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by Haifa Sun. / Thesis (Ph.D.)--Chinese University of Hong Kong, 1997. / Includes bibliographical references (p. 154-167). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web.

Magnesium plays several physiological roles, including the formation of bones and teeth, muscle contraction, and cardiovascular function. Magnesium deficiency affects cardiovascular health through the modulation of endothelial cell function, particularly by having a negative impact on endothelial cell proliferation, increasing monocyte adhesion, inhibiting cell migration and markedly altering endothelial cell gene expression. With the recognition of the protective role of magnesium in endothelial cells, the aim of this study was to investigate the effects of magnesium sulphate on human umbilical vein endothelial cells (HUVECs) proliferation, gene expression, and the pro-inflammatory response caused by a bacterial endotoxin lipopolysaccharide (LPS). After culture for 120 hours in low (0.1mM) and high (5mM) magnesium, the viability of HUVECs decreased in the low magnesium (P=0.024), whilst the proliferation of HUVECs increased in the high magnesium (P=0.016). Moreover, exposing the cells to LPS lowered viability in the culture with low magnesium (P=0.002), but high magnesium protected the HUVECs from LPS-induced cell death (P=0.037). Magnesium dose-dependent gene expression profiles of HUVECs were investigated via microarray, revealing extensive effects of low and high magnesium on the transcriptome (2930 up-regulated genes and 2828 down-regulated genes). Magnesium deficiency in endothelial cells activated inflammatory pathways through the transcription factor nuclear factor κB (NF-κB), which plays an important role in the early pathology of atherosclerosis. LPS-treated HUVECs cultured in low magnesium showed up-regulation of mRNA expression for pro-inflammatory factors, such as ICAM-1, VCAM-1, IL-8, and MCP-1, and the expression of cytokine proteins, including IL-2, IL-3, IL-8, IL-15, MCP-1, GRO, and GROa. In contrast, high magnesium decreased the expression of IL-6 and MCP-1 mRNA and the protein concentrations of IL-2 and IL-6. The study found that LPS activates the NF-κB pathway through the TLR2 and TLR4 receptors and this pathway was inhibited by high magnesium concentration. Overall, the work presented demonstrates that inflammatory processes in vascular endothelial cells are sensitive to magnesium. This suggests that magnesium nutrition may be an overlooked factor in CVD and is worthy of further investigation.

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Muitos estudos em diferentes áreas examinam como um conjunto de variáveis influencia algum tipo de percentagem, proporção ou frações. Modelos de regressão lineares não são satisfatórios para modelar tais dados. Uma classe de modelos de regressão beta que em muitos aspectos é semelhante aos modelos lineares generalizados foi proposto por Ferrari e Cribari--Neto~(2004). A resposta média é relacionada com um predictor linear por uma função de ligação e o predictor linear envolve covariáveis e parâmetros de regressão desconhecidos. O modelo também é indexado por um parâmetro de precisão. Smithson e Verkuilen,(2005), entre outros, consideram o modelo de regressão beta em que esse parâmetro varia ao longo das observações. Nesta tese foram desenvolvidas técnicas de diagnóstico para os modelos regressão beta com dispersão constante e com dispersão variável, sendo que o método e influência local (Cook,~1986) mostrou-se decisivo, inclusive no sentido de identificar dispersão variável nos dados. Adicionalmente, avaliamos através de estudos de simulação o desempenho de estimadores de máxima verossimilhança para o modelo de regressão beta com dispersão variável, as conseqüências de estimar o modelo supondo dispersão constante quando de fato ela é variável e de testes assintóticos para testar a hipótese de dispersão constante. Finalmente, utilizando um esquema de bootstrap (Davison e Hinkley,1997), desenvolvemos um procedimento de obtenção de limites de predição para o modelo de regressão com dispersão constante. Ilustramos a teoria desenvolvida com várias aplicações a dados reais. / Practitioners oftentimes wish to investigate how certain variables influence continuous variable that assumes values on the standard unit interval $(0,1)$, such as percentages, proportions, rates and fractions. Linear regression models are not suitable for modelling such data. A class of beta regression models which is in many aspects similar to that of generalised linear models was proposed by Ferrari and Cribari--Neto~(2004). The mean response is related to a linear predictor, which involves covariates and unknown regression parameters, through a link function. The model is also indexed by a precision parameter. Smithson e Verkuilen~(2005), among others, consider the beta regression model with variable dispersion, i.e., beta regression in which the precision parameter is not constant across observations. In this dissertation we develop diagnostic methods for beta regression models with both constant and variable dispersion. The method of local influence (Cook,~1986) proved to be particularly useful, since it is able to identify variable dispersion in the data. We have also used Monte Carlo simulation to evaluate the finite sample performance of maximum likelihood estimators in beta regression models with variable dispersion; we have also evaluated the consequences os misspecifying the model by incorrectly assuming constant dispersion when dispersion is variable and the finite sample behavior of heteroskedasticity tests based on first order asymptotics. of estimating the model supposing constant dispersion when Prediction bootstrap intervals (Davison e Hinkley,~1997) for the beta regression model with constant dispersion are also considered.Practical applications that employ real data are presented and discussed.

