921 resultados para Prone to accidents


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My dissertation consists of three essays. The central theme of these essays is the psychological factors and biases that affect the portfolio allocation decision. The first essay entitled, “Are women more risk-averse than men?” examines the gender difference in risk aversion as revealed by actual investment choices. Using a sample that controls for biases in the level of education and finance knowledge, there is evidence that when individuals have the same level of education, irrespective of their knowledge of finance, women are no more risk-averse than their male counterparts. However, the gender-risk aversion relation is also a function of age, income, wealth, marital status, race/ethnicity and the number of children in the household. The second essay entitled, “Can diversification be learned ?” investigates if investors who have superior investment knowledge are more likely to actively seek diversification benefits and are less prone to allocation biases. Results of cross-sectional analyses suggest that knowledge of finance increases the likelihood that an investor will efficiently allocate his direct investments across the major asset classes; invest in foreign assets; and hold a diversified equity portfolio. However, there is no evidence that investors who are more financially sophisticated make superior allocation decisions in their retirement savings. The final essay entitled, “The demographics of non-participation ”, examines the factors that affect the decision not to hold stocks. The results of probit regression models indicate that when individuals are highly educated, the decision to not participate in the stock market is less related to demographic factors. In particular, when individuals have attained at least a college degree and have advanced knowledge of finance, they are significantly more likely to invest in equities either directly or indirectly through mutual funds or their retirement savings. There is also evidence that the decision not to hold stocks is motivated by short-term market expectations and the most recent investment experience. The findings of these essays should increase the body of research that seeks to reconcile what investors actually do (positive theory) with what traditional theories of finance predict that investors should do (normative theory).

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In this dissertation, I first suggest an extension of the managerial rents model and more specifically the managerial skills typology that it offers. Building on research in international business, I propose adding country-specific skills (CSS) to this typology in addition to firm-specific, industry-specific, and generic skills. I define CSS as managers' abilities that are applicable and specific to a particular national institutional context. Such skills are distinct from the other three types identified and are likely to influence managers' performance and the performance of their firms. So if CSS are distinct skills, what are the implications for strategy and international business research? In an attempt to respond to this question, I conduct two empirical essays in which I examine the implications of this refinement of the typology of managerial skills for CEO selection and firms' mergers and acquisitions (M&A;) strategy. In the first empirical essay, I puzzle at the fact that although CSS constitute a barrier to high-level executive mobility across countries, there have been a growing number of foreign-born CEOs being appointed across the globe. Why are these individuals being selected for the post of CEO? Using information on the appointment of foreign-born and national CEOs from 2005 to 2010 among global 500 companies, I show that internationalization pressures help explain their selection and that two types of firms are likely to appoint foreign leaders: highly internationalized firms and firms that are likely to internationalize. In the second empirical essay, I examine the strategic implications of country-specific skills. Employing the same sample as the one used in the first empirical essay, I demonstrate that given that their mindset is likely to be less focused on firms' home market, foreign-born CEOs may be prone to institute more changes in firms' cross-border M&A; strategy than their domestic counterparts. I also theorize on the moderating influence of CEOs' insiderness.

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My dissertation consists of three essays. The central theme of these essays is the psychological factors and biases that affect the portfolio allocation decision. The first essay entitled, “Are women more risk-averse than men?” examines the gender difference in risk aversion as revealed by actual investment choices. Using a sample that controls for biases in the level of education and finance knowledge, there is evidence that when individuals have the same level of education, irrespective of their knowledge of finance, women are no more risk-averse than their male counterparts. However, the gender-risk aversion relation is also a function of age, income, wealth, marital status, race/ethnicity and the number of children in the household. The second essay entitled, “Can diversification be learned?” investigates if investors who have superior investment knowledge are more likely to actively seek diversification benefits and are less prone to allocation biases. Results of cross-sectional analyses suggest that knowledge of finance increases the likelihood that an investor will efficiently allocate his direct investments across the major asset classes; invest in foreign assets; and hold a diversified equity portfolio. However, there is no evidence that investors who are more financially sophisticated make superior allocation decisions in their retirement savings. The final essay entitled, “The demographics of non-participation”, examines the factors that affect the decision not to hold stocks. The results of probit regression models indicate that when individuals are highly educated, the decision to not participate in the stock market is less related to demographic factors. In particular, when individuals have attained at least a college degree and have advanced knowledge of finance, they are significantly more likely to invest in equities either directly or indirectly through mutual funds or their retirement savings. There is also evidence that the decision not to hold stocks is motivated by short-term market expectations and the most recent investment experience. The findings of these essays should increase the body of research that seeks to reconcile what investors actually do (positive theory) with what traditional theories of finance predict that investors should do (normative theory).

