Compte tenu de l'absence de traitement pharmacologique efficace contre la maladie d'Alzheimer (MA), le développement d'approches thérapeutiques alternatives telles que le régime cétogène (« ketogenic diet » : KD) pourrait être envisagé. Le KD est un régime riche en graisses, basé sur la production de corps cétoniques (« ketone nodies » : KB) dans le sang. En raison des effets bénéfiques du KD sur le système nerveux central et de l'absence de données publiées sur la barrière hémato-encéphalique (BHE), nous avons utilisé une approche in vivo / in vitro pour étudier l'effet du KD et des KB sur la BHE. Pour l'étude in vivo, le sang de souris 129Sv a été récolté afin d’effectuer le dosage du beta-hydroxybutyrate et du glucose. Les capillaires cérébraux ont été isolés de cortex des souris, et des RT-qPCR ont été effectuées pour évaluer l'expression de l'ARNm des transporteurs / récepteurs impliqués dans la synthèse et le transport de KB, de glucose et du peptide bêta amyloïde. Les analyses transcriptionnelles ont été réalisées également dans un modèle in vitro de BHE, composé de cellules endothéliales dérivées de cellules souches hématopoïétiques (BLECs) en état de cétose. Après confirmation de l'intégrité des jonctions cellulaires des BLECs, Enfin, des expériences de transport de peptides beta amyloïde fluorescents après traitement avec les KBs ont été réalisées in vitro. Nos résultats montrent que les KBs modulent la physiologie de la BBB et l'expression de certains transporteurs et récepteurs du peptide bêta amyloïde, renforcent ainsi notre motivation à décrypter les mécanismes moléculaires et cellulaires au niveau vasculaire et plus précisément au niveau de la BHE. / Given the current absence of an effective pharmacologic treatment for Alzheimer’s disease (AD), the development of alternative therapeutic approaches (such as the ketogenic diet, KD) might be considered. The KD is a low-carbohydrate, high-fat diet based on the production of ketone bodies (KBs) in the blood. In view of the KD’s beneficial effects on the central nervous system and the lack of published data on the blood brain barrier (BBB), we used an in vivo/in vitro approach to investigate the effect of the KD and KBs on the BBB. For the in vivo study, blood from 129Sv mice was assayed for beta-hydroxybutyrate and glucose dosage. Brain capillaries were isolated from mouse cortices, and RT-qPCR assays were used to evaluate the mRNA expression of transporters/receptors involved in the synthesis and transport of KBs, glucose and beta-amyloid peptide. The mRNA assays were also performed in an in vitro BBB model, based on brain-like endothelial cells (BLECs). After a ketotic state had been established and the BLECs’ integrity had been confirmed, we evaluated the mRNA expression of KB-, glucose- and amyloid-beta-related genes. Lastly, the transport of fluorescently labelled beta-amyloid peptide across the BBB was studied after treatment with KBs. Our results showed that KBs modulate the physiology of the BBB by regulating the expression of certain beta-amyloid peptide transporters/receptors and amyloid peptide-synthesizing enzymes. These data suggest that it is possible to modulate key molecular players in beta-amyloid peptide transport and synthesis at the BBB, and thus open up new perspectives for studying KB-related therapeutic approaches.

Thesis (M. Arch.)--Massachusetts Institute of Technology, Dept. of Architecture, 1988. / Includes bibliographical references (leaf 139). / The particular subject of this thesis is Housing for the Elderly. The intention is to propose an architecture which springs from an alternative attitude towards housing the elderly ... an attitude which purports that multiplicity and exchange are the elements crucial to one's well-being; in contrast to the current paradigm within the world of planning for the elderly ... one of segregation, classification and singularity. With a little license, I call this a research and design thesis, as it has been difficult to define. As a 'research' paper, it entails the use of a particular method of selecting, understanding, and (finally) using a range of references in order to distill from them some underlying principles of form. Yet unlike a true research thesis, it is loosely structured and left open-ended ... intentionally so! The 'design' work provides the testing ground for the principles gleaned from those references. It also allows me the opportunity to exercise myself in synthesizing and arranging architecture. Yet as a design thesis, the work is only the start of an architecture process ... far from being complete. In essence, the thesis is an endeavour in knowing a little more about the 'dancing' between referencing and designing. / by Julia A. Campbell. / M.Arch.

