Made available in DSpace on 2014-10-09T12:44:15Z (GMT). No. of bitstreams: 0 / Made available in DSpace on 2014-10-09T13:57:24Z (GMT). No. of bitstreams: 1 06884.pdf: 3958157 bytes, checksum: d230858464baf1ab2ee2867cf97407e4 (MD5) / Dissertacao (Mestrado) / IPEN/D / Instituto de Pesquisas Energeticas e Nucleares - IPEN/CNEN-SP

Background: Elucidating the role of intestinal drug transporter function in drug development is crucial, as transporter proteins can impact on drug absorption, efficacy and adverse events. In Vitro-In Vivo Extrapolation linked to Physiologically-Based Pharmacokinetic (IVIVE-PBPK) models aim to predict the in vivo impact of transporters from in vitro cell–based transport data and expression-based scaling factors. Currently, these models depend on relative measurements of transporter expression i.e., mRNA or immunoblotting. There is a critical need for physiologically relevant measures of transporter protein abundance to populate these biological frameworks. Objectives: The key objectives were to develop and validate a targeted proteomics workflow to quantify transporter protein abundances in human enterocytes and Caco-2 cells with a QconCAT technique. A cross-laboratory comparison on matched samples was also performed to assess between-laboratory bias in abundance determination. Together with abundance data from each laboratory, BCRP and P-gp transporter activities from Caco-2 cells were used to identify function-abundance relationships, to facilitate the potential development of abundance-function scaling factors. Results: Development of a differential centrifugation technique to obtain plasma membranes was undertaken using MDCK-II and Caco-2 cells. The plasma membrane fraction showed little enrichment from the preceding total membrane fraction and was contaminated with endoplasmic reticulum, as assessed by marker enzyme activities. There were also no differences in Na/K-ATPase, BCRP and P-gp abundances between plasma and total membrane fractions in Caco-2 cells. This may be due to losses of protein from the target membrane fraction, thus, a theoretical framework combining protein assay (BCA) and transporter abundance determinations was proposed. Pilot data on the generation of recovery correction factors using Villin and Na/K-ATPase abundances, to account for protein losses is also presented. The abundances of 6 transporters in jejunal enterocyte membranes (n=3), including the key efflux proteins BCRP (2.56±0.82 fmol/μg), P-gp (1.89±1.07 fmol/μg) and MRP2 (0.59±0.246 fmol/μg) were determined with precision. In addition, peptide losses during protein digestion stages were accounted for in abundance determinations. A cross laboratory comparison of transporter abundances from intestinal (n=4) and Caco-2 cells (n=7) measured in our laboratory and Bertin Pharma (BPh), showed that P-gp abundances were highly correlated (rs=0.72), yet BPh abundances were systematically lower than determined in our laboratory (2.0±2.08 versus. 4.8±3.51 fmol/μg, respectively). No differences or correlations were found for Na/K-ATPase and BCRP abundances between laboratories. A jejunal-Caco-2 cell relative expression factor (REF) for each protein for both laboratories was generated. The P-gp REF was similar for BPh and our laboratory (0.37 vs. 0.4, respectively) however, for BCRP there was a distinct difference (1.11 versus 2.22, respectively). These findings provide the first evidence that employing expression factors generated from abundances quantified in different laboratories may produce altered IVIVE-PBPK outcomes. Functional studies in Caco-2 cells using E-3-S and vinblastine as probes for BCRP and P-gp, respectively, show that protein abundance is more closely correlated to transporter activity than mRNA expression. In addition, it was only possible to verify that increasing P-gp abundances in Caco-2 cells were ranked alongside vinblastine intrinsic clearance, as there was little consistency when estimating Km between the different Caco-2 cell models expressing increasing P-gp abundances, which may be attributed to limited absorptive transport saturation. Thus, forming any conclusions with confidence on concentration dependent abundance-activity relationships was difficult. These data suggest the value of REF scaling factors based on protein abundances, but emphasises the need to generate these from both in vitro and in vivo samples, using the same proteomic workflow. Further work to verify abundance-function relationships is required. Conclusion: A targeted proteomic workflow has been developed allowing quantification of protein abundances for key drug transporters in human gut tissues and cell models. The study has highlighted important areas including losses of targeted proteins, contamination of plasma membrane fractions and standardisation between laboratories that need to be addressed before implementation of transporter abundances into PBPK models is undertaken. Nevertheless, the evidence for a close relationship between transporter abundance and function indicate the potential value of this data for generation of robust REF scaling factors.

