City Aggregation Machine- Project for HousingThe core concept of the project is Ambi-formalism. The main content of the design is urban morphology and an urban system of collective communities. Aim at creating a non-single perspective of reading, I call this intuitive experience, to increase presence to position “ourselves".Based on the generative logic of the Fengshui map and the European fortification map of the city wall, the origami method is used to decompose its shape, and the visual scale is used to decompose the schema into units and become a procedural grid of urban aggregation. Transform inoperable forms into operable urban unit systems. As an autonomous urban structure that can accommodate multiple reading views, in turn , which can trigger people's intuitive schema in it. so as to position ourselves.Residential district is the object designed to operate the system and skeleton of urban aggregation which mix of private and public volumes can accommodate a series of events, it aiso in itself constitutes an event. The visual layer  is the schematic route(events) into a dwelling, to identify each neighborhood.

[ES] Actualmente, el 54% de la población mundial vive en ciudades y se espera que en 2050 este porcentaje aumente al 68% (UNDESA, 2019). Una parte importante de esta población urbana se concentra en megaciudades, definidas como áreas urba-nas con más de 10 millones de habitantes. En América Latina, las principales megaciudades son Sao Paulo y Ciudad de México, con más de 20 millones de habitantes en cada una. Buenos Aires, Río de Janeiro, Lima y Bogotá son mega-ciudades aún en desarrollo (Cepal, 2013). La presente tesis doctoral tiene como objetivo identificar y analizar los impactos que la dinámica de crecimiento urbano de una megaciudad induce sobre el com-portamiento de las componentes del ciclo hidrológico. La investigación desarro-llada incorpora el efecto del cambio climático de forma conjunta con el efecto del cambio de uso de suelo urbano. Para ello, se ha planteado una metodología de agregación de parámetros hidrológicos en superficies urbanas que se ha aplicado a la megaciudad de Bogotá, utilizando el modelo hidrológico TETIS y el modelo de cambios de uso de suelo LCM, bajo los escenarios oficiales de cambio climático vigentes en Colombia. Los resultados obtenidos muestran que el análisis conjunto de cambio de uso de suelo y cambio climático proporciona herramientas valiosas para comprender el comportamiento hidrológico de la cuenca en la que se sitúan las megaciudades y predecir su evolución futura. En el caso de la megaciudad de Bogotá se ha obser-vado que el mayor efecto en las componentes del ciclo hidrológico se produce por el cambio de usos de suelo, el cual se ve incrementado por las acciones inducidas por el cambio climático. La utilización de modelos numéricos que consideren todos estos aspectos es de especial relevancia a la hora de definir los planes, políti-cas y programas de desarrollo en entornos densamente urbanizados. / [CA] Actualment, el 54% de la població mundial viu a ciutats i s'espera que el 2050 aquest percentatge augmenti al 68% (UNDESA, 2019). Una part important d'a-questa població urbana es concentra en megaciutats, definides com a àrees urba-nes amb més de 10 milions d'habitants. A Amèrica Llatina, les principals mega-ciutats són Sao Paulo i Ciutat de Mèxic, amb més de 20 milions d'habitants a cadascuna. Buenos Aires, Rio de Janeiro, Lima i Bogotá són megaciutats encara en desenvolupament (Cepal, 2013). Aquesta tesi doctoral té com a objectiu identificar i analitzar els impactes que la dinàmica de creixement urbà d'una megaciutat indueix sobre el comportament dels components del cicle hidrològic. La investigació desenvolupada incorpora l'efecte del canvi climàtic de forma conjunta amb l'efecte del canvi d'ús de sòl urbà. Per això, s'ha plantejat una metodologia d'agregació de paràmetres hidrolò-gics en superfícies urbanes que s'ha aplicat a la megaciutat de Bogotà, utilitzant el model hidrològic TETIS i el model de canvis d'ús de sòl LCM, sota els escenaris oficials de canvi climàtic vigents a Colòmbia. Els resultats obtinguts mostren que l'anàlisi conjunta de canvi d'ús de sòl i canvi climàtic proporciona eines valuoses per comprendre el comportament hidrològic de la conca on se situen les megaciutats i predir-ne l'evolució futura. En el cas de la megaciutat de Bogotà s'ha observat que l'efecte més gran en les components del cicle hidrològic es produeix pel canvi d'usos de sòl, el qual es veu incrementat per les accions induïdes pel canvi climàtic. La utilització de models numèrics que considerin tots aquests aspectes és especialment rellevant a l'hora de definir els plans, polítiques i programes de desenvolupament en entorns densament urbanit-zats / [EN] Currently 54% of the world population lives in cities and it is expected that by 2050 this percentage will increase to 68% (UNDESA, 2019). An important part of