875 resultados para Bad smells
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Poor pharmacokinetics is one of the reasons for the withdrawal of drug candidates from clinical trials. There is an urgent need for investigating in vitro ADME (absorption, distribution, metabolism and excretion) properties and recognising unsuitable drug candidates as early as possible in the drug development process. Current throughput of in vitro ADME profiling is insufficient because effective new synthesis techniques, such as drug design in silico and combinatorial synthesis, have vastly increased the number of drug candidates. Assay technologies for larger sets of compounds than are currently feasible are critically needed. The first part of this work focused on the evaluation of cocktail strategy in studies of drug permeability and metabolic stability. N-in-one liquid chromatography-tandem mass spectrometry (LC/MS/MS) methods were developed and validated for the multiple component analysis of samples in cocktail experiments. Together, cocktail dosing and LC/MS/MS were found to form an effective tool for increasing throughput. First, cocktail dosing, i.e. the use of a mixture of many test compounds, was applied in permeability experiments with Caco-2 cell culture, which is a widely used in vitro model for small intestinal absorption. A cocktail of 7-10 reference compounds was successfully evaluated for standardization and routine testing of the performance of Caco-2 cell cultures. Secondly, cocktail strategy was used in metabolic stability studies of drugs with UGT isoenzymes, which are one of the most important phase II drug metabolizing enzymes. The study confirmed that the determination of intrinsic clearance (Clint) as a cocktail of seven substrates is possible. The LC/MS/MS methods that were developed were fast and reliable for the quantitative analysis of a heterogenous set of drugs from Caco-2 permeability experiments and the set of glucuronides from in vitro stability experiments. The performance of a new ionization technique, atmospheric pressure photoionization (APPI), was evaluated through comparison with electrospray ionization (ESI), where both techniques were used for the analysis of Caco-2 samples. Like ESI, also APPI proved to be a reliable technique for the analysis of Caco-2 samples and even more flexible than ESI because of the wider dynamic linear range. The second part of the experimental study focused on metabolite profiling. Different mass spectrometric instruments and commercially available software tools were investigated for profiling metabolites in urine and hepatocyte samples. All the instruments tested (triple quadrupole, quadrupole time-of-flight, ion trap) exhibited some good and some bad features in searching for and identifying of expected and non-expected metabolites. Although, current profiling software is helpful, it is still insufficient. Thus a time-consuming largely manual approach is still required for metabolite profiling from complex biological matrices.
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This Master's thesis examines two opposite nationalistic discourses on the revolution of Zanzibar. Chama cha Mapinduzi (CCM), the party in power since the 1964 revolution defends its revolutionary and "African" heritage in the current multi-party system. New nationalists, including among others the main opposition party Civic United Front (CUF), question both the 1964 revolution and the post-revolution period and blame CCM for empty promises, corruption and ethnic discrimination. This study analyzes the role of a significant historical event in the creation of nationalistic ideology and national identity. The 1964 revolution forms the nucleus of various debates related to the history of Zanzibar: slavery, colonialism, racial discrimination and political violence. Representations of these Social constructivist principles form the basis of this study, and central concepts in the theoretical framework are nationalism, national identity, ethnicity and race. I use critical discourse analysis as my research method, lean on the work by Teun A. van Dijk and Norman Fairclough as the most significant researchers in this field. I examine particularly the ways in which linguistic methods, such as stereotypes and metaphors are used to form in- and out-groups ("us" vs. "others"). My material, both in Swahili and English, was collected mainly in Tanzania in the fall of 2007 and from online sources in the spring of 2009. It includes publications by the Zanzibari government between the years of 1964-2000 (12), official speeches for the Revolution Day or the Union Day (12), articles from Tanzanian newspapers from the 1990s until the year of 2009 (15), memoirs and political pamphlets (10), blog posts and opinion pieces from four different websites (8), and interviews or personal communication in Zanzibar, Dar es Salaam and Uppsala (8). Nationalistic rhetoric often creates enemy images by using binary good-bad oppositions. Both discourses in this study build identities on the basis of "otherness" and exclusion, with the intent of emphasizing the particularity of the own group and excluding "evilness" outside the own reference group. These opposite views on the 1964 revolution as the main axis of the history of Zanzibar build different portraits of the nation and Zanzibari-ness (Uzanzibari). CCM still relies on the pre-revolutionary enemy images of Arabs as selfish rulers and cruel slave traders. For CCM, Zanzibar is primarily an "African" nation and a part of Tanzania which is threatened by "Arabs", the outsiders. In contrast, the new nationalists stress the long history of Zanzibar as multi-racial, cosmopolitan and formerly independent country which has its own, separate culture and identity from mainland Tanzanians. Heshima, honour/respect, one of the basic values of Swahili culture, occupies a central role in both discourses: the main party emphasizes that the revolution returned "heshima" to the Zanzibari Africans after centuries of humiliation, whereas the new nationalists claim that ever since the revolution all "non-Africans" have been humiliated and lost their "heshima". According to the new nationalists, true Zanzibari values which include tolerance and harmony between different "races" were lost when the "foreign" revolutionaries arrived from the mainland. Consequently, they see the 1964 revolution as Tanganyikan colonialism which began with the help of Western countries, and maintain that this "colonialism" still continues in the violent multi-party elections.