How does gender-related legislation interact with the existing political, social, and religious norms? How do these interactions contribute to social changes, as well as to the theoretical discussion around gender norms and feminism in Africa? In the early 1990s, Africa saw a surge of women’s movements and activism supported by the wave of democratization on the continent. Along with discussions about women’s rights, there has been increased attention to how to improve women’s political visibility and participation in the region. Many countries have therefore turned to gender quotas and laws to remedy the relative absence of women in politics, and current research has partially shown that these legislative measures have some positive impact. Particularly, scholars have shown that gender quotas and laws have improved women’s political situation by discrediting the stereotypes that women are less capable than men, by increasing political opportunities for women, and by implementing policies directly related to women’s interests. This dissertation builds on these results and goes further by using the case of the gender parity law in Senegal to 1) examine some challenges these laws encounter, and 2) provide an African feminist framework. Based on in-depth interviews, ethnographic observation, and text analysis, the present research takes into account Senegal’s tradition, culture, and religion (Islam) to analyze the difficulties the gender parity law has had to face, including a weak legislative body and “religious justifications” as to why women should not hold the same political responsibilities as men. In a second part, the dissertation examines the discourse used by women in Senegal and highlights how the movement before and after the law, the language and the strategies used by the women can be interpreted within the larger debate in African feminist theories and traditions. Overall, the dissertation argues that 1) despite the initial success of the gender parity law, an overall consensus on the legitimacy of the law, especially from the male population, is still needed and the existing form of government (strong executive, weak legislative) and its effect on the law in the long term cannot be ignored. However, 2) the law remains part of the larger picture of the important and historical women’s movement in Senegal and contributes to the expansion of how to define gender norms specifically in Senegal and Africa.

Digital encoders are electro-mechanical sensors that measure linear or angular position using special binary patterns. The properties of these patterns influence the traits of the resulting encoders, such as their maximum speed, resolution, tolerance to error, or cost to manufacture. We describe a novel set of patterns that can be used in encoders that are simple and compact, but require some initial movement to register their position. Previous designs for such encoders, called absolute incremental encoders, tend to incorporate separate patterns for the functions of tracking incremental movement and determining the absolute position. The encoders in this work, however, use a single pattern that performs both functions, which maximizes information density and yields better resolution. Compared to existing absolute encoders, these absolute incremental encoders are much simpler with fewer pattern tracks and read heads, potentially allowing for lower-cost assembly of high resolution encoders. Furthermore, as the manufacturing requirements are less stringent, we expect such encoders may be suitable for use in D.I.Y. %27maker%27 projects, such as those undertaken recently by our lab.

A plot that includes multiple location and spread statistics can provide useful information about the shape of a distribution, not only with respect to location and variability but also with respect to skewness and kurtosis. We propose a plot containing the interquartile range, mean absolute deviation, standard deviation, and range of a dataset. The comparison of the spread statistics gives information about kurtosis and the comparison of the location statistics gives information about skewness. After the distribution has been divided into two parts by the median, the interquartile range can be thought of as the distance between the medians in each half of the distribution. We explain how the mean absolute deviation with respect to the median can similarly be visualized as half the distance between the means in each half of the distribution. An R function to produce the polyplot is available as an online supplement.

A new confidence interval for the coefficient of dispersion (mean absolute deviation from the median divided by median) is proposed and is shown to perform better than the BCa bootstrap confidence interval.

The Swedish healthcare system strives to maximize the health of the population and at the same time consider a fair distribution of health. In this consideration, the severity of disease is an important attribute as high severity signals a higher need for healthcare. Currently, the Dental and pharmaceuticals benefits agency (TLV) operationalizes this approach by striking a balance between efficiency and equity when deciding which prescription pharmaceuticals that should be reimbursed. The agency uses a qualitative approach to assess the severity of diseases. There are however quantitative methods that can be used to assess disease severity such as absolute and proportional shortfall, indicating how much health is lost compared to the general population. In this study, we quantify the severity of different diseases using absolute and proportional shortfall based on information available from TLV decisions and compare those with the agency´s qualitative assessment. To quantify severity, we use data from publicly available decision-documents from TLV and estimated health of the general population.  The results show that quantitative assessments of disease severity with absolute and proportional shortfall differ from the qualitative assessments made by TLV. A large range of absolute and proportional shortfall estimates was observed for diseases assessed to have a specific severity by TLV. A quantitative approach to disease severity could contribute to a more objective severity assessments than current practice. Furthermore, as disease severity is an important aspect of TLV´s prioritization a quantitative assessment could contribute to a fairer allocation of resources in healthcare. / Den svenska sjukvården strävar efter att maximera hälsan hos befolkningen samtidigt som hänsynskall tas till hur hälsan fördelas. Hur vårdens knappa resurser skall fördelas bygger på tre principerfrån en etisk plattform: människovärdesprincipen, behovs- och solidaritetsprincipen ochkostnadseffektivitetsprincipen. Sjukdomars svårighetsgrad är därmed en viktig prioriteringsgrundnär sjukvårdens resurser skall fördelas eftersom hög svårighetsgrad innebär ett större behov avvård. Tandvårds- och läkedelsförmånsverket (TLV) använder exempelvis denna ansats vid beslutom vilka förskrivningsläkemedel som skall få subvention. TLV använder idag en kvalitativ ansatsi bedömningen av svårighetsgrad. Det finns även kvantitativa metoder som bygger på hur myckethälsa patienter förväntas förlora jämfört med individer utan sjukdom, så kallade shortfallmått. Idenna studie kvantifierar vi svårighetsgraden med absolute och proportional shortfall försjukdomar som varit föremål för beslut av TLV och jämför dessa med TLV:s kvalitativabedömningar. För att kvantifiera svårighetsgraden används data från TLV:s beslutsunderlag samtskattad hälsa i normalpopulationen. Resultaten visar att de kvantitativa skattningarna av svårighetsgrad med absolute och proportionalshortfall skiljer sig från de kvalitativa bedömningarna från TLV. Det förekommer ett stort spannav absolute och proportional shortfall för sjukdomar med en specifik svårighetsgrad bedömd avTLV. En kvantitativ ansats kan därmed bidra till mer objektiva skattningar av svårighetsgradjämfört med dagens kvalitativa ansats. Eftersom bedömningen av svårighetsgrad är en viktig delav TLV:s prioriteringsbeslut är ett förslag att myndighetens kvalitativa ansats kompletteras medkvantitativa mått för att säkerställa en rättvis och effektiv resursfördelning inom hälso- ochsjukvården.