this urban population is concentrated in megacities, defined as urban areas with more than 10 million inhabitants. In Latin America, the main megacities are Sao Paulo and Mexico City, with more than 20 million inhabitants. Buenos Aires, Rio de Janeiro, Lima and Bogotá are megacities still in development (Cepal, 2013). This doctoral thesis aims to identify and analyse the impacts that the dynamics of urban growth of a megacity induce on the behaviour of of the hydrological cycle components. The research carried out incorporates the effect of climate change together with the effect of urban land use change. To do this, a methodology for aggregating hydrological parameters in urban areas has been proposed. This methodology has been applied to the megacity of Bogotá, using the TETIS hydro-logical model and the LCM land use change model, under the official climate change scenarios in force in Colombia. Results obtained show that the joint analysis of land use change and climate change provides valuable tools to understand the hydrological behaviour of the basin in which the megacities are located and predict their future evolution. In the case of the megacity of Bogotá, it has been observed that the greatest effect on the components of the hydrological cycle is produced by the land use change, which is increased by the actions induced by climate change. The use of numeri-cal models that consider all these aspects is of special relevance when defining development plans, policies and programs in densely urbanized environments. / Romero Hernández, CP. (2022). Análisis del impacto del crecimiento de las megaciudades sobre el ciclo hidrológico bajo escenarios de cambio climático. Aplicación a la cuenca del río Bogotá (Colombia) [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/191025

Le cancer de la prostate est l’un des cancers les plus fréquents chez les hommes. Le rôle de l’obésité dans son étiologie revêt un intérêt grandissant. Les associations observées sont souvent contradictoires selon le type d’obésité (générale ou abdominale), la durée ou le moment de l’exposition et l’agressivité du cancer. L’obésité abdominale figure parmi les pistes de recherche particulièrement prometteuses. L’objectif général de cette thèse était d’examiner la relation entre l’obésité et le cancer de la prostate, tant au niveau individuel que familial. Nous avons utilisé les données de PROtEuS, une étude cas-témoins populationnelle conduite en 2005-2012 à Montréal. Cette étude comprend un large éventail d’informations anthropométriques et liées aux habitudes de vie, recueillies chez 1931 cas et 1994 témoins de la population générale, ainsi que des informations anthropométriques relatives aux membres de leurs familles respectives. Les deux premiers objectifs spécifiques de la thèse visaient à explorer la corrélation entre différents indicateurs d’obésité et à développer une approche alternative à la mesure directe pour décrire l’obésité abdominale au moyen de modèles prédictifs. Les résultats suggèrent que les silhouettes de Stunkard et Sorensen sont étroitement liées à l’indice de masse corporelle (IMC) et au poids rapporté, tant au moment de l’entrevue que dans le passé. Nous avons montré qu’il était possible de prédire l’obésité abdominale relativement bien (R2=0.64), plus particulièrement la circonférence de la taille, à partir de l’IMC, la silhouette et la taille de pantalon. Les objectifs spécifiques 3 et 4 visaient à examiner l’association entre différents indicateurs d’obésité individuelle à plusieurs âges, ainsi que les trajectoires adultes d'obésité générale et abdominale, et le risque de cancer de la prostate. Nos résultats suggèrent un risque réduit de cancer de la prostate chez les personnes en surpoids ou obèses (rapport de cotes (RC) 0,71; intervalle de confiance à 95% (IC 95%) 0,59 - 0,85). À l’opposé, l’obésité abdominale récente, basée sur plusieurs indicateurs, était associée à un risque accru de cancer de haut grade (RC 1,33; IC 95% 1,03 - 1,71 pour une circonférence de la taille ≥ 102 cm). Les objectifs spécifiques 5 et 6 visaient à évaluer le risque de récurrence familiale d’obésité en fonction du nombre de membres de la famille atteints d’un cancer de la prostate et d’évaluer la co-agrégation familiale de l’obésité et du cancer de la prostate, indépendamment des agrégations familiales de l’obésité et du cancer de la prostate elles-mêmes. Le risque de récurrence familiale d’obésité était plus élevé lorsque deux cas ou plus de cancer de la prostate étaient observés dans la famille qu’en l’absence de cancer et ce, peu importe le nombre de cas d’obésité dans la famille. Pour les familles avec 3 parents présentant une obésité, le risque de récurrence d’obésité était de 0,35 (IC 95% 0,32 – 0,37) pour ceux n’ayant aucun cas de cancer dans la famille et de 0,38 (IC 95% 0,33 – 0,43) pour ceux avec au moins 2 cas de cancer dans la famille. La différence entre les risques de