No description available.

No description available.

No

Buildings and the cities they make up are in a state of constant change. Temples become churches, palaces become apartment complexes, and railway stations have been turned into hotels and museums. Paris is an example of a city which reuses existing buildings, and on a smaller scale as the city changes over time, buildings are split in half, windows become doors, and row houses become apartments. In its centuries long evolution, Paris has developed into one of the most beautiful cities in the world full of an architecture of reuse and renovation of existing structures. As this process of reuse occurs, the history of a building is revealed as its original materials, structure, and scars are uncovered and celebrated. In the Montmartre House, the building's original vaulted brick structure is exposed. This traditional structure, along with new partitions and rooms, form a modern house in which new and old contrast, enhancing each other and creating a new architecture. The aim is not to reconstruct the old brick building into what it once was, but to use it in conjunction with modern construction methods and materials and continue the subsequent reuse and transformation making this house a reflection of the architectural spirit of Paris itself. / Master of Architecture

This thesis deals with the relationship between form and strength in architecture. The proposed building is a Kindergarten which unites issues of shape, physics, and habitat. The roof is vaulted and the walls are curved for lateral resistance and in order to make folds scaled to a child. These physical moves work towards the theme of the Kindergarten: a place for the transition between home and school. / Master of Architecture

Die Kernhülle ist eine hoch spezialisierte Membran, die den eukaryotischen Zellkern umgibt. Sie besteht aus der äußeren und der inneren Kernmembran, die über die Kernporenkomplexe miteinander verbunden werden. Die Kernhülle reguliert nicht nur den Transport von Makromolekülen zwischen dem Nukleoplasma und dem Zytoplasma, sie dient auch der Verankerung des Chromatins und des Zytoskeletts. Durch diese Interaktionen hilft die Kernhülle, den Zellkern innerhalb der Zelle und die Chromosomen innerhalb des Zellkerns zu positionieren, und reguliert dadurch die Expression bestimmter Gene. In höheren Eukaryoten durchlaufen sowohl die Kernhülle, als auch die Kernporenkomplexe während der Zellteilung strukturelle Veränderungen. Zu Beginn der Mitose werden sie abgebaut, um sich am Ende der Mitose in den Tochterzellen erneut zu bilden. Die molekularen Mechanismen, die zum Wiederaufbau der Kernhülle führen, sind kaum geklärt. Ein geeignetes System, um bestimmte Ereignisse bei der Kernhüllenbildung zu untersuchen, liefert das zellfreie System aus Xenopus Eiern und Spermienchromatin (Lohka 1998). Es konnte bereits früher gezeigt werden, dass es im Eiextrakt von Xenopus laevis mindestens zwei verschiedene Vesikelpopulationen gibt, die zur Bildung der Kernhülle beitragen. Eine der Vesikelpopulationen bindet an Chromatin, fusioniert dort und bildet eine Doppelmembran. Die andere Vesikelpopulation bindet an die bereits vorhandene Doppelmembran und sorgt für die Ausbildung der Kernporenkomplexe. Ziel dieser Arbeit war es, diese beiden Membranfraktionen zu isolieren und zu charakterisieren, wobei das Hauptinteresse in der porenbildenden Membranfraktion lag. Durch Zentrifugation über einen diskontinuierlichen Zuckergradienten konnten die Membranvesikel in zwei verschiedene Vesikelfraktionen aufgetrennt werden. Eine Membranfraktion konnte aus der 40%igen Zuckerfraktion („40% Membranfraktion“) isoliert werden, die andere aus der 30%igen Zuckerfraktion („30% Membranfraktion“). Die verschiedenen Membranfraktionen wurden zu in vitro Kernen gegeben, in denen die Kernporen durch vorausgegangene Bildung von Annulate Lamellae depletiert worden waren. Nach Zugabe der 30% Membranfraktion konnte die Bildung von funktionalen Kernporen beobachtet werden. Im Gegensatz dazu zeigte die 40% Membranfraktion keine porenbildenden Eigenschaften. Unter Verwendung eines vereinfachten Systems, bestehend aus Zytosol, Spermienchromatin und den Membranen, wurde gezeigt, dass die 40% Membranfraktion an Chromatin bindet und ausreichend ist, um eine kontinuierliche Doppelmembran ohne Kernporen zu bilden. Die 30% Membranfraktion besitzt keine Chromatinbindungseigenschaften und wird aktiv entlang von Mikrotubuli zu den porenlosen Kernen transportiert. Dort interagiert sie mit der chromatingebundenen 40% Membranfraktion und induziert die Porenbildung. Nach dem Vergleich der Proteinzusammensetzung der beiden Membranfraktionen, konnte das Major Vault Protein (MVP) nur in der porenbildenden Membranfraktion gefunden werden. MVP ist die Hauptstrukturkomponente der Vault-Komplexe, einem Ribonukleo-proteinpartikel, der in den meisten eukaryotischen Zellen vorhanden ist (Kedersha et al., 1991). Bemerkenswerterweise wird über die Funktion der Vault-Komplexe, trotz ihrer übiquitären Expression und ihrem Vorkommen in fast allen eukaryotischen Zellen, immer noch diskutiert. Um mehr über die