<p> A series capillary viscometer has been used to measure the viscosity of nitrogen and air over a temperature range of 100 to 400°K and to pressures of 150 atmospheres. </p> <p>The low pressure results have been correlated using a modified Sutherland equation of the form: n = C1T^C2 / T+C3 </p> <p> Intermolecular force constants have been computed for nitrogen using the Chapman Enskog collision theory approach.</p> <p> The viscosity in the dense gas region was correlated using equations of the form n-no = A1ρ + A2ρ^2 and thus overall equations for viscosity as a function of temperature and density were formulated as n = C1T^C2 / T+C3 +A1ρ + A2ρ^2 </p> <p> These equations were used to generate tables of smoothed values of viscosity as a function of pressure and temperature.</p> / Thesis / Master of Engineering (MEngr)

During the 1920s, the Midwestern American architect Bruce Goff advanced a unique design approach that would govern his career: "Good architecture for everyone." Following the First World War, this period is considered the end of the Victorian and Edwardian era and "American innocence," and the beginning of the modern era—the 20th century. Goff challenged the predominant views of progressive modernism, the belief that science and technology were to be the "grand solution" to society's weaknesses. In contrast to his contemporaries who employed design methods of standardized building forms, mass production, and technology, which would later lead to societal alienation, Goff viewed his clients as individuals possessing a mind, a body, and a spirit living in a world together with other human beings. He believed that each person is endowed with five or more senses that "always" respond to Nature and its beauty. This dissertation will show that such an experiential and existential attitude is found in Goff's drawings, writings, lectures, and interviews and expressed in a clear commitment to the Bavingers (as clients), to their chosen site, and the architectural experiences designed for the Bavinger House. Informed by Gaston Bachelard's, poetic imagination, three journeys to and through the Bavinger House, reconstructed by generating drawings and bringing together a manifold of experiential methodologies to argue the claim that the Bavinger House is the preeminent paradigmatic example of Goff's work. The goal is to establish that Goff was indeed, a poetic architect who employed an imaginative organicism in his work. / Doctor of Philosophy / During the 1920s, the Midwestern American architect Bruce Goff advanced a unique design approach that would govern his career: "Good architecture for everyone." Following the First World War, this period is considered the end of the Victorian and Edwardian era and "American innocence," and the beginning of the modern era—the 20th century. Goff challenged the predominant views of progressive modernism, the belief that science and technology were to be the "grand solution" to society's weaknesses. In contrast to his contemporaries who employed design methods of standardized building forms, mass production, and technology, which would later lead to societal alienation, Goff viewed his clients as individuals possessing a mind, a body, and a spirit living in a world together with other human beings. He believed that each person is endowed with five or more senses that "always" respond to Nature and its beauty. This dissertation will show that such an experiential and existential attitude is found in Goff's drawings, writings, lectures, and interviews and expressed in a clear commitment to the Bavingers (as clients), to their chosen site, and the architectural experiences designed for the Bavinger House. Informed by Gaston Bachelard's, poetic imagination, three journeys to and through the Bavinger House, reconstructed by generating drawings and bringing together a manifold of experiential methodologies to argue the claim that the Bavinger House is the preeminent paradigmatic example of Goff's work. The goal is to establish that Goff was indeed, a poetic architect who employed an imaginative organicism in his work.

Studien undersöker hur självupplevt absolut gehör (SAG) påverkar musikundervisningen i skolan. Fyra musikpedagoger med SAG har intervjuats och gett sin syn på fenomenet; hur de anser att deras SAG färgar/påverkar musikundervisningen och deras didaktik samt hur det påverkar deras eget musicerande. Semistrukturerade intervjuer har använts som metod. Resultatdelen visar att SAG är till stor nytta vid transkribering av musik, vid ensembleundervisning och i det personliga musicerandet. Informanterna menar att SAG gör dem mer fria och mindre pappersbundna när de musicerar med andra. SAG kan dock vara en belastning vid körledning/körsång (särskilt då körens tonhöjd stiger eller sjunker) och i situationer då transponerade instrument används. Informanterna anser inte att deras SAG har haft några negativa effekter på deras relativa gehör (RG).