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Twenty-four manganese nodules from the surface of the sea floor and fifteen buried nodules were studied. With three exceptions, the nodules were collected from the area covered by Valdivia Cruise VA 04 some 1200 nautical miles southeast of Hawaii. Age determinations were made using the ionium method. In order to get a true reproduction of the activity distribution in the nodules, they were cut in half and placed for one month on nuclear emulsion plates to determine the alpha-activity of the ionium and its daughter products. Special methods of counting the alpha-tracks resolution to depth intervals of 0.125 mm. For the first time it was possible to resolve zones of rapid growth (impulse growth) with growth rates, s > 50 mm/106 yr and interruptions in growth. With few exceptions the average rate of growth of all nodules was surprisingly uniform at 4-9 mm/10 yr. No growth could be recognized radioactively in the buried nodules. One exceptional nodule has had recent impulse growth and, in the material formed, the ionium is not yet in equilibrium with its daughter products. Individual layers in one nodule from the Indian Ocean could be dated and an average time interval of t = 2600±400 yr was necessary to form one layer. The alternation between iron and manganese-rich parts of the nodules was made visible by colour differences resulting from special treatment of cut surfaces with HCl vapour. The zones of slow growth of one nodule are relatively enriched in iron. Earlier attempts to find paleomagnetic reversals in manganese nodules have been continued. Despite considerable improvement in areal resolution, reversals were not detected in the nodules studied. Comparisons of the surface structure, microstructure in section and the radiometric dating show that there are erosion surfaces and growth surfaces on the outer surfaces of the manganese nodules. The formation of cracks in the nodules was studied in particular. The model of age-dependent nodule shrinkage and cracking surprisingly indicates that the nodules break after exceeding a certain age and/or size. Consequently, the breaking apart of manganese nodules is a continuous process not of catastrophic or discontinuous origin. The microstructure of the nodules exhibits differences in the mechanism of accretion and accretion rate of material, shortly referred to as accretion form. Thus non-directional growth inside the nodules as well as a directional growth may be observed. Those nodules with large accretion forms have grown faster than smaller ones. Consequently, parallel layers indicate slow growth. The upper surfaces of the nodules, protruding into the bottom water appear to be more prone to growth disturbances than the lower surfaces, immersed in the sediment. Features of some nodules show, that as they develop, they neither turned nor rolled. Yet unknown is the mechanism that keeps the nodules at the surface during continuous sedimentation. All in all, the nodules remain the objects of their own distinctive problems. The hope of using them as a kind of history book still seems to be very remote.

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Culturing experiments were performed with the benthic foraminifer Ammonia aomoriensis from Flensburg Fjord, western Baltic Sea. The experiments simulated a projected rise in atmospheric CO2 concentrations. We exposed specimens to 5 seawater pCO2 levels ranging from 618 µatm (pH 7.9) to 3130 µatm (pH 7.2) for 6 wk. Growth rates and mortality differed significantly among pCO2 treatments. The highest increase of mean test diameter (19%) was observed at 618 µatm. At partial pressures >1829 µatm, the mean test diameter was observed to decrease, by up to 22% at 3130 µatm. At pCO2 levels of 618 and 751 µatm, A. aomoriensis tests were found intact after the experiment. The outer chambers of specimens incubated at 929 and 1829 µatm were severely damaged by corrosion. Visual inspection of specimens incubated at 3130 µatm revealed wall dissolution of all outer chambers, only their inner organic lining stayed intact. Our results demonstrate that pCO2 values of >=929 µatm in Baltic Sea waters cause reduced growth of A. aomoriensis and lead to shell dissolution. The bottom waters in Flensburg Fjord and adjacent areas regularly experience pCO2 levels in this range during summer and fall. Increasing atmospheric CO2 concentrations are likely to extend and intensify these periods of undersaturation. This may eventually slow down calcification in A. aomoriensis to the extent that net carbonate precipitation terminates. The possible disappearance of this species from the Baltic Sea and other areas prone to seasonal undersaturation would likely cause significant shifts in shallow-water benthic ecosystems in the near future.