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The Forest devil. Businessman Erik Johan Längman (1799 1863) in the transition of economic system In Finnish historiography, Erik Johan Längman (1799-1863) bears a bad reputation of his own level: a mean, profit-seeking businessman who did not care too much about methods in his operations. Although little known, Längman has been praised as one of the pioneers of modern industry in the Grand Duchy of Finland, which belonged to the Russian Empire. From the mid 1830s Längman owned iron mill and several sawmills around the country. The growing demand of the markets in the 1830s, especially in Great Britain, marked a strong stimulus to Finnish lumber industry. At the same time claims for stricter rule over the sawmill industry were raised by high officials. The momentum of the conflict, the Forest Act of 1851, brought an end to illegal overproduction. In this biography, particular emphasis is laid on the entrepreneurial behaviour of Längman, but also on the effect the entrepreneurs had on the Crown s policies. On the other hand, how did the limitations imposed by the Crown guide the actions of the sawmill owners? The solutions adopted by the sawmill owners and the manoeuvring of the government are in a constant dialogue in this study. The Finnish sawmill industry experienced a major change in its techniques and methods of acquiring timber during the 1830s. Längman particularly, with his acquisition organisation, was able to find and reach faraway forests with unexpected results. The official regulating system with its strict producing quotas couldn t follow the changes. When the battle against the sawmill industry really started on, in 1840, it didn t happen for the benefit of iron industry, as argued previously, but to save Crown forests from depletion. After the mid 1840s Längman and the leader of the Finnish nationalistic movement, J. V. Snellman questioned the rationality of the entire regulation system and in doing so they also posed a threat against the aristocratic power. The influential but now also badly provoked chairman of the economic division of senate, Lars Gabriel von Haartman, accused the sawmill-owners harder than ever and took the advantage of the reactionary spirit of imperial Russia to launch the state forest administration. Längman circumvented the conditions of privileges, felled Crown forests illegally and accusations were brought against him for destroying his competitors. The repeated conflicts spoke primarily about a superior business idea and organisational ability. Although Längman spent his last years mostly abroad he still had interests in Finnish timber business when the liberation of sawmill-industry was established, in 1861. Surprisingly, the antagonism around the Crown forests continued, probably even more heated.
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In the opening pages of Selling Sex we are introduced to 'Joy', a statue of a young female sex worker which stood in East Sydney for eighteen months during 1995- 1997. Following complaints by local residents, the statue was removed from public view and returned to its owner. Evidently, Joy was considered a reminder of the community's 'bad old days', when it was better known for prostitution than restaurants. In a nation in which almost every sizable community has proudly erected monuments to military men, the removal of Joy reveals much about labour and gender relations in Australia. For Frances, the removal of Joy is symbolic, our historical treatment of sex workers having parallels with our treatment of the convicts. This work sets out to give these women (male prostitutes do not figure in this history) a voice and break with the stereotypes of 'abandoned whores' or 'sad victims'. It also sets out to place the sex industry in the broader national and international context in which it has historically operated...
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If the sociology of deviance ‘died’ a few years back, as some have claimed, the continuing significance of deviance for sociologists, in both research and teaching, might be explained in terms of a ‘resurrection’. Sharyn Roach Anleu has been spreading both the good and bad news about deviance for some years now, this being not merely the second coming of her text, but its fourth. In terms of Australian tertiary publishing, this is no small accomplishment and gives further weight to the durability of sociological concern with the sub-field of deviance...
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We discuss the consistency, unitarity and Lorentz invariance of an anomalous U(1) gauge theory in four dimensions. Our analysis is based on an effective low-energy action valid in the chiral symmetry broken phase. The allegedly bad properties of anomalous theories (except non-renormalizability) are examined. It is shown that, in the low-energy context, the theory can be consistently and unitarily quantised, and is formally Lorentz covariant.
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The use of near infrared (NIR) hyperspectral imaging and hyperspectral image analysis for distinguishing between hard, intermediate and soft maize kernels from inbred lines was evaluated. NIR hyperspectral images of two sets (12 and 24 kernels) of whole maize kernels were acquired using a Spectral Dimensions MatrixNIR camera with a spectral range of 960-1662 nm and a sisuChema SWIR (short wave infrared) hyperspectral pushbroom imaging system with a spectral range of 1000-2498 nm. Exploratory principal component analysis (PCA) was used on absorbance images to remove background, bad pixels and shading. On the cleaned images. PCA could be used effectively to find histological classes including glassy (hard) and floury (soft) endosperm. PCA illustrated a distinct difference between glassy and floury endosperm along principal component (PC) three on the MatrixNIR and PC two on the sisuChema with two distinguishable clusters. Subsequently partial least squares discriminant analysis (PLS-DA) was applied to build a classification model. The PLS-DA model from the MatrixNIR image (12 kernels) resulted in root mean square error of prediction (RMSEP) value of 0.18. This was repeated on the MatrixNIR image of the 24 kernels which resulted in RMSEP of 0.18. The sisuChema image yielded RMSEP value of 0.29. The reproducible results obtained with the different data sets indicate that the method proposed in this paper has a real potential for future classification uses.