récurrence était encore plus marquée lorsque les familles issues du témoin index étaient comparées à celles dont le cas index avaient une tumeur de grade élevé au diagnostic. Pour les familles avec 3 parents présentant une obésité, le risque de récurrence d’obésité était de 0,35 (IC 95% 0,32 – 0,37) pour ceux dont le participant index était un témoin et de 0,41 (IC 95% 0,36 – 0,45) pour ceux dont le cas index avait une tumeur de grade élevé au moment du diagnostic. Nous n’avons pas observé de co-agrégation familiale entre obésité et cancer de la prostate dans son ensemble. Toutefois, cette co-agrégation était présente pour les cancers apparaissant avant l’âge de 55 ans (RC 1,35; IC 95% 1,11 - 1,65). Les résultats de cette thèse renforcent l’hypothèse d’un rôle important de l’obésité dans le développement du cancer de la prostate. Observation fort novatrice, l’obésité semble plus fréquente dans les familles avec plusieurs diagnostics précoces ou tumeurs agressives. La confirmation du rôle de l’obésité, facteur modifiable, dans l’étiologie de ce cancer très répandu aurait des retombées substantielles sur la santé publique. / Prostate cancer is among the most frequently diagnosed solid tumor among men. The role of obesity in its etiology is of mounting interest. The associations observed have been sometimes contradictory, varying according to the type of obesity (general or abdominal), the duration or the moment of exposure, and cancer aggressiveness. Abdominal obesity represents a promising research avenue. The general objective of this thesis was to examine the relationship between obesity and prostate cancer, both at the individual and familial levels. The main data source used was PROtEuS, a population-based case-control study conducted in 2005-2012 in Montreal. It collected a wide range of anthropometric and lifestyle information from 1,931 cases and 1,994 population controls, as well as information on obesity among their respective family members. The first two specific objectives of the thesis aimed to explore the correlation between different obesity indicators, and to develop an alternative approach to direct measurement to describe abdominal obesity using predictive models. Results suggested that Stunkard and Sorensen's silhouettes were closely related to body mass index (BMI) and reported weight, both at the time of the interview and in the past. The comparison of different predictive models showed that it was possible to estimate abdominal obesity relatively well (R2=0.64), more particularly waist circumference, from BMI, silhouette, and trousers size. Specific objectives 3 and 4 of the thesis aimed at examining the association between different indicators of individual obesity at different ages and adult obesity trajectories, and the risk of prostate cancer. Our results suggest a reduced risk of prostate cancer among overweight and obese people (odds ratio (OR) 0.71, 95% confidence interval (CI) 0.59 - 0.85). In contrast, recent abdominal obesity, estimated from various indices, was associated with an increased risk of high-grade prostate cancer (OR 1.33, 95% CI 1.03 – 1.71 for waist circumference ≥ 102 cm). Specific objectives 5 and 6 aimed to assess the familial recurrence risk of obesity according to the number of family members with prostate cancer and to assess the familial coaggregation of obesity and prostate cancer, independently of familial aggregations of obesity and prostate cancer themselves. The familial recurrence risk of obesity was higher when two or more cases of prostate cancer were observed in the family, than in the absence of cancer, regardless of the number of persons with obesity in the family. For families with 3 parents with obesity, the obesity recurrence risk was 0.35 (95% CI 0.32 – 0.37) for those with no cases of cancer in the family and 0.38 (95% CI 0.33 – 0.43) for those with at least 2 cases of cancer in the family. The difference in recurrence risks was even more marked when families whose index participant was a control were compared to those whose index case had a high-grade tumor at diagnosis. For families with 3 parents with obesity, the recurrence risk of obesity was 0.35 (95% CI 0.32 – 0.37) for those whose index participant was a control and 0.41 (95% CI 0.36 – 0.45) for those whose index case had a high-grade tumor at diagnosis. We did not observe familial co-aggregation between obesity and prostate cancer. However, this co-aggregation was present for cancers appearing before the age of 55 (OR 1.35; 95% CI 1.11 - 1.65). Results of this thesis reinforce the hypothesis of an important role of obesity in the development of prostate cancer. A particularly novel observation, obesity seems to be more frequent in families with several early-onset or aggressive tumours. Confirmation of a role of obesity, a modifiable risk factor, in the etiology of this very common cancer, would have substantial implications for public health.