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The diagnosis of nutritional status is extremely re levant in clinical practice and population assessment, due to the association betwe en body fat and metabolic alterations. The aim of this study is to analyze th e prevalence of metabolic syndrome (MS) and its components in the pubertal stages of f emale students in Rio Grande do Norte state, Brazil, in accordance with Internation al Diabetes Federation criteria. This is a cross-sectional study with 449 students aged betw een 8 and 19 years, stratified into pubertal stages systematized by Marshal and Tanner (1969), as follows: 27.6% prepubertal, 44.3% pubertal and 28.1% postpubertal, with mean ages of 9.4±1.27, 12.4±2.23 and 15.1±1.88 years, respectively. Preval ences were analyzed using distribution of frequencies and their respective 95 % confidence intervals, while the chi- square test and odds ratio were applied to analyze the associations between variables. The general prevalence of MS was 3.3% (CI: 2% - 5%) , without occurrences in the prepubertal stage, observing that it emerges from t he pubertal stage onwards with a prevalence of 2.5% (CI 95% 0.1% - 5%), 1% (CI 95% 0.4% - 2.3%) of cases with overweight and 1.5% (CI 95% -0.1% - 3.2%) with obes e individuals, while in the postpubertal stage the prevalence is 7.9% (CI 95% 3 .2% - 12.6%), 0.8% (CI 95% -0.8% - 2.3%) normal weight cases, 4% (CI 95% 0.6% - 7.4% ) overweight and 3.1% (CI 0.1% - 6.2%) obese individuals. There was an association (p<0.02) between pubertal stages and MS ( x 2 =5.2), with an OR of 3.3 (CI: 1.2 - 5), showing tha t postpubertal adolescents are more prone to SM than pubertals, while the OR i n obese individuals was 2.1 (CI: 2– 2.2) compared to the overweight. Body mass index (B MI) ( x 2 = 29.4; p<0.001) and age range ( x 2 = 13.1; p<0.001) showed a significant linear assoc iation with MS. Of the adolescents with MS, those aged ten years or younge r exhibited higher %G. The most prevalent components in all the stages were altered waist circumference (27.2% [CI 23% - 31%]) and low HDL cholesterol (39.6% [CI 35% – 44%]), which, coupled with hypertension, displayed significant differences in the postpubertal stage in relation to the other stages. The results show that MS emerges from the pubertal stage onwards in proportion to excess childhood body fat, a fact tha t calls for prevention strategies using an educational approach, reducing the large demand on the National Health System. Keywords: Metabolic syndrome, pubertal stages, risk factors.

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This study aimed to evaluate the influence of the main meteorological mechanisms trainers and inhibitors of precipitation, and the interactions between different scales of operation, the spatial and temporal variability of the annual cycle of precipitation in the Rio Grande do Norte. Além disso, considerando as circunstâncias locais e regionais, criando assim uma base científica para apoiar ações futuras na gestão da demanda de água no Estado. Database from monthly precipitation of 45 years, ranging between 1963 and 2007, data provided by EMPARN. The methodology used to achieve the results was initially composed of descriptive statistical analysis of historical data to prove the stability of the series, were applied after, geostatistics tool for plotting maps of the variables, within the geostatistical we opted for by Kriging interpolation method because it was the method that showed the best results and minor errors. Among the results, we highlight the annual cycle of rainfall the State which is influenced by meteorological mechanisms of different spatial and temporal scales, where the main mechanisms cycle modulators are the Conference Intertropical Zone (ITCZ) acting since midFebruary to mid May throughout the state, waves Leste (OL), Lines of instability (LI), breeze systems and orographic rainfall acting mainly in the Coastal strip between February and July. Along with vortice of high levels (VCANs), Complex Mesoscale Convective (CCMs) and orographic rain in any region of the state mainly in spring and summer. In terms of larger scale phenomena stood out El Niño and La Niña, ENSO in the tropical Pacific basin. In La Niña episodes usually occur normal or rainy years, as upon the occurrence of prolonged periods of drought are influenced by EL NIÑO. In the Atlantic Ocean the standard Dipole also affects the intensity of the rainfall cycle in State. The cycle of rains in Rio Grande do Norte is divided into two periods, one comprising the regions West, Central and the Western Portion of the Wasteland Potiguar mesoregions of west Chapada Borborema, causing rains from midFebruary to mid-May and a second period of cycle, between February-July, where rains occur in mesoregions East and of the Wasteland, located upwind of the Chapada Borborema, both interspersed with dry periods without occurrence of significant rainfall and transition periods of rainy - dry and dry-rainy where isolated rainfall occur. Approximately 82% of the rainfall stations of the state which corresponds to 83.4% of the total area of Rio Grande do Norte, do not record annual volumes above 900 mm. Because the water supply of the State be maintained by small reservoirs already are in an advanced state of eutrophication, when the rains occur, act to wash and replace the water in the reservoirs, improving the quality of these, reducing the eutrophication process. When rain they do not significantly occur or after long periods of shortages, the process of eutrophication and deterioration of water in dams increased significantly. Through knowledge of the behavior of the annual cycle of rainfall can have an intimate knowledge of how it may be the tendency of rainy or prone to shortages following period, mainly observing the trends of larger scale phenomena