Thesis. 1975. M.Arch.--Massachusetts Institute of Technology. Dept. of Architecture. / Bibliography: leaves 166-167. / M.Arch.

Thesis. 1979. M.C.P.--Massachusetts Institute of Technology. Dept. of Urban Studies and Planning. / MICROFICHE COPY AVAILABLE IN ARCHIVES AND ROTCH. / Bibliography: leaves 115-119. / M.C.P.

The blood-brain barrier (BBB) is physiologically essential for brain homeostasis. While it protects the brain from noxious agents, it prevents almost all currently available drugs from crossing to the parenchyma. This greatly hinders drug delivery for the treatment of neurological diseases and disorders such as Parkinson’s, Alzheimer’s and Huntington’s, as well as the development of drugs for the treatment of such diseases. Current drug delivery techniques to the brain are either invasive and target specific, or non-invasive with low special specificity. Neither group of techniques are optimal for long term treatment of patients with neurological diseases or disorders. Focused ultrasound coupled with intravenous administration of microbubbles (FUS) has been proven as an effective technique to selectively and noninvasively open the BBB in multiple in vivo models including non-human primates (NHP). Although this technique has promising potential for clinical outpatient procedures, as well as a powerful tool in the lab, the safety and potential neurological effects of this technique need to be further investigated. This thesis focuses on validating the safety and efficacy of using the FUS technique to open the BBB in NHP as well as the ability of the technique to facility drug delivery. First, a longitudinal study of repeatedly applying the FUS technique targeting the basal ganglia region in four NHP was conducted to determine any potential long-term adverse side effects over a duration of 4-20 months. The safety of the technique was evaluated using both MRI as well as behavioral testing. Results demonstrated that repeated application of the FUS technique to the basal ganglia in NHP did not generate permanent side effects, nor did it induce a permanent opening of the BBB in the targeted region. The second study investigated the potential of the FUS technique as a method to deliver drugs, such as a low dose of haloperidol, to the basal ganglia in NHP and mice to elicit pharmacodynamical effects on responses to behavioral tasks. After opening the BBB in the basal ganglia of mice and NHP, a low dose of haloperidol was successfully delivered generating significant changes in their baseline motor responses to behavioral tasks. Domperidone was also successfully delivered to the caudate of NHP after opening the BBB and induced transient hemilateral neglect. In the final section of this thesis, the safety and efficacy of the FUS technique was evaluated in fully alert NHP. The FUS technique was successful in generating BBB opening volumes larger on average to that of the BBB opening volumes in anesthetized experiments. Safety results through MRI verification as well as behavioral testing during application of the technique demonstrated that the FUS technique did not generate adverse neurological effects. Conversely, the FUS technique was found to induce slight positive effects on the response of the NHP to the behavioral task. Collectively, the work presented in this thesis demonstrates the safety and effectiveness of the FUS technique to open the BBB and deliver neuroactive drugs in the NHP.