Funktion und die Lokalisation der Vaults/MVP zu lernen, wurden die Vaults in Anlehnung an die Methode von Kedersha und Rome (1986) aus Xenopus Eiern isoliert. Zusätzlich wurde rekombinantes Xenopus MVP hergestellt, das unter anderem für die Produktion von Antikörpern in Meerschweinchen verwendet wurde. Um herauszufinden, ob die Anwesenheit von MVP in der 30% Membranfraktion in direktem Zusammenhang mit deren porenbildender Eigenschaft steht, wurden gereinigte Vault-Komplexe oder rekombinantes MVP, das alleine ausreichend ist, um in sich zu den charakteristischen Vault-Strukturen zusammenzulagern, zu porenlosen Kernen gegeben. Sowohl gereinigte Vault-Komplexe, als auch rekombinantes MVP waren in der Lage in den porenlosen Kernen die Bildung von funktionalen Kernporen zu induzieren. Untersuchungen zur Lokalisation von MVP zeigten, dass MVP teilweise an der Kernhülle und den Kernporenkomplexen lokalisiert, während der Großteil an MVP zytoplasmatisch vorliegt. Dies sind die ersten Daten, die Vaults/MVP mit der Kernporenbildung in Verbindung bringen. Deshalb bietet diese Arbeit die Grundlage, um diese unerwartete Rolle der Vaults in Zukunft genauer zu charakterisieren. / The nuclear envelope (NE) is a highly specialized membrane that delineates the eukaryotic cell nucleus. It is composed of the inner and outer nuclear membranes that are connected by the nuclear pore complexes (NPCs). The NE not only regulates the trafficking of macromolecules between nucleoplasm and cytosol but also provides anchoring sites for chromatin and cytoskeleton. Through these interactions, the NE helps position the nucleus within the cell and chromosomes within the nucleus, thereby regulating the expression of certain genes. In higher eukaryotic cells, both NE and NPCs undergo structural changes during cell division as they disassemble at the onset of mitosis and need to reform in the daughter cells at the end of mitosis. The molecular mechanisms governing the reassembly of the NE are only poorly understood. A particular suitable system to analyze specific events involved in NE assembly is provided by the cell-free system based on Xenopus egg extract and sperm chromatin (Lohka 1998). Previously it could be shown that in Xenopus egg extract there exist at least two different vesicle populations that are involved in nuclear envelope assembly. One type of vesicle binds to chromatin where it fuses and forms a bilayered nuclear envelope. The other vesicle population binds to the double nuclear membrane and is required for nuclear pore complex formation. Aim of this study was to isolate and characterize these two membrane fractions with special regard to the pore-forming membrane fraction. By centrifugation on a discontinuous sucrose gradient the membrane vesicles could be separated into two different vesicle fractions. One membrane fraction was recovered from the 40% sucrose fraction (“40% membrane fraction”) and the other one from the 30% sucrose fraction (“30% membrane fraction”). The different membrane fractions were added to in vitro nuclei, where nuclear pores were depleted by formation of annulate lamellae. After addition of the 30% membrane fraction formation of functional nuclear pores could be observed. In contrast the 40% membrane fraction had no pore-forming property. Using a simplified system consisting of cytosol, spermchromatin an membranes it was demonstrated that the 40% membrane fraction binds to chromatin and is sufficient to form a continuous double membrane without NPCs. The 30% membrane fraction lacks chromatin targeting signals and is actively transported along microtubules to the pore-free nuclei. There it interacts with the chromatin-bound 40% membranes and induces formation of NPCs. Comparing the protein composition of both membrane fractions, the major vault protein (MVP) was found to be exclusively in the pore-inducing membrane fraction. MVP is the major structural component of vaults, a ribonucleoprotein particle found in most eukaryotic cells (Kedersha et al., 1991). Remarkably, despite their ubiquitous expression and abundance in nearly all eukaryotic cells, the functional role of vaults is still being debated. To learn more about the functional role and localization of vaults/MVP, vaults were isolated from Xenopus eggs following the procedure of Kedersha and Rome (1986). In addition recombinant Xenopus MVP was prepared and used to generate antibodies in guinea pigs. To find out whether the presence of MVP in the 30% membrane fraction is related to its pore-forming capacity, purified vault complexes or recombinant MVP, which alone is sufficient to selfassemble into the characteristic vault structure, were added to poreless nuclei. Both purified vaults and recombinant MVP induce the formation of functional NPCs in the pore-free nuclei. Studying the localization of MVP it was demonstrated, that MVP localizes in part at the nuclear envelope and the nuclear pore complexes, whereas most MVP is cytoplasmically. These are the first data that link vaults/MVP to NPC assembly. Therefore this work displays fundamental features to study this unexpected role of vaults in more detail.

