In modern combat aircraft, the most common localization method integrates a Global Navigation Satellite System (GNSS) with an Inertial Navigation System (INS). Although GNSS is the optimal choice for navigation, there are situations when the GNSS satellite signal is unavailable. This can happen due to various reasons such as jamming, physical obstacles, or technical failures. An alternative method to GNSS is utilizing Signals of Opportunity (SOP), which leverages signals not intended for navigation, such as those from cellular towers. These signals are transmitted from non-controllable sources, and challenges may arise due to the lack of guarantee regarding their quality and availability. Therefore, it is crucial that any estimation method utilizing SOP is robust to ensure accurate aircraft localization. This thesis investigates three different localization approaches to address this challenge. This study explores SOP sources with both known and unknown positions. For known signal source positions, an Extended Kalman Filter (EKF) based solution is utilized as a baseline to evaluate how well unknown signal sources can be used to estimate the aircraft's location. To address the challenge of unknown signal source positions, an EKF combined with a Simultaneous Localization and Mapping (SLAM) method, referred to as EKF SLAM, is used. In this case, the sources are introduced through two different approaches. The first approach, undelayed initialization, introduces the signal source directly when observed. The second approach, delayed initialization, involves inverse depth parameterization (IDP) and preprocessing of the signal source position before fully introducing it into the aircraft system. While both approaches outperform an unassisted INS approach, they do not achieve the same level of performance as when the source positions are known. Moreover, various factors, including the aircraft's trajectory, measurement noise, measurement frequency, and the initial covariance of new landmarks, influence the performance of the EKF SLAM approaches. Additionally, delayed initialization is strongly influenced by a threshold assessing landmark position estimate linearity, underscoring its sensitivity to accuracy. The concept behind delayed initialization aims to reduce the error of the signal source position before it is introduced to the system. This method has been proven to significantly reduce the signal source position error. However, its robustness is influenced by several factors, including the parallax angle, sudden changes in the aircraft's direction, and particularly the initial covariance of a landmark estimate. The accuracy of the aircraft's position is crucial, resulting in a trade-off between preprocessing and rapidly initializing a signal source position to the aircraft system. In contrast, undelayed initialization is less sensitive to trajectory changes, even though it introduces the signal sources with greater initial error. There is a significant difference in computational time when comparing known and unknown sources. As the number of sources increases, the computational time for unknown sources is more affected than for known sources. The delayed source initialization method increases computational time due to its preprocessing, especially as more sources are used. Conversely, initializing sources directly reduces the computational time, as no preprocessing is required. / I moderna stridsflygplan är den vanligaste lokaliseringsmetoden att integrera ett Global Navigation Satellite System (GNSS) med ett Inertial Navigation System (INS). Även om GNSS är det optimala valet för navigation finns det situationer när GNSS-satellitsignalen inte är tillgänglig. Detta kan inträffa på grund av olika orsaker som störningar, fysiska hinder eller tekniska fel. En alternativ metod till GNSS är att använda Signals of Opportunity (SOP), som utnyttjar signaler som inte är avsedda för navigation, till exempel de från mobilmaster. Dessa signaler kommer från okontrollerbara källor, vilket kan medföra utmaningar på grund av att deras kvalitet och tillgänglighet inte kan garanteras. Därför är det viktigt att varje lokaliseringsmetod som använder SOP är robust för att säkerställa en bra och korrekt flygplans positionering. Detta examensarbete undersöker tre olika lokaliseringsmetoder för att hantera denna utmaning. Denna studie utforskar SOP-källor med både kända och okända positioner. För kända positioner används en lösning baserad på ett Extended Kalman Filter (EKF) som en baslinje för att utvärdera hur väl okända signalkällor kan användas för att uppskatta flygplanets position. För att hantera utmaningen med okända signalkällors positioner används ett EKF kombinerad med en metod vid namn Simultaneous Localization and Mapping (SLAM), även kallad EKF SLAM. I detta fall introduceras källorna genom två olika tillvägagångssätt. Det första tillvägagångssättet, ofördröjd initialisering, introducerar signalkällan direkt när den observeras. Det andra tillvägagångssättet, fördröjd initialisering, involverar inverse depth parameterization (IDP) och förbearbetning av signalkällans position innan den introduceras i flygplanets lokaliseringssystem. Även om båda tillvägagångssätten presterar bättre än en oassisterad INS-metod uppnår de inte samma prestandanivå som när källornas position är kända. Dessutom påverkar olika faktorer prestandan hos EKF SLAM-metoderna, vilka främst är flygplanets flygbana, mätbrus, mätfrekvens och den initiala kovariansen av nya landmärken. Dessutom påverkas fördröjd initialisering starkt av en tröskel som bedömer linjäritet hos landmärkes positionen, vilket understryker dess känslighet för noggrannhet. Konceptet bakom fördröjd initialisering syftar till att minska felet i signalkällans position innan den introduceras i lokaliseringssystemet. Denna metod har visat sig kunna minska felet i signalkällans position avsevärt. Emellertid påverkas dess robusthet av flera faktorer, inklusive parallaxvinkeln, plötsliga förändringar i flygplanets riktning och särskilt den initiala kovariansen av uppskattningen av ett landmärkes position. Noggrannheten i flygplanets position är avgörande, vilket resulterar i en avvägning mellan förbearbetning och snabb initialisering av en signalkällas position till flygplanets lokaliseringssystem. Till skillnad från fördröjd initialisering är ofördröjd initialisering mindre känslig för förändringar i flygbanan, även om den introducerar signalkällorna med större initialt fel. Det finns en anmärkningsvärd skillnad i beräkningstid när man jämför kända och okända källors. När antalet källor ökar påverkas beräkningstiden för okända källor mer än för kända källor. Den fördröjda källinitialiseringsmetoden ökar beräkningstiden på grund av dess förbearbetning, särskilt när många källor används. Däremot minskar beräkningstiden när källor initialiseras direkt, eftersom ingen förbearbetning krävs.

