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KIT receptor (CD117) is a receptor tyrosine kinase crucial for homeostasis of mast cells (MCs) in tissues and recruitment to sites of inflammation and tumors in response to its ligand Stem cell factor (SCF). Gain of function mutations in KIT (e.g. D816V) are frequently observed in systemic mastocytosis and other cancer types. Src Homology 2 domain containing phosphatase-2 (SHP2 or PTPN11) is a protein tyrosine phosphatase that promotes cell proliferation, survival and motility in multiple pathways and cell types. To study SHP2 function in MCs, we generated novel MC-specific Shp2 knock-out (KO) mice (MC-shp2 KO). These mice had reduced numbers of MCs in skin and peritoneum, and defective contact hypersensitivity responses compared to control mice, consistent with SHP2 promoting MC homeostasis. Using an inducible SHP2 KO bone marrow-derived MC (BMMC) culture model, we found that SHP2 KO cells were prone to apoptosis and had no MC repopulating activity in vivo. Mechanistically, SHP2 enhanced ERK activation and downregulation of pro-apoptotic protein Bim. SHP2 KO BMMCs also had defects in chemotaxis towards SCF, due to impaired activation of a Lyn/Vav/Rac pathway in SHP2 KO BMMCs. This correlated with defects in cell spreading, and F-actin polymerization in response to SCF. Treatment of BMMCs with a SHP2 inhibitor (II-B08) also led to reduced chemotaxis, consistent with SHP2 phosphatase activity being required for KIT-induced chemotaxis. Lastly, we tested whether SHP2 regulates oncogenic KIT signaling using a P815 mouse mastocytoma model. Stable silencing of SHP2 in P815 cells led to reduced cell growth and survival in vitro, and less aggressive systemic mastocytosis development in syngeneic mice. Overall, these studies identify SHP2 as a key node in SCF/KIT and oncogenic KIT pathways, and as a potential therapeutic target in several human diseases. / Thesis (Ph.D, Biochemistry) -- Queen's University, 2013-06-25 12:03:57.818

Vibration exposure can occur at work, commuting between home and work, and in leisure activities. Any form of transportation will expose humans to some degree of vibration. Exposure to vibration can cause health problems, but more likely comfort problems. Health problems are normally related to back pain. Comfort on the other hand is related to both physiological and psychological factors, which can have a wide range of effects from a general annoyance to a reduced work capability. The standard ISO 2631-1 (1997) provides a guidance, which can be used to measure, evaluate and assess effects of whole-body vibration to discomfort. The standard allows several interpretations, which can lead to different results, as the standard does not provide an explicit guidance for selecting which axes and locations to measure and which averaging method to use for evaluating the axes. The suggested averaging method is the root mean square (r.m.s.) method, but additionally vibration dose value (VDV) can be used. This can lead to different results, as VDV emphasises shocks more than the r.m.s. method. The standard guides to measure and evaluate at least the seat translational axes, but the additional nine axes from the seat, backrest and floor are not mandatory. However, this can result in a different comfort value, as the values from the measured axes are combined. So taking into account all possible interpretations the assessment can vary significantly for the same environment. The selection of the averaging method is not a technical issue, as both methods are supported by all commercial equipment. However, it is rare that more than three axes are possible to be measured with typical whole-body vibration measurement equipment, thus the majority of studies have published results based on only the seat translational axes. Especially the rotational axes have been missing in most studies. The full method (i.e. using all possible axes to calculate the comfort value) of ISO 2631-1 (1997) has been rarely used and there is very little information on how accurate the method is for assessing discomfort in a multi-axis environment. There are only a few studies that have used the full method, but there are no known studies which have actually validated the full ISO 2631-1 method. The objective of the thesis was to validate and, if necessary, to improve the full method of the ISO 2631-1 standard for evaluating discomfort from whole-body vibration in a multi-axis environment. It was assumed that the ISO 2631-1 method can be used to predict discomfort in practice, but there are a relatively low number of studies to confirm this. Frequency weightings have been the focus of many published studies and it was assumed that these are broadly correct. Other aspects of the ISO 2631-1 method are the focus of this thesis. The goal was to keep a backward compatibility to previous studies and the current commercial equipment, thus several limitations were defined for the improvement of the standard. Several laboratory experiments, field measurements, and field and laboratory trials were conducted to validate the standard method. At first it was concluded that practical equipment for measuring 12-axis data was needed as there was no commercial system available. The equipment and software was validated in two