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Contemporary reports showing negative temporal trends in human sperm quality have provided a weight of evidence, in spite of recognised methodological weaknesses of the early research, strongly indicative of declining male fertility over the past six decades. Other aspects of human male reproductive development, such as hypospadias, cryptorchidism and testis cancer are also showing negative trends in incidence and geographic variation in prevalence. Together these negative changes in parameters of fertility, which have comorbidity, are termed Testicular Dysgenesis Syndrome (TDS). The relative short time period of the trend data and the spatial heterogeneity of these factors suggest an environmental aetiology. Two neighboring and ethno-linguistic similar countries, Denmark and Finland, are used as evidence of this as Denmark has significantly decreased sperm quality as well as an increased incidence of other aspects of TDS when compared to neighboring Finland. Additionally, exposure to persistent environmental chemical pollutants has been associated with decreased sperm quality and increases in other components of TDS. The suggested underlying cause of TDS is perturbed foetal/embryonal programming and reproductive development. In spite of overall poor epidemiological information and a paucity of empirical research data from companion animals there are suggestions that environmental pollutants are affecting the health of cats and dogs. Indeed, the dog may be a relevant research model as it shares our environment and ill health associated with it, such as human TDS. Based on the evidence of environmental pollutants affecting human and animal reproductive development and fertility, this PhD project was developed in order to determine if man’s closest companion, and the animal which wholly shares our environment, demonstrates any parallel reproductive impairment. Specifically, this thesis aims to investigate negative temporal trends related to canine fertility, determine the presence of and geographic variation in tissue concentrations of exemplar environmental pollutants and examine testes tissue and sperm cells, via culture and histology, for association between chemical concentrations and quantitative assessments. Canine testes were collected from three countries; UK (n = 58), Finland (Helsinki region) (n = 20), Denmark (Copenhagen region) (n = 10). These samples were tested for concentrations of three representative chemical groups: PCBs, PBDEs, DEHP. Samples of commercial dog food (n = 28), and a range of canine body fluid was also analysed for these same chemical groups. A retrospective analysis of database information from a population of service dogs in the UK was used to determine temporal trends in canine sperm quality and cryptorchidism over a 26 year period. The concentrations of the three chemical pollutant types were additionally analysed against land use with a Geographic Information System (GIS) and two CORINE land use categories: Artificial and Agricultural. These tissues were assessed histologically using histomorphometric scores, CYP11A1 area stained. Canine testes tissue and sperm were cultured with PCB153 and DEHP to determine direct effects of short term exposures to environmental pollutants by assessing testosterone production (testes explant culture), motility (CASA), sperm viability (hypo osmotic swelling test, chromatin integrity, live:dead ratio). Database analysis of service dog fertility reported two components of TDS: negative temporal trends in sperm quality and a concurrent increased incidence of cryptorchidism. Samples of canine testes tissue contained measurable concentrations of three exemplar pollutants (PCBs, PBDEs, DEHP). These pollutants were also largely present in commercial dog food and some were also present in prostatic fluid, full ejaculate and bitches milk. The profile of EDs and concentrations of specific chemicals showed significant variation across three regions of the UK (Southeast, East Midlands, and West Midlands). Notably, concentrations of legacy industrial chemicals (PCBs, PBDEs) were highest in the West Midlands and phthalate (DEHP) was highest in the southeast. The concentrations of DEHP was significantly higher in Artificial land categories compared to tissue collected in Agricultural land use areas (P < 0.05). Canine testis samples collected