Noble metal nanoparticles such as gold and silver are of interest because of the unique electro-optical properties (e.g., localized surface plasmon resonance [LSPR]) that originate from the collective behavior of their surface electrons. These nanoparticles are commonly developed and used for biomedical and industrial application. A recent report has predicted that the global market for gold nanoparticles will be over 12.7 tons by year 2020. However, these surface-functionalized nanoparticles can be potential environmental persistent contaminants post-use due to their high colloidal stability in the aquatic systems. Despite, the environmental risks associated with these nanoparticles, just a few studies have investigated the effect of nanofeature factors such as size and shape on the overall fate/transport and organismal uptake of these nanomaterials in the aquatic matrices. This study presents a comprehensive approach to evaluate the colloidal stability, fate/transport, and organismal uptake of these nanoparticles while factoring in the size and shape related properties. We demonstrate the importance and effect of anisotropicity of a gold nanoparticle on the colloidal behavior and interaction with ecologically susceptible aquatic biota. We also show how readily available characterization techniques can be utilized to monitor and assess the fate/transport of this class of nanoparticles. We further describe and investigate the relationship between the aspect ratio (AR) of these elongated gold nanoparticles with clearance mechanisms and rates from the aquatic suspension columns including aggregation, deposition, and biopurification. We illustrate how a fresh water filter-feeder bivalve, Corbicula fluminea, can be used as a model organism to study the size and shape-selective biofiltration and nanotoxicity of elongated gold nanoparticles. The results suggest that biofiltration by C. fluminea increases with an increase in the size and AR of gold nanoparticle. We develop a simple nanotoxicity assay to investigate the short-term exposure nanotoxicity of gold nanoparticles to C. fluminea. The toxicity results indicate that for the tested concentration and exposure period that gold nanoparticles were not acutely toxic (i.e., not lethal). However, gold nanoparticles significantly inhibited the activities of some antioxidant enzymes in gill and digestive gland tissues. These inhibitions could directly affect the resistance of these organisms to a secondary stressor (temperature, pathogens, hypoxia etc.) and threaten organismal health. / Ph. D. / Nanoparticles are fine particles that cannot be seen with naked eye and possess unique chemical and physical properties. Gold and silver nanoparticles are specifically of interest due to tunable optical properties and are commonly developed and used for biomedical and industrial applications. Unfortunately, these metallic nanoparticles can be potential environmental persistent contaminants post-use in the soil and aquatic systems. Despite, the environmental risks associated with these metallic nanoparticles, just a few studies have investigated the effect of size and shape of these nanoparticles on their interaction and transportation in the surrounding environment and with existing organisms. This study presents a comprehensive approach to evaluate the stability, transportation, and organismal uptake of these nanoparticles while factoring in the size and shape related properties. We also show how readily available detection techniques can be utilized to monitor and assess the presence and transport of this class of nanoparticles. We illustrate how a fresh water bivalve, Corbicula fluminea, can be used as a model organism to study the size and shape-selective uptake and toxicity of gold nanoparticles. The results suggest that nanoparticles uptake by C. fluminea increases with an increase in the size of gold nanoparticle. We develop a simple toxicity assay to investigate the short-term exposure toxicity of gold nanoparticles to C. fluminea. The toxicity results suggest that for the tested concentration and exposure period that gold nanoparticles were not acutely toxic (i.e., not lethal) but affect the resistance of these organisms to an environmental change (temperature, pathogens, hypoxia etc.) and threaten organismal health.

Increased proliferation of nanotechnology has led to concerns regarding its implication to the water environment. Gold nanoparticles (AuNP) were used as a model nanomaterial to investigate the fate and dynamics of nanoparticles in the complex water environment. A column study was performed to examine the fate and transport of gold nanoparticles with two different coatings in porous media. The resulting data suggested that gold nanoparticles aggregate significantly in the porespace of the column interior, a finding that is not predicted by traditional colloidal filtration theory or Derjaguin-Landau-Verwey-Overbeek (DLVO) theory. Surface-enhanced Raman spectroscopy (SERS) was developed as a new technique to investigate AuNP aggregation in water with varying salt levels. The SERS technique proved valuable as an analytical technique, elucidating information about aggregation as well as AuNP surface interactions with dissolved halides in water. A thorough investigation examining Aunt aggregation with monovalent and divalent salts utilizing SERS, ultraviolet-visible light (UV-Vis) spectroscopy, and dynamic light scattering (DLS) was conducted. Each technique provided data describing different aspects of the dynamic behavior of AuNPs in complex water environments. Results suggest that in addition to attractive and repulsive interactions described by DLVO theory, chemical interactions between the AuNP surface and dissolved halides were also a significant driving force for aggregation and other transformative behaviors of AuNPs in water. The SERS technique developed in this work was shown to be a viable tool to help unveil the vastly complex dynamics of nanomaterial in the water environment. / Ph. D. / Nanotechnology is everywhere. It is in our smartphones, in our food, in our clothes, even if we do not recognize it is there. And this is a good thing, because nanotechnology – that is, technology that utilizes nanomaterials – can provide things that traditional technology often cannot. This is all because many nanomaterials have “superpowers” due to their size range: they are generally larger than what we may think of when we think of chemical molecules, but much smaller than macroscopic materials whose behaviors can be approximated by classic physics and chemistry. For example, we all know that gold has a shiny yellow metallic appearance. However, if we make little particles of gold – and these are going to be very tiny, with diameters about 10,000 times smaller than that of a strand of human hair (but about 100 times larger than what we would typically think of as molecules of chemicals) – and put them in water, the resulting mixture will be ruby-red like wine. One of the “superpowers” these gold nanoparticles possess is that they interact with light in a very different way than bulk gold. Currently, researchers in the biomedical field are producing promising work employing these particles in nextgeneration imaging, and much more. In this study, we were interested in what happens to these materials once they are released to the water environment. Because of the “superpowers” these gold nanoparticles possess, we really do not know how they will behave once they are released to either surface or groundwater because the physics and chemistry of those environments can be quite variable and complex. In this work, we have shown that traditional assumptions about particulate contaminants in water systems do not necessarily hold for gold nanoparticles. Laboratory simulations show that interactions between these particles and the surrounding environment that were once thought to be negligible, are in fact highly significant. As our title suggests, we are developing new and advanced “photonics” methods to help us discover the dynamic complexity dictating the fate of these gold nanoparticles once they are in the water environment. Photonics methods are techniques that employ light as a probing tool. These techniques use a well understood laser light source that is directed towards the particles in a water environment, and we then measure changes in the scattered light after it has interacted with the particles. The technique we have employed here (called surface-enhanced Raman spectroscopy, or SERS) simultaneously provides us information about different behaviors of gold nanoparticles in water, including how they may aggregate (that is, stick to one another and form big clumps) and how they interact with existing dissolved chemicals that may be present in the natural water environment. By pairing this method with other existing methods, we were able to paint a more complete picture of how these nanoparticles behave in the water environment, and we can answer some questions as to why they do not follow some previously held assumptions. In the end, the work in this dissertation will help future scientists continue to unlock the complexity of nanomaterial fate and dynamics in the water environment.