experiments, which showed that simple and affordable components could be used to develop equipment for the full method. Even though the standard does not include information about a six-axis sensor for measuring both translational and rotational axes, there was a method to validate the sensor. The first field study included measuring several machines using all twelve axes. The analysis showed that the seat and backrest translational axes will contribute about 90 % of the overall vibration total value of the standard method, thus very little justification was found for including the seat rotational and floor translational axes. Similar results were found based on the data from the previous 12-axis studies. It was also found that the neglected axes could be compensated with a factor for estimating the overall vibration total value including all twelve axes. As the overall vibration total value is directly related to the number of used axes, the compensating factors can be used to compare results which used different axes. The laboratory trial confirmed the results from the field study, and it was concluded that sufficient accuracy to predict discomfort can be achieved using just the seat translational axes, even though the correlation improved when more axes were included. It was found that the evaluation of discomfort was improved by the use of the frequency weighting curves and the r.m.s. averaging method. However, as the multiplying factors degraded correlation, it was concluded that a new set of factors should be calculated. The new factors showed that a higher emphasis on the seat horizontal axes should be given (x=2.7, y=1.8 and z=1.0). The new factors improved the correlation systematically for all subjects. The field trial showed a similar trend, where optimised multiplying factors improved the correlation, but it was also noted that different multiplying factors are required for different environments, thus a procedure to optimise the standard method to different environments was developed. The trial showed systematic behaviour and the optimised multiplying factors were best for all subjects and groups. Keywords: Discomfort, whole-body vibration, standard, ISO 2631-1, multi-axis, multiplying factors

In this paper, the performance of a new measurement system CITE (CNC Integrity Tracing Equipment) is investigated. CITE measurement system is the name given to the data acquisition hardware and software developed by University West for recording the movements of CNC machine tools. It can be used for monitoring of the milling process and recording the milling errors. The aim of this study is investigate the capability of the CITE system in prediction of the surface roughness. In an example cutting test, the CITE measurement system was used for recording selected sections in straight milling process and curved milling process. After that, surface roughness, predicted by the CITE measurement system, was compared with the CMM (Coordinate measurement machine). The investigation shows that the CITE measurement system is comparable to the CMM for evaluation of roughness in curved sections. In straight sections, the evaluation of roughness by CMM machine is close to the simulation values that predicts surface roughness considering tool run-out.

Daniel K. Inouye Solar Telescope (formerly known as Advanced Technology Solar Telescope) will be the largest optical solar telescope ever built to provide greatly improved image, spatial and spectral resolution and to collect sufficient light flux of Sun. To meet the requirements of the telescope the design adopted a 4m aperture off-axis parabolic primary mirror with challenging specifications of the surface quality including the surface figure, irregularity and BRDF. The mirror has been completed at the College of Optical Sciences in the University of Arizona and it meets every aspect of requirement with margin. In fact this mirror may be the smoothest large mirror ever made. This paper presents the detail fabrication process and metrology applied to the mirror from the grinding to finish, that include extremely stable hydraulic support, IR and Visible deflectometry, Interferometry and Computer Controlled fabrication process developed at the University of Arizona.

Callous-unemotional (CU) traits have been shown to designate a particular subgroup of antisocial youth that are particularly violent, recidivistic, and more likely to continue offending in adulthood. Disordered neuroendocrine function may be a mechanism for the development of CU traits. We examined whether altered stress responsivity served as a mechanism linking stress exposure and the expression of CU traits. Participants were 15 incarcerated adolescent girls with CU traits. Measures of CU traits, stress exposure, and salivary cortisol were collected. Results revealed girls with CU traits had higher morning levels of cortisol, an intact cortisol awakening response (CAR), and flatter diurnal rhythms. Results indicated the type of stressor being measured and time since stressor onset are crucial to the interpretation of neuroendocrine function. We also found support for a neurobiological model for the development of CU traits drawing on the Adaptive Calibration Model. Implications of the study and directions for further research are discussed.