Cranial vault thickness (CVT) has been reported at many different osteometric landmarks and features on the vault. Historically, only a few landmarks are used, often bregma, lambda, vertex, and right and left euryon, and frequently comparisons are based only on “thick” versus “thin” to describe the vault overall. What is inherent in this strategy is the use of a few locations to characterize the entire vault. The problem remains that there is little information concerning CVT variation throughout an individual's vault, and the causes of variation within recent Homo sapiens important to investigating thickness variation between species in Homo. This work describes thickness variation over the entire superior vault and compares the sexes, age groups and populations in recent H. sapiens. A proportional grid is applied to the superior vault to measure thickness at 219 sampling points in a geographically diverse sample of recent H. sapiens. Thickness values are analyzed in their two-dimensional spatial relationships to determine patterns of vault thickness. Males were identified to be thicker than females at more lateral locations and along the midsagittal plane, although this finding is not statistically significant. Individuals over the age of 45 years are found to be statistically significantly thicker than individuals younger than 31 years at more lateral locations of the vault. Aboriginal Australians are statistically significantly thicker at more lateral locations of the vault than any other populations, whereas Northern Canada/Greenland individuals were thinner than other populations at these locations. The trend of thicker vaults in the older age group and the Australians is identified across the vault, although is not statistically significant at more locations. Several thickness patterns are identified. The boss thickening pattern is the most common pattern, followed by a midsagittal pattern, a posterior pattern, and an anterior pattern. Some specimens do not demonstrate thickness variation and are coded as undifferentiated. Each pattern is observed alone and in combination with others, signifying that pattern causes are not mutually exclusive. Boss thickening is interpreted as the result of passive bone thickening during normal bone and brain growth during fetal and adolescent development. The midsagittal thickness pattern coincides with inferred strain along the sagittal suture from nuchal muscle engagement during mastication. Previous researchers have proposed adaptive explanations for thickness variation, such as protection from interpersonal violence; the patterns of cranial vault thickness reported here point to normal growth and development of the brain as a driving force, a relationship that could drive thickness variation in other Homo species. Comparing thickness at bregma, and the frontal and parietal eminences for recent H. sapiens and H. erectus, there is no statistical difference between African and Asian H. erectus, and between the on average thicker H. sapiens populations and H. erectus, based on published data. Future work will investigate the presence or absence of thickness patterns in these fossil species.

Inom utvecklingen av de flesta typer av datorsystem används datormodeller för att strukturera lagringen och användningen av data. Likaså finns det flera olika datamodelleringsmetoder att välja bland för detta ändamål. I samarbete med ett företag har en fallstudie genomförts med syfte att undersöka hur agiliteten i två av dessa metoder påverkar utvecklingen av ett Data Warehouse (DW).  De två datamodelleringsmetoder som undersökts är Data Vaulting och Hyper Agility och arbetet har fokuserat på att undersöka skillnaderna mellan dessa när det gäller mängden ETL-kod som måste skrivas, funktionaliteten i datatransformationerna, möjligheten till att uppdatera systemstrukturen samt den totala kostnaden för utvecklingen av DW-lösningen. Inom ramen för fallstudien har en litteraturstudie genomförts och kombinerats med material från sex intervjuer, där respondenterna varit konsulter såväl som företagsrepresentanter.   Resultaten av fallstudien visar att respektive metods agilitet har en stor påverkan på den kod som utvecklas. Ju högre agilitet metoden har desto mindre kod, tid och andra resurser som krävs. Dock medför även en förhöjd agilitet större komplexitet samt eventuell risk för ett misslyckat utvecklingsprojekt.