from three international regions contained concentrations of PCBs and DEHP which were significantly higher in the UK (P < 0.05) and PBDEs which were significantly higher in Finland (P < 0.05). The histomorphometric assessment of testes showed significant variations across the three countries. The quantification of immunohistochemical testis area stained for CYP11A1 from the three countries showed a significant variation (P=0.0001), and tissue from Denmark showed a significant association between area stained and concentrations of DEHP (P < 0.05). Tissue exposed, via testes explant culture, to PCB153 and DEHP at two concentrations showed no significant blunting of LH stimulated testosterone secretion. Sperm exposed, via culturing with two environmentally relevant concentrations of PCB153 and DEHP, exhibited significantly increased (P < 0.05) and decreased (P < 0.05) measures of motility with these chemicals respectively. Additionally sperm viability, measured using the hypo osmotic swelling assay, was significantly reduced in the presence of PCB153 (P < 0.05) and a significant increased when cultured with DEHP (P < 0.01). Both chemicals significantly increased sperm DNA fragmentation. Additionally, short term exposure to both chemicals significantly reduced the Live:Dead ratio of sperm (P < 0.05). Robust, determinative evidence of negative trends in canine sperm quality and incidence of cryptorchidism indicate that canine and human male fertility are decreasing in parallel. An environmental aetiology is supported by the presence of environmental chemicals in canine diet, testes tissue, prostatic fluid and full canine ejaculate. Geographic differences (National and International) in testis chemical profiles and concentrations may equate with reported regional differences in human TDS. In support of this hypothesis, specific canine testis chemical concentrations were associated with histomorphometric scores from the same cohort of samples. Direct effects of PCB153 and DEHP on sperm motility and viability may be indicative of an alternative acute negative effect on male fertility. These data suggest that the dog, while living in a shared environment with humans, exhibits some parameters of TDS and that canine, as well human, male fertility is declining due to exposure to environmental chemicals.

In vertebrates, muscle precursor cells delaminate and migrate from the somites into the limb, where they proliferate and differentiate to muscle masses. Many transcription factors, including Pax and the myogenic regulatory factors (Mrfs) play a vital role in regulating limb muscle growth and development. In the limb, the progenitors begin the process of myogenesis by expressing the myogenic determination factors Myf5 and MyoD, and differentiation factors Myog and Mrf4 then eventually form dorsal and ventral skeletal muscle masses. However, the role of insulin-like growth factors (IGFs) in regulating the early processes of limb myogenesis, and the functional relevance of IGF-1 and IGF-2 in myogenic determination remains poorly defined. By whole-mount in situ hybridisation (WISH), the present study first characterised the expression of both Mrfs and components of the IGF in chick limbs at precise stages during embryonic development. The analysis of the spatial and temporal expression patterns of both Mrfs and IGFs allowed further interventions to be precisely targeted. Therefore, to determine the mechanism of how these factors interact, application of IGF-soaked beads into chick limb during the development was followed by analysis of muscle specific marker genes. Both Pax3 and MyoD were selected as markers for undifferentiated and differentiated myogenic cells respectively. First, the present study demonstrated both IGF-1 and IGF-2 as novel players in early limb myogenesis in vivo by stimulating the activation of Pax3 and MyoD expression. IGF-1 was also shown to increase numbers of both Pax3+ve and mitotic cells, but not the numbers of mitotic Pax3+ve cells, suggesting the increase in Pax3 expression was not simply via increased proliferation. IGF signalling was then examined using picropodophyllotoxin (or PPP) as a specific inhibitor of the IGF-1 receptor. The present data showed that blocking of IGF-1R with PPP inhibited both IGF-1 and IGF-2 induced expression of both Pax3 and MyoD. To confirm the mechanisms for the effects of the IGFs, the current study