Die Huntington''sche Krankheit (Huntington''s disease, HD) ist eine tödliche neurodegenerative Erkrankung mit einem extensiven Verlust von Neuronen im Striatum. Die Ursache für HD ist eine genetische Mutation, bei der eine CAG-Wiederholungssequenz verlängert wird. Im resultierenden Protein, das Huntingtin (htt) genannt wurde, diese Mutation führt zur Missfaltung und Aggregation von htt. Ich habe untersucht ob die Bildung von htt-Aggregaten die Transkription von Genen dass sie von HD-assoziierten Transkriptionsfaktoren kontrolliert werden, verändert. Zur Untersuchung der Transkription wurden die zu untersuchenden Gene auf cDNA-Mikroarrays aufgebracht und mit RNA, welche aus den Zellen nach der Induktion der Expression des mutierten htt gewonnen wurde, hybridisiert. Es wurden keine systematischen Veränderungen innerhalb der durch spezifische Transkriptionsfaktoren regulierten Gengruppen gefunden. Ich habe auch mehrere mathematische Modelle erstellt, welche die htt-Aggregation und den Zelltod beschreiben. Die Ergebnisse zeigten, dass eine transiente Dynamik im System und die nicht-monotone Reaktion auf Parameteränderungen zu den nicht-intuitiven Ergebnissen bei Behandlungsansätzen, welche die htt-Aggregation beeinflussen, führen könnten. Für den Fall, dass Aggregate die toxische Form von htt sind, zeigten die numerischen Simulationen dass das Einsetzen der Aggregation, welches durch ein Überschießen der Aggregatkonzentration gekennzeichnet ist, am ehesten zum Zelltod führt. Dieses Phänomen wurde "one-shot"-Modell genannt. Es gibt, auch bei HD-Patienten mit gleicher Länge der CAG-Wiederholungssequenz, eine große Varianz des Alters bei Krankheitsausbruch (age of onset, AO). Ich habe ein stochastisches Modell für den neuronalen Zelltod im Striatum entwickelt. Das Modell zeigte, dass ein signifikanter Anteil der nicht erklärbaren Varianz des AO der intrinsischen Dynamik der Neurodegeneration zugeschrieben werden kann. / Huntington''s disease (HD) is a fatal neurodegenerative disorder characterized by a progressive neuronal loss in the striatum of HD patients. HD is caused by a CAG repeat expansion which translates into a polyglutamine stretch at the N-terminus of the huntingtin protein (htt). The polyQ stretch induces misfolding, cleavage and aggregation of htt. To test the hypothesis that the sequestration of transcription factors into the htt aggregates causes transcriptional changes observed in HD models, I compiled lists of genes controlled by the transcription factors associated with HD. These genes were spotted on cDNA microarrays that were later hybridized with RNA extracted from cells expressing a mutant htt fragment. In this study, no systematic changes related to a specific transcription factors were observed. Formation and the accumulation of htt aggregates causes neurotoxicity in different HD model systems. To investigate the consequences of therapeutic strategies targeting aggregation, I derived several mathematical models describing htt aggregation and cell death. The results showed that transient dynamics and the non-monotonic response of cell survival to a change of parameter might lead to the non-intuitive outcome of a treatment that targets htt aggregation. Also, the numerical simulations show that if aggregates are toxic, the onset of aggregation, marked by the overshoot in the concentration of aggregates, is the event most likely to kill the cell. This phenomenon was termed a one-shot model. The principal cause of the variability of the age at onset (AO) is the length of the CAG repeat. Still, there is a great variance in the AO even for the same CAG repeat length. To study the variability of the AO, I developed a stochastic model for clustered neuronal death in the HD striatum. The model showed that a significant part of the unexplained variance can be attributed to the intrinsic stochastic dynamics of neurodegeneration.

