to maximize apoptosis in CRC organoids to further reduce the emergence of therapy-resistant subpopulations. However, effective treatment combinations remain cell-line dependent. By separately analyzing cell differentiation state and cell signaling state I contributed to our understanding of how tumor cells can evade targeted therapy by non-genetic resistance mechanisms. Using MAPK inhibition to reduce cell heterogeneity in combination with other inhibitors may be used in the future to optimize therapy success.
180

Influence of spatial and temporal factors on plants, pollinators and plant-pollinator interactions in montane meadows of the western Cascades Range

Pfeiffer, Vera W. 01 June 2012 (has links)
Montane meadows comprise less than 5% of the landscape of the western Cascades of Oregon, but they provide habitat for diverse species of plants and pollinators. Little is known about plant-pollinator network structure at these sites. This study quantified plant-pollinator interactions over the summer of 2011, based on six observations of 10 permanent subplots in 15 meadows, stratified by size and isolation. The study examined (1) relationships between richness and abundance of flowers, pollinators, and interactions; (2) distribution of abundance and richness of flowers, pollinators, and interactions with regards to surrounding meadow habitat; (3) change in flower and pollinator abundance over the season; (4) factors associated with the presence of various guilds of pollinators; and (5) the structure of plant-pollinator networks. The study showed that (1) richness of pollinators increased 2x faster than richness of flowers with increased abundance; (2) density of flowers and interactions was positively correlated with meadow size and diversity of pollinators and interactions were both correlated with surrounding habitat at two spatial scales; (3) peak flower abundance coincided with or preceded peaks in pollinator populations; (4) abundance of three guilds of bees exhibited different patterns of association to surrounding habitat and meadow soil moisture corresponding to various dispersal potential and phenology of guild species; and (5) the number of network pairings for plants and pollinators increased with increasing species richness of potential interaction partners and all networks were found to be significantly nested. Results of this study indicate that plant-pollinator networks are complex assemblages of species, in which spatial and temporal patterns of habitat affect species composition and network structure. In particular, flower and pollinator abundance and richness are depressed in small and isolated meadows. Significant nestedness emerged as a pattern of network level organization across the study meadows. / Graduation date: 2013

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