Introdução: A exposição frequente dos profissionais de enfermagem a estressores relacionados ao trabalho tem sido amplamente descrita na literatura. Entretanto, a magnitude e intensidade do estresse dependem não somente dos estressores, mas também da interação destes com a avaliação cognitiva da situação estressora, com os recursos de enfrentamento e com a reação psiconeuroendócrina do estresse. Embora diversos estudos tenham descrito as reações psicológicas do estresse e seu enfrentamento nos profissionais de enfermagem, pouco se sabe sobre as características da reação neuroendócrina. Isto é particularmente importante, dado que padrões atípicos de secreção diurna de cortisol, principal hormônio do estresse, estão associados ao aumento da susceptibilidade ao desenvolvimento de doenças cardiovasculares, imunológicas e transtornos mentais. Assim, questiona-se a frequência de padrões atípicos de cortisol e sua relação com manifestações psicológicas nestes profissionais. Objetivo: Analisar o padrão diurno de secreção de cortisol dos profissionais de enfermagem de unidades hospitalares. Método: Foram incluídos 56 profissionais de enfermagem randomicamente selecionados, alocados nas unidades ambulatório, clínica médica, clínica cirúrgica, centro cirúrgico, pronto socorro infantil e adulto, unidade de terapia intensiva adulto e pediátrica de um hospital universitário. Para avaliação do padrão diurno de secreção de cortisol foram coletadas amostras de saliva em dois dias úteis consecutivos de trabalho e, para as manifestações psicológicas, foram aplicados os instrumentos escala de estresse percebido (EEP), questionário de sofrimento mental (SRQ-20), inventário de depressão de Beck (IDB) e escala de estresse no trabalho (EET). Os dados foram armazenados e analisados utilizando o programa estatístico SPSS versão 14.0 e o nível de significância adotado foi de 5%. Resultados: Quanto ao padrão de secreção de cortisol, 42,5% dos profissionais de enfermagem apresentaram padrão atípico de secreção de cortisol, sendo que 19,5% eram técnicos de enfermagem. Quanto às variáveis psicológicas, 54,5% perceberam-se com alto nível de estresse (EEP), 51,2% referiram que o estresse estava relacionado ao trabalho (EET), 15,5% apresentaram distmia e depressão (IDB) e 56,8% apresentam sinais de sofrimento mental (SRQ-20). Não houve associação entre padrão de secreção de cortisol e as variáveis psicológicas. Conclusão: Mais de um terço da amostra de profissionais de enfermagem apresentou padrões atípicos de secreção de cortisol, além de relatarem elevados níveis de estresse, estresse relacionado ao trabalho e sofrimento mental. Estes dados sugerem que estes profissionais podem estar expostos a uma sobrecarga não apenas mental, mas biológica, estando expostos ao risco para o adoecimento. / Background: Frequent exposure of nurses to work-related stressors has been widely described in the literature. However, the magnitude and intensity of the stress depends not only on stressors, but also their interaction with the cognitive appraisal of stressful situation, the resources and coping with the psychoneuroendocrine stress response. Although several studies have described the psychological reactions of stress and coping with it in nursing, little is known about the characteristics of the neuroendocrine response of stress. This is particularly important since atypical patterns of diurnal cortisol secretion are associated with increased susceptibility to the development of cardiovascular, immunological diseases and mental disorders. Thus, we arised the question about the frequency of atypical patterns of cortisol and its relationship with psychological manifestations in nursing professionals. Objective: To analyze the diurnal pattern of cortisol secretion of nursing professionals at a hospital setting. Methods: Fifty six (n = 56) nursing professionals were randomly selected allocated to the outpatient clinic, medical clinic, surgical clinic, surgical center, pediatric unit, adult and pediatric emergency department and intensive care unit of a university hospital. To evaluate the diurnal pattern of cortisol secretion, saliva samples were collected on two consecutive working days. For the psychological manifestations of stress the following instruments were applied: the Perceived Stress Scale (PSS), the Self-report Questionnaire (SRQ-20), the Beck Depression Inventory (BDI) and the work-related stress scale (WSS). Data were stored and analyzed using SPSS version 14.0 and the level of significance was 5%. Results: Regarding the pattern of cortisol secretion 42.5% of nurses had atypical pattern of cortisol secretion and 19.2% were from nursing technical professional category. Regarding psychological variables, 54.5% perceived themselves at high stress level, 51.2% reported that stress were work-related 15.5% had depression and dysthymia and 56.8% showed signs of mental distress. There was no association between pattern of cortisol secretion and the psycological variables. Conclusion: More than one third of the sample exhibited atypical pattern of cortisol secretion as well as high levels of stress, work-related stress and mental distress. These data suggest that these workers may be exposed not just to psychological overload, but also to biological burden and could be exposed to a risk for the illness.