Eine Gemeinsamkeit verschiedener neurodegenerativer Erkrankungen ist die abnormale Ansammlung von Proteinen im Gehirn, wie z. B. von alpha-Synuclein (Syn)-Aggregaten bei der Parkinson''schen Krankheit (PD) oder von Huntingtin (Htt)-Aggregaten bei Chorea Huntington (HD). Am Anfang dieser Studie wurde eine Bibliothek von ca. 5000 natürlichen Substanzen nach Inhibitoren der Htt-Aggregation durchsucht. Eine der wirksamen Substanzen war (-)-Epigallocatechingallat (EGCG), eine Verbindung, die in grünem und schwarzem Tee vorkommt. Die antioxidativen Eigenschaften von EGCG wurden bereits mit einer neuroprotektiven Wirkung in Verbindung gebracht, was EGCG zu einem vielversprechenden Kandidaten für die Entwicklung einer neuen Behandlungsmethode macht. Eine inhibierende Wirkung auf Proteinaggregation wurde jedoch bis jetzt noch nicht nachgewiesen. Diese Studie zeigt, dass EGCG die Aggregation von Htt und Syn hemmt, indem es dosisabhängig eine oligomere Proteinkonformation stabilisiert. Diese Oligomere wirken jedoch nicht als Keime in Aggregationsreaktionen. Zusätzlich verändert EGCG die Exposition bestimmter Epitope, die von konformationsspezifischen Antikörpern im Laufe der Aggregation erkannt werden. Daher könnte die Substanz Proteine, die zur Aggregation neigen, auf einen alternativen Faltungspfad in der Missfaltungskaskade führen. Weiterhin legen die Ergebnisse nahe, dass eine direkte Wechselwirkung zwischen EGCG und Proteinen in einer ungefalteten Konformation stattfindet. In verschiedenen Zellkultur-Modellsystemen verringerte EGCG die Toxizität, die von missgefalteten Proteinen ausgeht, was nahelegt, dass die neu geformten oligomeren Spezies nicht toxisch sind. EGCG könnte daher ein chemisches Chaperon darstellen, das die Missfaltung und Toxizität von Proteinen, die mit neurodegenerativen Krankheiten assoziiert sind, verringert. Die Substanz könnte daher die Basis zur Entwicklung einer neuen Therapie für diese unheilbaren Krankheiten darstellen. / A common feature of neurodegenerative disorders is the abnormal accumulation of aggregated protein the brain, such as alpha-Synuclein (Syn) aggregates in Parkinson''s disease (PD) and Huntingtin (Htt) aggregates in Huntington''s disease (HD). In this study, a library of approximately 5000 natural compounds was screened for inhibitors of Htt aggregation. One of the hits was (-)- Epigallocatechin gallate (EGCG), a compound present in green and black tea. The antioxidant properties of this substance have been linked to neuroprotection before, making it a promising candidate for the development of a treatment for neurodegenerative diseases. Inhibition of protein aggregation by EGCG, however, has not been demonstrated so far. This study shows that EGCG inhibits the aggregation of Htt and Syn by stabilizing an oligomeric conformation of the respective proteins in a dose-dependent manner. These oligomers do not seed the aggregation of Htt and Syn. Also, EGCG modifies the exposure of different epitopes recognized by conformation-specific antibodies during the aggregation process. The compound might therefore lead aggregation-prone proteins on an alternative folding pathway in the misfolding cascade. The results furthermore suggest that direct interaction occurs between EGCG and proteins in an unfolded conformation. EGCG also reduces toxicity caused by misfolded Htt or Syn in cell culture model systems, suggesting that the oligomeric protein species formed in the presence of EGCG are not toxic to living cells. EGCG might therefore represent a chemical chaperone that can modulate misfolding and toxicity of proteins associated with neurodegenerative diseases and could provide the basis for the development of a novel pharmacotherapy for these fatal disorders.