O treinamento aeróbio de forma crônica está correlacionado com menor grau de inflamação e pode ser considerado um dos principais responsáveis por criar condições favoráveis para o equilíbrio intestinal. A mucosa do intestino consiste em uma monocamada de células epiteliais com função principal de absorção de nutrientes e formação de barreira contra entrada de potenciais antígenos que podem prejudicar sua função. A permeabilidade da barreira intestinal pode ser controlada por diferentes processos. Um aumento de antígenos luminais como lipopolissacarídeo (LPS) pode gerar um aumento na permeabilidade paracelular através de quebra das principais proteínas de função barreira, claudina e ocludina, ativando o sistema imune local, levando a um processo de inflamação e dano do tecido. Essas alterações da função barreira estão ligadas com algumas doenças como a doença inflamatória intestinal e o câncer. Por essa razão, faz-se necessário entender o papel do exercício físico na regulação da integridade da mucosa intestinal e seu efeito terapêutico. Assim, o objetivo deste trabalho é avaliar o efeito do treinamento aeróbio sobre a morfologia e função barreira da mucosa intestinal em ratos wistar. Na primeira etapa, os animais foram divididos em 2 grupos: grupo 1 - controle sedentário (CTRL), grupo 2 - treinado (T) e desenvolvido um treinamento aeróbio durante 8 semanas com uma carga correspondente a 65% da velocidade máxima atingida no teste de exercício físico progressivo até a exaustão, por 60 minutos durante 5 vezes por semana. 9 O treinamento físico promoveu uma maior perda de peso nos animais treinados sem aumento do consumo de ração comparado com animais sedentários. A segunda etapa ocorreu após o período de treinamento para um tratamento com 3 dias de injeção de LPS intraperitoneal. Os animais foram divididos em 4 subgrupos: grupo 1 - controle sedentário (CTRL), grupo 2 - treinado (T), grupo 3 - controle sedentário com LPS (CTRL + LPS) e grupo 4 - treinado com LPS (treinado + LPS). Os animais sedentários com LPS apresentaram uma maior perda de peso e menor consumo de ração além de maior perda de altura das vilosidades intestinais em detrimento ao maior grau de inflamação com aumento também de infiltrados no cólon. Em contrapartida, o treinamento físico apresentou um efeito protetor sobre a perda de peso e as vilosidades intestinais observados nos animais treinados com LPS. Além disso, foi analisado a expressão gênica de algumas interleucinas pró e anti-inflamatórias (IL 1?, IL 6, IL 10 e IL 23) e os genes para claudina 1 e ocludina. O principal aumento foi observado no perfil gênico da IL23 uma citocina pró inflamatória e da claudina 1 nos animais sedentários com LPS em comparação ao controle como uma ação compensatória para reparação da permeabilidade intestinal e função barreira. Juntos, esses resultados apoiam a hipótese de que o treinamento físico é um fator importante para proteção da integridade da mucosa e função barreira intestinal / Chronic aerobic training correlates with low level of inflammation and is considered one of the main factors in creating favorable conditions for intestinal balance. The intestinal mucosa consists of a monolayer of epithelial cells whose the main function is to absorb nutrients and form a barrier against entry of potential antigens that may impair its function. Different processes control the permeability of the intestinal barrier. An increase in luminal antigens such as lipopolysaccharides (LPS) may lead to an increase in paracellular permeability through the breakdown of the main barrier proteins, claudin and occludin, activating the local immune system, leading to a process of inflammation and tissue damage. These changes in barrier function are linked to some pathologies including inflammatory bowel disease and cancer. For this reason, it is necessary to understand the role of physical exercise in regulating the integrity of the intestinal mucosa and its therapeutic effect. Thus, the objective of this study was to evaluate the effect of aerobic training on the morphology and barrier function of the intestinal mucosa in wistar rats. For the first stage of this project, animals were separated into 2 groups: group 1 - sedentary control (CTRL), group 2 - trained (T) which involved 8 weeks of aerobic training, five sessions of one hour, with a load corresponding to 65% of the maximum speed attained in a progressive exercise test to exhaustion. Physical training promoted weight loss in trained animals without increased 11 feed intake compared to sedentary animals. The second stage of this project was performed after the training period and involved 3 days of intraperitoneal LPS injections. The animals were separated into 4 subgroups: group 1 - sedentary control (CTRL), group 2 - trained (T), group 3 - sedentary control with LPS (CTRL + LPS) and group 4 - trained with LPS (trained + LPS). Sedentary LPS animals presented greater weight loss and lower feed intake, as well as greater height loss of intestinal villi, a higher degree of inflammation and also increased colon infiltrates. In contrast, physical training had a protective effect on weight loss and intestinal villi in animals who trained and received LPS. In addition, gene expression of some pro and anti-inflammatory interleukins (IL-1?, IL-6, IL-10 and IL-23) and the genes for claudin 1 and occludin were analyzed. The main increase was shown in the gene profile of IL23 a proinflammatory cytokine and claudin 1 in sedentary with LPS animals as a compensatory action for repair of intestinal permeability and barrier function. Together, these results support the hypothesis that physical training is an important factor for protection of mucosal integrity and intestinal barrier function