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"Klo-Ku-Ba" the first apartment of Hans and Elizabeth in the basement of the Jewish Hospital in Hannover, Germany. The one room served as kitchen, bedroom, and bathroom which was shared by the other residents on the medical staff. Klo-Ku-Ba: Klosett, Kueche, Bad
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The aim of this research is to study the boundary zone of home and work and the tensions people experience while reconciling home and work? How are the requirements of the family, the home and the work taken care of in everyday life? What kind of difficulties does the individual experience when reconciling home activities and job requirements together? What kind of activity policies have families created to ease the everyday life? What kind of goals and requirements do families feel behind the difficulties in adjusting home and work? What kind of changes would make the adjusting of home and work easier? The changing family life, everyday home activities and the changing Finnish working life are studied to describe the adjusting of home and work. In addition the boundary zone of home and work and its tensions are studied. 337 research persons who find reconciling home and work challenging were elected from different sectors of the working life. Research persons were gathered from the public, private and third sectors. The research material was gathered with a semi-structured qualitative questionnaire published in internet. Contents analysis was the analysis method of the research material. The tensions of adjusting home and work are various. Several activity systems meet on the boundary zone of home and work causing boundary zones to expand and tensions to increase and expand like a network. In the everyday life of an individual the boundary zone fades out and home and work overlap. Tensions can be examined as internal conflicts of the individual through the activity system of everyday life. Individuals balance between individualism and familism, feeling bad, suffering from lack of time and struggling with childcare organizing problems and inflexible employers. The solutions to reconciling home and work difficulties are situational. Often is the help of family and friends required without any solid solutions. The conflict of the goals, requirements and the reality is behind the problems as well as the tightening terms of the working life and its growing expectations. Change requests are proposed on the levels of individual, home, work and the society. Reconciling home and work is not only a challenge between the employee and the employer. It s a problem that needs multilateral solutions and changes on the levels of individual, home, work and society. The challenge remaining is to find out if it would be successful to take the everyday life as starting point to negotiate the reconciling of home and work and how the possible family, social and work political solutions appear in everyday life.
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Digital Image
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One of the most important factors determining the development of atherosclerosis is the amount of LDL particles in the circulation. In general, LDL particles are clinically regarded as “bad cholesterol” since these particles get entrapped within the vascular wall, leading to atherosclerosis. Circulating HDL particles are conversely regarded as “good cholesterol” because of their ability to transport cholesterol from peripheral tissues to the liver for secretion as bile salts. Once inside the artery wall LDL particles are engulfed by macrophages, resulting in macrophage foam cells. If the macrophage foam cells are not able to efflux the cholesterol back into the bloodstream, the excessive cholesterol ultimately leads to cell death, and the deposition of cellular debris within the atherosclerotic lesion. The cells ability to secrete cholesterol is mainly dependent on the ABCA1 transporter (ATP-binding cassette transporter A1) which transfers cellular cholesterol to extracellular apoA-I (apolipoprotein A-I) particles, leading to the generation of nascent HDL particles. The process of atherosclerotic plaque development is therefore to a large extent a cellular one, in which the capacity of the macrophages in handling the excessive cholesterol load determines the progression of lesion development. In this work we have studied the cellular mechanisms that regulate the trafficking of LDL-derived cholesterol from endosomal compartments to other parts of the cell. As a basis for the study we have utilized cells from patients with Niemann-Pick type C disease, a genetic disorder resulting from mutations in the NPC1 and NPC2 genes. In these cells, cholesterol is entrapped within the endosomal compartment, and is not available for efflux. By identifying proteins that bypass the cholesterol trafficking defect, we were able to identify the small GTPase Rab8 as an important protein involved in ABCA1 dependent cholesterol efflux. In the study, we show that Rab8 regulates cholesterol efflux in human macrophages by facilitating intracellular cholesterol transport, as well as by regulating the plasma membrane availability of ABCA1. Collectively, these results give new insight in to atherosclerotic lesion development and intracellular cholesterol processing.
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Digital Image
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Digital Image
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"Klo-Ku-Ba" the first apartment of Hans and Elizabeth in the basement of the Jewish Hospital in Hannover, Germany. The one room served as kitchen, bedroom, and bathroom which was shared by the other residents on the medical staff. Klo-Ku-Ba: Klosett, Kueche, Bad
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Digital Image