Le cancer du sein est le cancer le plus fréquemment observé chez les femmes en France et dans le monde. Bien que le nombre de cas observés chaque année a tendance à diminuer depuis 2005, notamment grâce au dépistage organisé, cette maladie reste la première cause de décès par cancer chez les femmes. De nombreux travaux ont montré que la progression tumorale est dépendante des cellules tumorales mais également des cellules " saines " du microenvironnement (ou stroma) qui entourent la tumeur. Dans le cas du cancer du sein, les adipocytes, type cellulaire majeur du stroma mammaire, représentent des acteurs émergents dans la progression tumorale. Mon équipe est l'une des premières à avoir montré que les adipocytes péritumoraux étaient impliqués dans l'agressivité des cancers du sein. Du dialogue bidirectionnel qui s'instaure entre les adipocytes et les cellules cancéreuses mammaires résulte des modifications des deux types cellulaires : (i) les cellules tumorales " éduquées " par les adipocytes présentent des capacités invasives augmentées et une plus grande résistance aux traitements et (ii) les adipocytes co-cultivés avec les cellules tumorales acquièrent un phénotype activé avec des modifications spécifiques telles que délipidation, perte de marqueurs adipocytaires, surexpression de cytokines pro-inflammatoires et sécrétion de protéines de la matrice extracellulaire, qui nous ont amené à les nommer CAA pour " Cancer-Associated Adipocytes ". De façon intéressante, le dialogue paracrine entre les tumeurs et les adipocytes pourrait être amplifié dans l'obésité, où l'équilibre normal des protéines sécrétées par le tissu adipeux est perturbé. Dans le cancer du sein, l'obésité est associée à une augmentation des risques de survenue après la ménopause et une aggravation du pronostic indépendamment du statut ménopausique s'expliquant par une augmentation de la dissémination locale et à distance et par une réponse diminuée aux traitements, notamment par une résistance plus importante. L'objectif de ma thèse a été d'évaluer le rôle des adipocytes dans la chimiorésistance des cellules tumorales mammaires. En effet, la résistance est une limite majeure à l'efficacité des traitements et contribue à l'apparition de rechutes, lesquelles sont augmentée chez les patientes obèses. Au moyen d'un modèle de co-culture en 2D, nous avons montré que les adipocytes sont capables de promouvoir une résistance pléïotropique (doxorubicine, paclitaxel, 5-fluorouracile et cyclophosphamide) dans diverses lignées tumorales mammaires, indépendamment du type de tumeur. Grâce aux propriétés de fluorescence des anthracyclines, nous avons montré que cette résistance implique une augmentation de l'efflux de doxorubicine, l'empêchant d'agir au niveau de son site d'action nucléaire. Ce mécanisme d'efflux implique un processus original, qui fait intervenir la protéine de voûte majeure MVP / LRP (Major vault protein / Lung resistance protein), un transporteur nucléocytoplasmique dont la fonction reste à ce jour mal comprise. Suite à l'efflux nucléaire de drogue, celle-ci s'accumule dans des vésicules cytoplasmiques avant d'être effluée hors de la cellule via des vésicules extra cellulaires. Nous avons également pu montrer que cette résistance médiée par MVP s'explique par la sécrétion de facteurs solubles adipocytaires et est amplifiée en conditions d'obésité. En conclusion, nos résultats montrent que les adipocytes péritumoraux sont capables d'influencer la progression tumorale en favorisant la chimiorésistance via un mécanisme original impliquant la protéine MVP, qui pourrait potentiellement devenir un marqueur de résistance aux traitements. Ces travaux pourraient expliquer, au moins en partie, le mauvais pronostic des cancers du sein chez les patientes obèses et ouvrent donc, à plus long terme, des perspectives thérapeutiques intéressantes, destinées à interrompre le dialogue délétère entre adipocytes et cellules tumorales, en particulier chez les patients obèses. / Breast cancer is the most common cancer among women in France, as well as in the European Union and the United States. Although the number of cases observed each year has tended to decrease since 2005, notably due to organized screening, this disease remains the leading cause of cancer death in women. Many studies have shown that tumor progression is dependent on tumor cells but also on the "healthy" cells of the microenvironment (or stroma) that surround the tumor. In the case of breast cancer, adipocytes, the major cell type of the mammary stroma, represent emerging actors in tumor progression. My team is one of the first to have shown that peritumoral adipocytes were involved in the aggressiveness of breast cancers. From the bi-directional dialogue that takes place between adipocytes and mammary cancer cells results some changes in both cell types : (i) the tumor cells "educated" by the adipocytes have increased invasive capacities and greater resistance to treatments and (ii) the adipocytes co-cultured with the tumor cells acquire an activated phenotype with specific modifications such as delipidation, loss of adipocyte markers, overexpression of pro-inflammatory cytokines and secretion of proteins of the extracellular matrix, which led us to name them CAA for "Cancer-Associated Adipocytes". Interestingly, the paracrine dialogue between tumors and adipocytes could be amplified in obesity, where the normal balance of proteins secreted by adipose tissue is disrupted. In breast cancer, obesity is associated with an increased risk of occurrence after menopause and a worsening prognosis independent of menopausal status due to increased dissemination (local and remote) and decreased response to treatments, in particular by a greater resistance. The objective of my thesis was to evaluate the role of adipocytes in the chemoresistance of mammary tumor cells. Indeed, resistance is a major limit to the effectiveness of treatments and contributes to the onset of relapses, which are increased in obese patients. Using a 2D co-culture model, we have shown that adipocytes are able to promote pleiotropic resistance (doxorubicin, paclitaxel, 5-fluorouracil and cyclophosphamide) in various mammary tumor lines, irrespective of tumor type. By taking advantage of the fluorescence properties of anthracyclines, we have shown that this resistance implies an increase in the doxorubicin efflux, preventing it from acting at its site of nuclear action. This efflux mechanism implies an original process involving the major vault protein MVP / LRP (Major Vault Protein / Lung Resistance Protein), a nucleocytoplasmic transporter whose function remains poorly understood to date. Following nuclear drug efflux, it accumulates in cytoplasmic vesicles before before being expelled from the cell via extracellular vesicles. We also showed that this resistance mediated by MVP could be explained by the soluble factors secreted from adipocytes and is amplified in obesity conditions. In conclusion, our findings highlight that peritumoral adipocytes are able to influence tumor progression by promoting chemoresistance via an original mechanism involving the MVP protein, which could potentially become a marker of resistance to treatments. This work may explain, at least in part, the poor prognosis of breast cancers in obese patients and thus could provide interesting therapeutic perspectives, in order to interrupt the deleterious dialogue between adipocytes and tumor cells, particularly in obese patients.