Essa tese aborda a consolidação do eixo territorial Rio de Janeiro - São Paulo como núcleo principal do desenvolvimento nacional, através do planejamento econômico e da ação direta do Estado. Ao enfocar o período do 1o Ciclo Desenvolvimentista, de1930 a 1964, evidencia a opção pela industrialização como caminho para o desenvolvimento. Como consequência da subordinação do país à condição de periferia do sistema capitalista internacional, apesar da transformação estrutural do sistema de produção, de nação agroexportadora para urbano-industrial, há continuidade na reprodução das desigualdades, de regionais a intraurbanas.O eixo territorial se estrutura na base de seus vetores lineares, entrelaçando relações de seus núcleos urbanos articulados por uma malha de caminhos e percursos que remontam historicamente à forma de ocupação dos nativos indígenas. As relações entre as Capitais do Rio de Janeiro e de São Paulo, as cidades que se fundam ao longo da história do Vale do Paraíba do Sul e os diversos ciclos econômicos que prevaleceram em determinados momentos forjaram o espaço regional.A tese verifica a hipótese de que a lógica da materialização da produção social do espaço urbano e a dos desequilíbrios dos processos de urbanização brasileiros foram fundamentalmente consolidadas nesse período histórico, a partir de definições determinadas no plano econômico e não por planos urbanísticos concebidos no sentido da organização do meio urbano. Estes, por sua vez, reproduziram modelos para apoiar a construção da imagem de uma sociedade modernizada e assumiriam papel coadjuvante nos processos de urbanização. / This thesis concerns the consolidation of the Rio de Janeiro - Sao Paulo territorial axis as main core of Brazil\'s national development, through economic planning and the direct action of the State. Focusing the period of the 1st Developmental Cycle, from 1930 to 1964, and on the option for industrialization as the path to development. As a consequence of the country\'s subordination to a peripheral condition in the international capitalistic system, though there was structural change in the production system, from agro exporter to urban industrial, there was continuity on the reproduction of inequalities, from regional to intra urban. The territorial axis structures itself on the basis of linear vectors, interweaving relationships of its urban centers articulated by a network of paths and trails that date back to the native indians\' occupation. The relationships between the Capitals cities of Rio de Janeiro and Sao Paulo, the cities that were founded along the Paraiba do Sul Valley\'s history and the several economic cycles that prevailed in determined moments shaped the regional space. The thesis finds support for the hypothesis that the logic of materialization of the social production of the urban space and the unbalanced Brazilian urbanization processes were fundamentally consolidated in this historical period, based on definitions determined by economic, rather than urbanistic plans, conceived in the sense of urban means arrangements. These, in turn, reproduced models to stand the construction of the image of a modernized society and assumed a supporting role in the urbanization processes.

In the fruit fly, Drosophila melanogaster, accumulation of osk mRNA at the posterior pole of the oocyte and local translation initiate assembly of the pole plasm, which is required for germ cell formation and posterior patterning of the embryo. I have used fluorescence in situ hybridization (FISH) in combination with immunofluorescence and laser scanning confocal microscopy to examine the spatial and temporal control of osk transcript localization and translation. Drosophila oocytes develop within cysts of 16 interconnected cells. One cell in each cyst differentiates to form the oocyte while the remaining cells form nurse cells that produce RNAs and proteins that are transported to the oocyte. osk mRNA is produced by the nurse cells and accumulates in the oocyte throughout oogenesis, but is only specifically localized to the posterior pole and translated during mid to late oogenesis. My studies help define distinct steps in the osk mRNA localization process. An early step in posterior localization is removal of osk mRNA from most of the cortex, leading to accumulation in the oocyte interior. This process requires microtubules, the microtubule motor protein Kinesin I, the actin binding protein Tropomyosin, and the RNA binding protein Staufen. Transcript then moves from the oocyte interior to the posterior pole through a microtubule independent process. The genes cappuccino, chickadee, spire, armitage, maelstrom, par-1 and gurken are all required for this next step in osk mRNA localization. The final capturing or tethering osk mRNA at the cortex requires an intact actin filament system, but additional components of this anchoring system remain to be identified. I also find that osk mRNA first begins to accumulate at the posterior pole during oogenesis stage 8, but protein is not detectable until stage 9. In addition, grk and par-1 mutations that block osk mRNA localization to the posterior pole and lead to transcript accumulation in the interior do not prevent translation; again, Osk protein production is only observed during stage 9 and later. These observations indicate that posterior localization is neither sufficient nor necessary to trigger osk mRNA translation, which appears to be under tight temporal control.