A distância de visibilidade de parada deve ser garantida ao longo de toda a extensão de uma rodovia por questões de segurança. Elementos da seção transversal podem se tornar obstruções que interferem nas distâncias de visibilidade do projeto. Este é o caso do uso de barreiras ao invés de canteiros centrais em rodovias bidirecionais, especialmente ao longo de curvas à esquerda. Desta forma, este trabalho analisa o posicionamento de barreiras em cenários hipotéticos aclives planos e declives com uso de simulações gráficas tridimensionais. O afastamento lateral da barreira, em relação à pista de rolamento, foi definido em função de cada velocidade de projeto e de cada raio de curva horizontal analisados. Os diagramas gerados foram comparados com modelo de afastamento de objetos fixos em curvas horizontais, presente como recomendações em manuais nacionais. As diferenças encontradas indicam a viabilidade da metodologia utilizada, em que o projeto foi considerado como um todo, o qual se desenvolve tridimensionalmente. / Stopping Sight Distance must be guaranteed throughout of a highway for safety reasons. However, cross section elements can become obstructions which interfere on design sight distances. This occurs when barriers are used instead of medians on bidirectional highways, especially along left curves. Therefore, this paper analyzes the barriers placement on hypothetical scenarios upgrades, plans and downgrades using three-dimensional graphics simulations. The lateral offset of the barrier in relation to the roadway was defined according to each design speed and each radius of the horizontal curve analysis. For each scenario were generated diagrams, which use compared with offset model of fixed objects on horizontal curves presents as recommendation in national manuals. The differences indicate the viability of the methodology used, where the project was considered as a whole, which develops three-dimensionally.

Residual stresses are generally considered to be the driving forces for the failure of APS TBCs. In this thesis, the residual stress distribution as a function of depth in APS TBC has been measured by synchrotron XRD and explained by image based modelling based on the microstructure detailed studied by SEM and CT. The residual stress/ strain distribution as a function of depth was measured by synchrotron XRD in transmission and reflection geometry. The residual stress/ strain values were analysed using full pattern Rietveld refinement, the sin square psi method and XRD2 method. For the reflection geometry, a new method was developed to deconvolute the residual stress value in each depth from the measured averaged values. Two types of residual stress/strain distribution were observed. The first kind of residual stress was found to be compressive and followed a non-linear trend, which increased from the surface to the interface, decreased slightly and increased again to the interface. This trend showed a jump feature near the interface. The second kind of residual stress distribution possessed two jump features: one near the interface similar to the first kind and another jump feature near the sample surface. The residual stress in both beta and gama phase in the bond coat were also investigated which showed a tensile stress state. The stress trend predicted by our analytical model followed a linear relationship. Comparing this with the first kind of residual stress distribution, two main differences were shown. Firstly the jump feature near the interface and secondly the much larger overall stress gradient. The 3D and 2D microstructure of the sample with the first kind of residual stress distribution was observed by X-ray CT and SEM. The effect of pores, inter-splat cracks and the rumpling interface on the residual stress distribution was investigated by image based modelling. It was proved that the pores and the inter-splat cracks had no large influence on the stress distribution and the jump feature near the interface was a result of the rumpling interface. The much larger stress gradient observed in the measured residual stress distribution was an indication of the stress relaxation in the coating which was proved by a specially designed mechanical test. To explain the jump feature near the sample surface in the second kind of stress distribution. 3D microstructures of the measured samples were observed using X-ray CT. The effect of vertical and the side cracks on the stress distribution were investigated by image based modelling. It was found that the vertical crack had no large influence on the residual stress distribution and the jump feature in the stress trend near the surface could be attributed to the side crack. The effect of other kinds of cracks that were not directly observed in our samples, such as middle or through side cracks, were also investigated. These results were used to develop a semi-destructive method to determine the existence and distribution of cracks in APS TBC.