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Studies reveal that in recent decades a decrease in sleep duration has occurred. Social commitments, such as work and school are often not aligned to the "biological time" of individuals. Added to this, there is a reduced force of zeitgeber caused by less exposure to daylight and larger exposure to evenings. This causes a chronic sleep debt that is offset in a free days. Indeed, a restriction and extent of sleep called "social Jet lag" occurs weekly. Sleep deprivation has been associated to obesity, cancer, and cardiovascular risk. It is suggested that the autonomic nervous system is a pathway that connects sleep problems to cardiovascular diseases. However, beyond the evidence demonstrated by studies using models of acute and controlled sleep deprivation, studies are needed to investigate the effects of chronic sleep deprivation as it occurs in the social jet lag. The aim of this study was to investigate the influence of social jet lag in circadian rest-activity markers and heart function in medical students. It is a cross-sectional, observational study conducted in the Laboratory of Neurobiology and Biological Rhythmicity (LNRB) at the Department of Physiology UFRN. Participated in the survey medical students enrolled in the 1st semester of their course at UFRN. Instruments for data collection: Munich Chronotype Questionnaire, Morningness Eveningness Questionnaire of Horne and Östberg, Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale, Actimeter; Heart rate monitor. Analysed were descriptive variables of sleep, nonparametric (IV60, IS60, L5 and M10) and cardiac indexes of time domain, frequency (LF, HF LF / HF) and nonlinear (SD1, SD2, SD1 / SD2). Descriptive, comparative and correlative statistical analysis was performed with SPSS software version 20. 41 students participated in the study, 48.8% (20) females and 51.2% (21) males, 19.63 ± 2.07 years. The social jet lag had an average of 02: 39h ± 00:55h, 82.9% (34) with social jet lag ≥ 1h and there was a negative correlation with the Munich chronotype score indicating greater sleep deprivation in subjects prone to eveningness. Poor sleep quality was detected in 90.2% (37) (X2 = 26.56, p <0.001) and 56.1% (23) excessive daytime sleepiness (X2 = 0.61, p = 0.435). Significant differences were observed in the values of LFnu, HFnu and LF / HF between the groups of social jet lag <2h and ≥ 2h and correlation of the social jet lag with LFnu (rs = 0.354, p = 0.023), HFnu (rs = - 0.354 , p = 0.023) and LF / HF (r = 0.355, p = 0.023). There was also a negative association between IV60 and indexes in the time domain and non-linear. It is suggested that chronic sleep deprivation may be associated with increased sympathetic activation promoting greater cardiovascular risk.

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Rapid development in industry have contributed to more complex systems that are prone to failure. In applications where the presence of faults may lead to premature failure, fault detection and diagnostics tools are often implemented. The goal of this research is to improve the diagnostic ability of existing FDD methods. Kernel Principal Component Analysis has good fault detection capability, however it can only detect the fault and identify few variables that have contribution on occurrence of fault and thus not precise in diagnosing. Hence, KPCA was used to detect abnormal events and the most contributed variables were taken out for more analysis in diagnosis phase. The diagnosis phase was done in both qualitative and quantitative manner. In qualitative mode, a networked-base causality analysis method was developed to show the causal effect between the most contributing variables in occurrence of the fault. In order to have more quantitative diagnosis, a Bayesian network was constructed to analyze the problem in probabilistic perspective.