Batch experiments have been used to assess the sorption properties of a potential repository backfill, NRVB (Nirex Reference Vault Backfill). In this study, UO22+, Eu3+, Am3+ and Th4+ have been used as model radionuclides and ethylenediaminetetraacetic acid (EDTA), isosaccharinic acid (ISA) and humic acid (HA) as competing ligands. The NRVB is an effective scavenger of all radionuclides, with the majority sorbed within minutes. Ultrafiltration showed that for solutions of U in contact with NRVB, for the small amount of U remaining in solution, nearly all (79 %) was present as clusters or colloidal material in a very narrow and relatively small size range (0.9 – 1.4 nm); for Eu (> 94 %) is attached to large NRVB derived colloids or particulates; for Th (82 %) is present in the true solution; whilst for Am 58 % is in the true solution. High concentrations of EDTA (>0.01 M) were able to reduce the extent of sorption at apparent equilibrium for all metal ions. ISA was very effective as a competing ligand for all metal ions, generally at a lower concentration than EDTA in equivalent systems. Humic acid was found to be ineffective as a competing ligand at any realistic concentration. In all systems, there was evidence of significant irreversibility, with concentrations of EDTA and ISA that were able to prevent sorption unable to remove radionuclides from contaminated NRVB. For the uranyl systems, luminescence spectroscopy was used to analyse the mechanism of sorption. For CSH (calcium silicate hydrate), the spectra were consistent with surface complexation, followed by some degree of incorporation. For NRVB, the spectrum was dominated by a feature that was similar to uranyl sorbed to CSH as a surface complex and/or incorporated into the structure. There was also a minor component that was assigned as a calcium uranate like surface precipitate. The sorption data were fitted with a simple surface complexation model, which had a single surface binding site. The modelling showed that the uptake of all radionuclides is consistent with surface complexation or surface precipitation. The model was less effective at predicting the effects of the competing ligands on sorption. Thermodynamic speciation and surface complexation modelling were able to explain the behaviour in the systems qualitatively, but cannot be used to predict sorption absolutely.