The nuclear waste inventory of the UK comprises large quantities of intermediate level wastes (ILW), which will be immobilised by encapsulation within a cementitious grout in stainless steel containers, followed by disposal in a deep engineered geological disposal facility (GDF) within a suitable geological formation. These wastes contain, in addition to radioactive elements, a heterogeneous mix of organic materials, including plastics, cellulose and rubber. Cellulosic items, such as cloth, tissue, filters, paper and wood, are considered particularly problematic, because they are known to be susceptible to degradation under alkaline conditions, forming small chain organic acids with the ability to complex metals and radionuclides. It is predicted that under alkaline conditions isosaccharinic acid (ISA) will form particularly strong complexes with Ni(II), Am(III), Eu(III), Np(IV), Th(IV), and U(IV). As a result, the presence of ISA could affect the migration behaviour of these elements, by increasing their solubility and reducing sorption, thus enhancing their mobility into the near and far field surrounding a GDF. During site operation and then after closure of a GDF, microbial communities have the potential to colonise the steep biogeochemical gradients, running from highly alkaline in the GDF “near field” to circumneutral pH conditions in the surrounding geosphere. Within these steep pH gradients microbial processes can control the fate of organic compounds, such as ISA, and have therefore been considered as an effective self-attenuating mechanism to remove ISA from the groundwater. This thesis aims to deliver a greater understanding of the microbial processes that can potentially use ISA as a carbon source and electron donor, removing it from solution, and thus having a positive impact on radionuclide mobility under GDF-relevant conditions. A microbial enrichment approach was chosen that approaches GDF-relevant conditions to explore the biodegradation of ISA. Cross-disciplinary analyses of water chemistry (pH, Eh, photospectroscopy, IC, ICP), mineralogy (ESEM, XRD, TEM, XAS) and microbiology (light microscopy, next generation sequencing) have demonstrated the ability of bacteria to degrade ISA over a wide range of biogeochemical conditions. Furthermore, key radionuclides (and their non-active analogues), including Ni(II) and U(VI), were precipitated from the groundwater system during ISA biodegradation. Moreover, in the case of uranium, microbial metabolism led to the reduction of U(VI) to U(IV), which is also less soluble. This study highlights the potential for microbial activity to help remove chelating agents from groundwaters surrounding an ILW GDF, and suggests that safety cases that do not include microbial processes may be overly conservative, over-estimating the impact of ISA on radionuclide transport.

The literature suggests that when taking tax effects into account, debt ought to be preferable to equity. Thus, with all else being equal, levered firms are expected to show higher firm values. However, there are no uniform predictions of the size of this tax benefit from interest deductibility nor on the effect of changes in interest deductibility. We believe that the German corporate tax reform in 2008, which introduced an interest barrier, can serve as a promising "quasiexperiment" to investigate the effects from a reform of interest deductibility. A study of this reform on the basis of German financial statement data is of general interest because, first, similar interest barriers have been introduced in several countries and proposed by the OECD to fight BEPS. Second, the major characteristics of the German tax system can be regarded as representative for most European and major Asian countries. Third, single entity financial statements for German companies allows us to capture tax and capital structure details that have not been available in most prior studies. With significance at the 5% level, we find evidence that the companies that are affected by the interest barrier reduce their leverage by 4.7 percentage points more than companies that are not affected by the interest barrier. We are the first to employ a detailed matching approach to the underlying rich dataset, which enables us to overcome several limitations of previous studies. Our results imply that capital structure reactions most likely have been underestimated in previous studies. / Series: WU International Taxation Research Paper Series