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The oceanic carbon cycle mainly comprises the production and dissolution/ preservation of carbonate particles in the water column or within the sediment. Carbon dioxide is one of the major controlling factors for the production and dissolution of carbonate. There is a steady exchange between the ocean and atmosphere in order to achieve an equilibrium of CO2; an anthropogenic rise of CO2 in the atmosphere would therefore also increase the amount of CO2 in the ocean. The increased amount of CO2 in the ocean, due to increasing CO2-emissions into the atmosphere since the industrial revolution, has been interpreted as "ocean acidification" (Caldeira and Wickett, 2003). Its alarming effects, such as dissolution and reduced CaCO3 formation, on reefs and other carbonate shell producing organisms form the topic of current discussions (Kolbert, 2006). Decreasing temperatures and increasing pressure and CO2 enhance the dissolution of carbonate particles at the sediment-water interface in the deep sea. Moreover, dissolution processes are dependent of the saturation state of the surrounding water with respect to calcite or aragonite. Significantly increased dissolution has been observed below the aragonite or calcite chemical lysocline; below the aragonite compensation depth (ACD), or calcite compensation depth (CCD), all aragonite or calcite particles, respectively, are dissolved. Aragonite, which is more prone to dissolution than calcite, features a shallower lysocline and compensation depth than calcite. In the 1980's it was suggested that significant dissolution also occurs in the water column or at the sediment-water interface above the lysocline. Unknown quantities of carbonate produced at the sea surface, would be dissolved due to this process. This would affect the calculation of the carbonate production and the entire carbonate budget of the world's ocean. Following this assumption, a number of studies have been carried out to monitor supralysoclinal dissolution at various locations: at Ceara Rise in the western equatorial Atlantic (Martin and Sayles, 1996), in the Arabian Sea (Milliman et al., 1999), in the equatorial Indian Ocean (Peterson and Prell, 1985; Schulte and Bard, 2003), and in the equatorial Pacific (Kimoto et al., 2003). Despite the evidence for supralysoclinal dissolution in some areas of the world's ocean, the question still exists whether dissolution occurs above the lysocline in the entire ocean. The first part of this thesis seeks answers to this question, based on the global budget model of Milliman et al. (1999). As study area the Bahamas and Florida Straits are most suitable because of the high production of carbonate, and because there the depth of the lysocline is the deepest worldwide. To monitor the occurrence of supralysoclinal dissolution, the preservation of aragonitic pteropod shells was determined, using the Limacina inflata Dissolution Index (LDX; Gerhardt and Henrich, 2001). Analyses of the grain-size distribution, the mineralogy, and the foraminifera assemblage revealed further aspects concerning the preservation state of the sediment. All samples located at the Bahamian platform are well preserved. In contrast, the samples from the Florida Straits show dissolution in 800 to 1000 m and below 1500 m water depth. Degradation of organic material and the subsequent release of CO2 probably causes supralysoclinal dissolution. A northward extension of the corrosive Antarctic Intermediate Water (AAIW) flows through the Caribbean Sea into the Gulf of Mexico and might enhance dissolution processes at around 1000 m water depth. The second part of this study deals with the preservation of Pliocene to Holocene carbonate sediments from both the windward and leeward basins adjacent to Great Bahama Bank (Ocean Drilling Program Sites 632, 633, and 1006). Detailed census counts of the sand fraction (250-500 µm) show the general composition of the coarse grained sediment. Further methods used to examine the preservation state of carbonates include the amount of organic carbon and various dissolution indices, such as the LDX and the Fragmentation Index. Carbonate concretions (nodules) have been observed in the sand fraction. They are similar to the concretions or aggregates previously mentioned by Mullins et al. (1980a) and Droxler et al. (1988a), respectively. Nonetheless, a detailed study of such grains has not been made to date, although they form an important part of periplatform sediments. Stable isotopemeasurements of the nodules' matrix confirm previous suggestions that the nodules have formed in situ as a result of early diagenetic processes (Mullins et al., 1980a). The two cores, which are located in Exuma Sound (Sites 632 and 633), at the eastern margin of Great Bahama Bank (GBB), show an increasing amount of nodules with increasing core depth. In Pliocene sediments, the amount of nodules might rise up to 100%. In contrast, nodules only occur within glacial stages in the deeper part of the studied core interval (between 30 and 70 mbsf) at Site 1006 on the western margin of GBB. Above this level the sediment is constantly being flushed by bottom water, that might also contain corrosive AAIW, which would hinder cementation. Fine carbonate particles (<63 µm) form the matrix of the nodules and do therefore not contribute to the fine fraction. At the same time, the amount of the coarse fraction (>63 µm) increases due to the nodule formation. The formation of nodules might therefore significantly alter the grain-size distribution of the sediment. A direct comparison of the amount of nodules with the grain-size distribution shows that core intervals with high amounts of nodules are indeed coarser than the intervals with low amounts of nodules. On the other hand, an initially coarser sediment might facilitate the formation of nodules, as a high porosity and permeability enhances early diagenetic processes (Westphal et al., 1999). This suggestion was also confirmed: the glacial intervals at Site 1006 are interpreted to have already been rather coarse prior to the formation of nodules. This assumption is based on the grain-size distribution in the upper part of the core, which is not yet affected by diagenesis, but also shows coarser sediment during the glacial stages. As expected, the coarser, glacial deposits in the lower part of the core show the highest amounts of nodules. The same effect was observed at Site 632, where turbidites cause distinct coarse layers and reveal higher amounts of nodules than non-turbiditic sequences. Site 633 shows a different pattern: both the amount of nodules and the coarseness of the sediment steadily increase with increasing core depth. Based on these sedimentological findings, the following model has been developed: a grain-size pattern characterised by prominent coarse peaks (as observed at Sites 632 and 1006) is barely altered. The greatest coarsening effect due to the nodule formation will occur in those layers, which have initially been coarser than the adjacent sediment intervals. In this case, the overall trend of the grain-size pattern before and after formation of the nodules is similar to each other. Although the sediment is altered due to diagenetic processes, grain size could be used as a proxy for e.g. changes in the bottom-water current. The other case described in the model is based on a consistent initial grain-size distribution, as observed at Site 633. In this case, the nodule reflects the increasing diagenetic alteration with increasing core depth rather than the initial grain-size pattern. In the latter scenario, the overall grain-size trend is significantly changed which makes grain size unreliable as a proxy for any palaeoenvironmental changes. The results of this study contribute to the understanding of general sedimentation processes in the periplatform realm: the preservation state of surface samples shows the influence of supralysoclinal dissolution due to the degradation of organic matter and due to the presence of corrosive water masses; the composition of the sand fraction shows the alteration of the carbonate sediment due to early diagenetic processes. However, open questions are how and when the alteration processes occur and how geochemical parameters, such as the rise in alkalinity or the amount of strontium, are linked to them. These geochemical parameters might reveal more information about the depth in the sediment column, where dissolution and cementation processes occur.