Computermodelle stellen heute ein Standardwerkzeug in vielen wissenschaftlichen Disziplinen dar. Einer ihrer Hauptzwecke ist die Verknüpfung von Prozessen verschiedener Skalen. Verzichtet man auf diese Verknüpfung im Modell, sind realistische Prognosen meist ausgeschlossen, bildet man die Realität 1:1 nach, wird das Modell unlösbar. Wichtig ist daher eine gute Balance zwischen Genauigkeit und Abstraktion. Ich untersuche Möglichkeiten, skalenübergreifende Interaktionen in der Landnutzungsmodellierung effizient zu implementieren. Fokus liegt dabei auf zwei Prozessen: 1.Der Nutzung hochaufgelöster Daten im Modell. 2.Dem technologischer Wandel als landwirtschaftlichem Treiber. Häufig können hochaufgelöste Daten augrund limitierter Modellkomplexität nicht direkt verwendet werden. Meist wird dieses Problem gelöst, indem die Daten nach einem statischen Aggregationsschema hochskaliert werden. Als Alternative diskutiere ich den Einsatz von Clusteralgorithmen. Meine Untersuchungen zeigen, dass der entstehende Informationsverlust bei Verwendung von Clusteralgorithmen signifikant geringer ist als bei der Verwendung statischer Aggregationsvorschriften. Ein weiterer in der Landwirtschaft wichtiger Prozess ist technologischer Wandel. Während in der Vergangenheit Steigerungen in der Produktion meist durch Landexpansion erreicht wurden, so geschieht dies heute häufig durch Intensivierung. Ich präsentiere eine Modellimplementierung dieses Prozesses mitsamt der Rückkopplung der Landnutzungsintensität auf die Effektivität zugehöriger Investitionen. Grundlage dafür ist ein neuentwickeltes Maß für landwirtschaftliche Landnutungsintensität. Damit zeige ich, dass die Effektivität von Investitionen mit steigender Landnutzungsintensität sinkt. Meine Arbeit zeigt, dass außer dem Detailgrad eines Modells auch die Struktur der verwendeten Implementierungen einen signifikanten Einfluss auf die generelle Qualität der Simulation hat und insgesamt mehr Beachtung in der Modellierung finden sollte. / Computer models have become a common tool in various disciplines. A major challenge in modeling is the linking of processes on different scales. Neglecting cross-scale interactions leads to biases in model projections while a 1:1 representation is computational infeasible. Therefore, a good balance between accuracy and abstraction is essential. I investigate efficient implementations of cross-scale interactions in agricultural land-use models. I focus on two dominant aspects: First, the inclusion of spatially explicit data in a global optimization model; second, the proper representation of technological change as a driver for land use change. As a consequence of limitations in complexity of global optimization models the problem arises that high-resolution data cannot be used directly as model input. Typically, the spatially explicit data is upscaled by using a static upscaling rule. As an alternative I discuss the use of clustering methods for upscaling. I provide a general framework including the creation of clusters, the upscaling of inputs, and the downscaling of outputs. My investigations show that the information loss due to upscaling decreases significantly with cluster methods compared to static grids. Another important process in agriculture is technological change. Whereas in the past increases in agricultural production were mainly achieved by agricultural land expansion, nowadays most increases in total production are outcome of intensification due to technological change. To model this feedback I introduce a measure for agricultural land-use intensity. Based on this measure I show that the effectiveness of investments in technological change decreases with the agricultural land-use intensity. My findings imply that apart from detailedness especially the implementation has a significant impact on general model quality. Therefore, in model development the framework used for implementation should be emphasized to a greater extent.

The efficiency of organic light-emitting diodes (OLEDs) typically decreases with increasing current density. This so-called roll-off impedes the market entry of OLEDs in high-brightness applications such as general lighting. One of the most important processes causing roll-off is exciton annihilation, which evolves upon high exciton densities. This mechanism is especially pronounced in phosphorescent molecules due to their long triplet lifetime. In order to reduce the roll-off in phosphorescent OLEDs, this thesis focusses on decreasing the local exciton density by modifying the exciton lifetime, the spatial exciton distribution, and the tendency of emitters to form aggregates. The obtained results lead to a deeper understanding of efficiency roll-off and help sustaining the OLED efficiency at high brightness. The emitter lifetime can be influenced by the optical environment around the emitting dipoles through the Purcell effect. In order to study this effect, the distance between emitter and metal cathode is varied for two different OLED stacks. A strong influence of emitter position and orientation on roll-off is observed and explained by modelling the data with triplet-triplet annihilation theory. Furthermore, design principles for optimal high-brightness performance are established by simulating the roll-off as a function of emitter-cathode distance, emissive dipole orientation, and radiative efficiency. Next, a method is developed that allows extracting the spatial exciton distribution. Therefore, a thin sensing layer that locally quenches excitons is introduced into the emission layer at varying positions. The resulting quenching profile is then fitted using a comprehensive