also used a panel of pharmacological inhibitors, such as U0126 and LY294002 to block the mitogen activated protein kinase (MAPK) and AKT signalling pathways, respectively as well as Nocodazole to inhibit cell proliferation. Results showed that the effects of both IGF-1 and IGF-2 on Pax3 and MyoD expression were mediated by the MAPK pathway. In contrast, inhibition of the AKT signalling pathway inhibited IGF-2 (but not IGF-1) stimulated Pax3 expression, as well as IGF-1 (but not IGF-2) stimulated MyoD expression. Inhibition of cell proliferation with Nocodazole had no effect on IGF-1 stimulated Pax3 or MyoD expression. Similarly Nocodazole had no effect on IGF-2 stimulated Pax3 expression, whereas it inhibited IGF-2 stimulated MyoD expression. SU5402, an inhibitor of FGF receptor, showed no effect on IGF-1 and IGF-2 stimulated Pax3 expression whereas it inhibited their stimulation of MyoD. These findings led to the proposal of a model where IGF signalling directs the timing of the early steps of myogenic cells by stimulating Pax3 expression, whereas the upregulation in MyoD expression is indirectly controlled via Fgf. Together, these results give new insights into the early embryonic development of limb muscle in birds. Additionally, a deeper knowledge of a specific interaction between IGFs and Mrfs may well provide a molecular basis for preventing the loss of muscle and muscle diseases in animals and humans. The present study may well also shed a light to improve the production of chicken meat.

The purpose of this scientific study is to investigate how educators interpret their democratic mission to work with the children's influence on activities they do at the preschool. The study also aims to contribute to an increased knowledge about how educators can work with children's influence at preschool. The study asks two questions: What does influence mean according to teachers? and How does the teacher create opportunities for pupils to have an influence in the activities they do at pre-school? A qualitative research method is used with a phenomenological research effort. The theoretical framework for the essay is based on five concepts: influence, child perspective, listening and communication proximal development. The results show that, according to educators, influence means for educators that the children have the opportunity to do what they want and what they are interested in. The results also shows that educators create opportunities for children to have influence by responding to them as individuals whose opinions and thoughts are taken seriously. The children may speak, be listened to and regarded as competent individuals. The children themselves can choose activities in the classroom and they take their own initiative. Teachers talks with the children and gives them space to express their thoughts and opinions.

On September 17, 2011, protestors set up camp in Zuccotti Park in New York's financial district, initiating a 59-day social and political movement known as Occupy Wall Street. Writing about the protest, James C. McKinley Jr. of the New York Times declared that the movement "lacks a melody" compared with protest movements of the previous century. Despite the common perception that little music accompanied the movement, organizers released Occupy This Album: 99 Songs for the 99%, a collection of songs connected with, written for, or written about the Occupy Wall Street movement. This thesis investigates the place of Occupy Wall Street in society through its musicking and through Occupy This Album: 99 Songs or the 99%. Building upon the sociomusicological work of R. Serge Denisoff and the work of Garth S. Jowett and Victoria O'Donnell, I propose a framework for a categorization of songs through their lyrical content and apply it to the music found on Occupy This Album. Then, using this framework, I determine the potential "progressiveness" of Occupy Wall Street through the modernization theory of Talcott Parsons. I contend that Occupy this Album: 99 Songs for the 99% shows Occupy Wall Street to be a modernizing movement as indicated through its large output of propaganda songs, showing a commitment to communication of diverse knowledge and ideologies and a generalization of value sets. This analysis and its conclusion situate Occupy Wall Street in society through its musical output rather than through its cultural and political effects