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The increasing demand in electricity and decrease forecast, increasingly, of fossil fuel reserves, as well as increasing environmental concern in the use of these have generated a concern about the quality of electricity generation, making it well welcome new investments in generation through alternative, clean and renewable sources. Distributed generation is one of the main solutions for the independent and selfsufficient generating systems, such as the sugarcane industry. This sector has grown considerably, contributing expressively in the production of electricity to the distribution networks. Faced with this situation, one of the main objectives of this study is to propose the implementation of an algorithm to detect islanding disturbances in the electrical system, characterized by situations of under- or overvoltage. The algorithm should also commonly quantize the time that the system was operating in these conditions, to check the possible consequences that will be caused in the electric power system. In order to achieve this it used the technique of wavelet multiresolution analysis (AMR) for detecting the generated disorders. The data obtained can be processed so as to be used for a possible predictive maintenance in the protection equipment of electrical network, since they are prone to damage on prolonged operation under abnormal conditions of frequency and voltage.

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Fetal growth restriction (FGR) is characterized by the birth weight and body mass below the tenth percentile for gestational age. FGR is a major cause of perinatal morbidity and mortality and babies born with FGR are prone to develop cardiovascular diseases later in life. The underlying pathology of FGR is inadequate placental transfer of nutrients from mother to fetus, which can be caused by placental insufficiency. Hydrogen sulfide (H2S), a gaseous messenger is produced endogenously by cystathionine-lyase (Cth), cystathionine-β-synthase (CBS) and 3-mercaptopyruvate sulfurtransferase (3-MST), which are present in human placenta. Recently, we demonstrated that the dysregulation of H2S/Cth pathway is associated with preeclampsia and blockade of CSE activity induces preeclampsia-like condition in pregnant mice. We hypothesized that defect in H2S pathways promote FGR and H2S donor restores fetal growth in mice where CBS or CSE activity has been compromised. Western blotting and qPCR revealed that placental CBS expressions were significantly reduced in women with FGR. ELISA analysis showed reduced placental growth factor production (PlGF) from first trimester (8–12 weeks gestation) human placental explants following inhibition of CBS activity by aminooxyacetic acid (AOA). Administration of AOA to pregnant mice had no effects on blood pressure, but caused fetal growth restriction. This was associated with reduced PlGF production. Histological analysis revealed a reduction in the placental junction zone, within which trophoblast giant cells and glycogen cells were less prominent in CBS inhibitor treated mice. These results imply that placental CBS is required for placental development and that dysregulation of CBS activity may contribute to the pathogenesis of FGR but not preeclampsia.