theory based on the diffusion equation, which renders the exciton distribution and diffusion length with nanometer resolution. This method is applied to an emission layer comprising an ambipolar host material. Contrary to expectations which suggest that ambipolar materials exhibit broad exciton formation, a narrow emission zone close to the electron transport layer is found. Additional explorations of structures that might broaden the emission zone point to a narrow emission zone in double emission layers and broader exciton formation in mixed emission layers. Previous investigations revealed a strong correlation between emitter aggregation and molecular dipole moment of the emitter. Within this thesis, the range of studied emitters is significantly extended. It is shown that homoleptic emitters show a stronger tendency to form aggregates than heteroleptic compounds. This is probably not only related to their higher dipole-dipole potential, but also to the molecular structure. Systematic analysis of the deposition parameters shows that aggregate formation depends on the underlying material and increases with increasing substrate temperature and decreasing evaporation rate. The two green emitters Ir(ppy)3 and Ir(ppy)2(acac) are additionally studied by means of X-ray diffraction. Both emitters form crystallite grains and exhibit a preferred orientation. Doping the emitters into an amorphous host, both orientation and crystallite formation retain at the investigated doping concentrations above 20 wt%. This result is a first step toward further understanding of the mechanism of transition dipole orientation. / Die Effizienz organischer Leuchtdioden (OLEDs) nimmt üblicherweise mit ansteigender Stromdichte ab. Dieser so genannte Roll-Off erschwert den Markteintritt von OLEDs in Bereichen, die hohe Helligkeiten erfordern, wie beispielsweise in der Beleuchtung. Einer der wichtigsten Prozesse, die zu Roll-Off führen, ist die Annihilation von Exzitonen. Diese nimmt mit steigender Exzitonendichte zu und ist vor allem in phosphoreszenten OLEDs aufgrund der dort vorhandenen langen Triplettlebensdauer ein großer Verlustfaktor. Im Rahmen dieser Dissertation werden Methoden vorgestellt, die mittels Reduzierung der Exzitonendichte den Roll-Off in phosphoreszenten OLEDs verringern können. Dazu gehören die Veränderung der Exzitonenlebensdauer, die Untersuchung der räumlichen Verteilung der Exzitonen und die Erforschung der Bildung von Emitteraggregaten. Die gewonnenen Ergebnisse führen zu einem besseren Verständnis des Effizienz Roll-Offs und helfen, die Effizienz von OLEDs bei hohen Helligkeiten zu verbessern. Die Emitterlebensdauer kann über den Purcell-Effekt durch Veränderung des die emittierenden Dipole umgebenden elektromagnetischen Felds beeinflusst werden. Dieser Effekt wird genutzt, indem der Abstand zwischen Emitter und Metallelektrode für zwei verschiedene OLED-Aufbauten variiert wird. Der Roll-Off ist stark abhängig von der Position und Orientierung des Emitters und kann durch Modellierung der Daten auf Basis von Triplett-Triplett-Annihilation erklärt werden. Durch Simulation des Roll-Offs in Abhängigkeit des Emitter-Kathode-Abstands, der Orientierung und der strahlenden Effizienz der emittierenden Dipole werden Prinzipien zur optimalen Leistung von OLEDs bei hohen Helligkeiten entwickelt. Als nächstes wird eine Methode eingeführt mittels derer die räumliche Exzitonenverteilung extrahiert werden kann. Dafür wird eine dünne Sensorschicht in die Emissionsschicht eingebracht, die lokal Exzitonen auslöscht. Unter Variation der Position des Sensors wird ein Profil der Auslöschungsintensität bestimmt. Die gemessene Intensität wird mittels einer umfassenden Theorie auf Grundlage der Diffusionsgleichung angepasst, wodurch sich die räumliche Verteilung der Exzitonen und die Diffusionslänge mit einer Auflösung von 1nm ergibt. Die Methode wird auf eine Emissionsschicht angewandt, die das ambipolare Matrixmaterial CBP enthält. Entgegen der Erwartung, dass die Exzitonenbildung in ambipolaren Materialien weiter ausgedehnt ist, ist die gemessene Emissionszone sehr schmal und befindet sich an der Grenze zur Elektronentransportschicht. Um eine Verbreiterung des Emissionsprofils zu ermöglichen, werden weitere Strukturen untersucht. Dabei wird eine schmale Emissionszone in Doppelemissionsschichten beobachtet, wohingegen gemischte Emissionsschichten zu einer Verbreiterung der Exzitonenbildung führen können. Vorangegangene Untersuchungen deckten einen Zusammenhang zwischen der Aggregation von Emittermolekülen und dem Dipolmoment des Emitters auf. In dieser Arbeit werden weitere Emittermoleküle untersucht, wobei eine stärkere Aggregation von homoleptischen Emittern im Vergleich zu heteroleptischen festgestellt wird. Dies ist einerseits im höheren Dipol-Dipol-Potential der homoleptischen Verbindungen und andererseits in der Molekülstruktur begründet. Eine systematische Analyse der Herstellungsparameter zeigt, dass die Aggregatbildung von dem darunter liegenden Material abhängt und mit steigender Substrattemperatur und sinkender Verdampfungsrate zunimmt. Die zwei Grünemitter Ir(ppy)3 und Ir(ppy)2(acac) werden zusätzlich mittels Röntgenspektroskopie untersucht. Beide Emitter bilden kristalline Körner und weisen eine bevorzugte Orientierung auf. Sowohl die Kristallbildung als auch die Orientierung bleiben erhalten, wenn die Emitter mit mehr als 20 Gewichtsprozent in das Matrixmaterial CBP dotiert werden. Dieses Ergebnis ist ein erster Schritt zum besseren Verständnis der in vielen Iridium-Emittern beobachteten Orientierung des Übergangsdipolmoments.

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