Os Transtornos por Uso de Substâncias (TUS) são propostos pela Associação Norte-Americana de Psiquiatria e englobam diversas dependências químicas, incluindo o tabagismo e a dependência de crack. O uso de crack tem aumentado consideravelmente nos últimos anos, segundo dados de levantamentos brasileiros e mundiais. Com mecanismo de ação semelhante ao da cocaína, porém com efeito mais rápido, o crack é uma droga que causa grave prejuízo a seus usuários e conduz à dependência em pouco tempo. O tabagismo também é uma condição bastante prevalente no mundo inteiro, sendo que os prejuízos relacionados a esse transtorno envolvem principalmente o desenvolvimento de doenças respiratórias e câncer. Diversos trabalhos têm buscado identificar fatores de suscetibilidade a esses transtornos, sendo que estudos de associação envolvendo genes do sistema de resposta a estresse vêm ganhando importância. O eixo Hipotálamo- Pituitária-Adrenal (HPA) é o sistema de resposta a estresse mais conhecido em humanos e alvo do presente trabalho, uma vez que o funcionamento dessa cascata de sinalização da produção de cortisol pode desempenhar um papel relevante no desenvolvimento de psicopatologias. Além disso, o eixo HPA pode ser considerado um mediador da relação entre situações adversas na infância e o surgimento de TUS. O objetivo desse trabalho, portanto, é investigar o papel de polimorfismos no gene CRHR1 (que codifica o receptor tipo 1 do hormônio liberador de corticotrofina – CRH, hormônio inicial do eixo HPA) sobre o desenvolvimento e características clínicas da dependência química. Para isso, foram realizados dois estudos, envolvendo amostras de mulheres. No primeiro artigo, a partir de três amostras – (1) 136 usuárias de crack, (2) 55 tabagistas e (3) 262 voluntárias saudáveis – foram identificadas diferenças de freqüências alélicas e genotípicas do SNP rs12944712; além disso, a análise de haplótipos envolvendo tal SNP e o rs110402 revelou maior frequência do haplótipo contendo o alelo G nos dois polimorfismos nos grupos de usuárias de crack e tabagistas. No segundo artigo, foi avaliado o efeito da interação geneambiente envolvendo os mesmos polimorfismos e situações adversas na infância – estimada pela escala Childhood Trauma Questionnaire (CTQ) –sobre características clínicas da amostra de usuárias de crack, como craving e gravidade da dependência – estimados, respectivamente, pelas escalas Cocaine Selective Severity Assessment (CSSA) e Addiction Severity Index (ASI6). A análise não revelou uma interação significativa. A presente dissertação, portanto, revela um efeito do gene CRHR1 sobre o desenvolvimento de TUS, embora esse efeito pareça não se manifestar sobre a gravidade. Mais estudos são necessários visando esclarecer o real efeito do gene e do eixo HPA como um todo sobre os fenótipos e comportamentos aditivos, bem como os mecanismos subjacentes a essa relação. / The Substance Use Disorders (SUD) are proposed by the American Psychiatric Association and comprise several addictions, including tobacco and crack cocaine smoking. The prevalence of crack cocaine dependence has grown considerably, according to survey data from Brazil and worldwide. With mechanism of action similar to cocaine but with faster effect, crack is a drug that causes severe impairments to its users and leads to dependence in a short time. Tobacco smoking is also a highly prevalent condition worldwide, and the impact related to this disorder includes cancer and respiratory diseases. Several studies have attempted the identification of susceptibility factors to these disorders, and association studies involving stress response system genes have been performed. The Hypothalamic-Pituitary-Adrenal (HPA) axis is the best known stress response system, and the signaling cascade production of cortisol may play a role in the development of psychopathology. In addition, HPA axis can be considered a mediator of the relationship between early life adversity and SUD. The aim of this study is to investigate the role of polymorphisms in CRHR1 gene (encoding the corticotrophin releasing factor – CRH – receptor type 1, an initial factor in HPA axis response) on the development and clinical traits of drug dependence. Two studies were conducted on women samples. In the first article, three groups were compared - (1) 136 crack smokers, (2) 55 tobacco smokers and (3) 262 healthy volunteers. Differences in allele and genotype frequencies of the SNP rs12944712 were identified; in addition, the haplotype analysis involving this SNP and rs110402 revealed a higher frequency of the haplotype containing G allele in both polymorphisms in the groups of nicotine dependents and crack smokers. In the second article, we evaluated the effect of a gene-environment interaction involving the same polymorphisms and childhood adversity - estimated by Childhood Trauma Questionnaire (CTQ) scale – on clinical characteristics of the sample of crack users, such as craving and severity of dependence - estimated respectively by the Cocaine Selective Severity Assessment (CSSA) and Addiction Severity Index (ASI6) scales. The analysis did not reveal a significant interaction. This dissertation thus shows an effect of CRHR1 genepolymorphism on the development of SUD, although this effect does not seem to impact disorder severity. More studies are needed in order to clarify the actual effect of the gene and of the HPA axis as a whole on addictive behaviors.