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INTRODUCTION: Fetal growth restriction (FGR), which causes perinatal morbidity and mortality, is characterized by birth weight and body mass being below 10th percentile for gestational age. FGR babies are prone to develop cardiovascular diseases later in life. Inadequate placental transfer of nutrients from mother to fetus due to placental insufficiency is considered the underlying cause of FGR. Recently, we demonstrated that blockade of cystathionine-γ-lyase (CSE) activity induces preeclampsia-like condition in pregnant mice. We hypothesized that defect in cystathionine-β-synthase (CBS) / H2S pathway may promote FGR. METHODS: Placental CBS expressions were determined in women with FGR (n=9) and normal controls (n=14) by Western blotting and real-time qPCR. ELISA was used to determine angiogenic factors levels in plasma and first-trimester (8–12 weeks gestation) human placental explants. Time pregnant mice were treated with CBS inhibitor, aminooxyacetic acid (AOA). Mean arterial blood pressure (MBP), histological assessments of placenta and embryos were performed. RESULTS: Placental CBS expressions were significantly reduced in women with FGR. Inhibition of CBS activity by AOA reduced PlGF production from first-trimester human placental explants, Administration of AOA to pregnant mice had no effects on blood pressure, but caused fetal growth restriction, which was associated with reduced placental PlGF production. Histological analysis revealed a reduction in the placental junction zone, within which trophoblast giant cells and glycogen cells were less prominent in CBS inhibitor-treated animals. Furthermore, H2S donor GYY4137 treatment restored fetal growth in pregnant mice exposed to high level of sFlt-1. CONCLUSIONS: These results imply that placental CBS is required for placental development and that dysregulation of CBS activity may contribute to the pathogenesis of FGR but not preeclampsia opening up the therapeutic potentials of H2S therapy in this condition.

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Magnetic resonance imaging is a research and clinical tool that has been applied in a wide variety of sciences. One area of magnetic resonance imaging that has exhibited terrific promise and growth in the past decade is magnetic susceptibility imaging. Imaging tissue susceptibility provides insight into the microstructural organization and chemical properties of biological tissues, but this image contrast is not well understood. The purpose of this work is to develop effective approaches to image, assess, and model the mechanisms that generate both isotropic and anisotropic magnetic susceptibility contrast in biological tissues, including myocardium and central nervous system white matter.

This document contains the first report of MRI-measured susceptibility anisotropy in myocardium. Intact mouse heart specimens were scanned using MRI at 9.4 T to ascertain both the magnetic susceptibility and myofiber orientation of the tissue. The susceptibility anisotropy of myocardium was observed and measured by relating the apparent tissue susceptibility as a function of the myofiber angle with respect to the applied magnetic field. A multi-filament model of myocardial tissue revealed that the diamagnetically anisotropy α-helix peptide bonds in myofilament proteins are capable of producing bulk susceptibility anisotropy on a scale measurable by MRI, and are potentially the chief sources of the experimentally observed anisotropy.

The growing use of paramagnetic contrast agents in magnetic susceptibility imaging motivated a series of investigations regarding the effect of these exogenous agents on susceptibility imaging in the brain, heart, and kidney. In each of these organs, gadolinium increases susceptibility contrast and anisotropy, though the enhancements depend on the tissue type, compartmentalization of contrast agent, and complex multi-pool relaxation. In the brain, the introduction of paramagnetic contrast agents actually makes white matter tissue regions appear more diamagnetic relative to the reference susceptibility. Gadolinium-enhanced MRI yields tensor-valued susceptibility images with eigenvectors that more accurately reflect the underlying tissue orientation.

Despite the boost gadolinium provides, tensor-valued susceptibility image reconstruction is prone to image artifacts. A novel algorithm was developed to mitigate these artifacts by incorporating orientation-dependent tissue relaxation information into susceptibility tensor estimation. The technique was verified using a numerical phantom simulation, and improves susceptibility-based tractography in the brain, kidney, and heart. This work represents the first successful application of susceptibility-based tractography to a whole, intact heart.

The knowledge and tools developed throughout the course of this research were then applied to studying mouse models of Alzheimer’s disease in vivo, and studying hypertrophic human myocardium specimens ex vivo. Though a preliminary study using contrast-enhanced quantitative susceptibility mapping has revealed diamagnetic amyloid plaques associated with Alzheimer’s disease in the mouse brain ex vivo, non-contrast susceptibility imaging was unable to precisely identify these plaques in vivo. Susceptibility tensor imaging of human myocardium specimens at 9.4 T shows that susceptibility anisotropy is larger and mean susceptibility is more diamagnetic in hypertrophic tissue than in normal tissue. These findings support the hypothesis that myofilament proteins are a source of susceptibility contrast and anisotropy in myocardium. This collection of preclinical studies provides new tools and context for analyzing tissue structure, chemistry, and health in a variety of organs throughout the body.

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The evolution of reproductive strategies involves a complex calculus of costs and benefits to both parents and offspring. Many marine animals produce embryos packaged in tough egg capsules or gelatinous egg masses attached to benthic surfaces. While these egg structures can protect against environmental stresses, the packaging is energetically costly for parents to produce. In this series of studies, I examined a variety of ecological factors affecting the evolution of benthic development as a life history strategy. I used marine gastropods as my model system because they are incredibly diverse and abundant worldwide, and they exhibit a variety of reproductive and developmental strategies.

The first study examines predation on benthic egg masses. I investigated: 1) behavioral mechanisms of predation when embryos are targeted (rather than the whole egg mass); 2) the specific role of gelatinous matrix in predation. I hypothesized that gelatinous matrix does not facilitate predation. One study system was the sea slug Olea hansineensis, an obligate egg mass predator, feeding on the sea slug Haminoea vesicula. Olea fed intensely and efficiently on individual Haminoea embryos inside egg masses but showed no response to live embryos removed from gel, suggesting that gelatinous matrix enables predation. This may be due to mechanical support of the feeding predator by the matrix. However, Haminoea egg masses outnumber Olea by two orders of magnitude in the field, and each egg mass can contain many tens of thousands of embryos, so predation pressure on individuals is likely not strong. The second system involved the snail Nassarius vibex, a non-obligate egg mass predator, feeding on the polychaete worm Clymenella mucosa. Gel neither inhibits nor promotes embryo predation for Nassarius, but because it cannot target individual embryos inside an egg mass, its feeding is slow and inefficient, and feeding rates in the field are quite low. However, snails that compete with Nassarius for scavenged food have not been seen to eat egg masses in the field, leaving Nassarius free to exploit the resource. Overall, egg mass predation in these two systems likely benefits the predators much more than it negatively affects the prey. Thus, selection for environmentally protective aspects of egg mass production may be much stronger than selection for defense against predation.

In the second study, I examined desiccation resistance in intertidal egg masses made by Haminoea vesicula, which preferentially attaches its flat, ribbon-shaped egg masses to submerged substrata. Egg masses occasionally detach and become stranded on exposed sand at low tide. Unlike adults, the encased embryos cannot avoid desiccation by selectively moving about the habitat, and the egg mass shape has high surface-area-to-volume ratio that should make it prone to drying out. Thus, I hypothesized that the embryos would not survive stranding. I tested this by deploying individual egg masses of two age classes on exposed sand bars for the duration of low tide. After rehydration, embryos midway through development showed higher rates of survival than newly-laid embryos, though for both stages survival rates over 25% were frequently observed. Laboratory desiccation trials showed that >75% survival is possible in an egg mass that has lost 65% of its water weight, and some survival (<25%) was observed even after 83% water weight lost. Although many surviving embryos in both experiments showed damage, these data demonstrate that egg mass stranding is not necessarily fatal to embryos. They may be able to survive a far greater range of conditions than they normally encounter, compensating for their lack of ability to move. Also, desiccation tolerance of embryos may reduce pressure on parents to find optimal laying substrata.

The third study takes a big-picture approach to investigating the evolution of different developmental strategies in cone snails, the largest genus of marine invertebrates. Cone snail species hatch out of their capsules as either swimming larvae or non-dispersing forms, and their developmental mode has direct consequences for biogeographic patterns. Variability in life history strategies among taxa may be influenced by biological, environmental, or phylogenetic factors, or a combination of these. While most prior research has examined these factors singularly, my aim was to investigate the effects of a host of intrinsic, extrinsic, and historical factors on two fundamental aspects of life history: egg size and egg number. I used phylogenetic generalized least-squares regression models to examine relationships between these two egg traits and a variety of hypothesized intrinsic and extrinsic variables. Adult shell morphology and spatial variability in productivity and salinity across a species geographic range had the strongest effects on egg diameter and number of eggs per capsule. Phylogeny had no significant influence. Developmental mode in Conus appears to be influenced mostly by species-level adaptations and niche specificity rather than phylogenetic conservatism. Patterns of egg size and egg number appear to reflect energetic tradeoffs with body size and specific morphologies as well as adaptations to variable environments. Overall, this series of studies highlights the importance of organism-scale biotic and abiotic interactions in evolutionary patterns.