A ghrelina, hormônio secretado principalmente por células gástricas, liga-se ao seu receptor, o receptor de secretagogo de GH (GHSR - Growth hormone secretagogue receptor), localizado no hipotálamo e na hipófise, estimulando a síntese e secreção do GH. Recentemente foram identificadas mutações no gene GHSR em crianças com baixa estatura idiopática (BEI) e com deficiência isolada de GH (DGH). No presente estudo investigamos a presença de mutações no gene GHSR em crianças com DGH isolada de causa não identificada e crianças com BEI, incluindo um subgrupo de crianças com atraso constitucional de crescimento e desenvolvimento (ACCD). Foram selecionados 14 pacientes com deficiência isolada de GH sem alterações anatômicas da região hipotálamo-hipofisária e 96 pacientes com BEI, destes 31 (32%) apresentavam ACCD. Também foram estudados 150 controles adultos e 197 crianças controle com crescimento e puberdade normais. A região codificadora do GHSR foi amplificada utilizando-se oligonucleotídeos iniciadores específicos, seguida de purificação enzimática e seqüenciamento automático. Encontramos 6 variantes alélicas em heterozigose no GHSR: nenhuma delas presente nos controles estudados, e quatro destas variantes estão localizadas em regiões conservadas do gene. Uma variante foi encontrada em uma paciente do grupo DGH (p.Val249Leu) e as outras cinco (c.-6 G>C, p.Ser84Ile, p.Val182Ala, p.Ala169Thr e p.Ala358Thr) foram encontradas em pacientes do subgrupo ACCD do grupo BEI. As variantes missense foram submetidas a estudo funcional que evidenciou que as mutações p.Ser84Ile e p.Val182Ala possuem diminuição na atividade basal associadas à diminuição da expressão do receptor na superfície celular. Adicionalmente, a mutação p.Ser84Ile também apresenta redução na atividade do GHSR induzida pelo ligante. A variante p.Val249Leu foi encontrada em uma paciente do sexo feminino com diagnóstico de DGH isolado. A falta de segregação familiar associada à ausência de déficit funcional da variante nos estudos in vitro sugere que, neste caso, a variante p.Val249Leu não é a causa do fenótipo de DGH nesta família e trata-se de uma variante alélica rara. As 5 variantes alélicas no GHSR (c.-6 G>C, p.Ser84Ile, p.Val182Ala, p.Ala169Thr e p.Ala358Thr) encontradas nos pacientes com BEI foram identificadas apenas naqueles com puberdade atrasada, ou seja, pertencentes ao subgrupo ACCD (3 do sexo masculino e 2 do sexo feminino). A freqüência de variantes neste grupo de pacientes foi de 16%, significativamente maior que nos outros grupos, e a ausência de variantes gênicas novas no grupo de crianças obesas com altura normal e mesmo no grupo de crianças com BEI sem ACCD sugere que nosso achado não foi casual e que as alterações descritas podem estar associadas ao fenótipo de ACCD. Os estudos in vitro mostraram prejuízos funcionais em 2 destas variantes (p.Ser84Ile e p.Val182Ala) porém, devido à limitação dos estudos funcionais (celulas heterólogas) não podemos afastar que as demais não tenham algum impacto funcional in vivo. Em conclusão, nossos resultados sugerem um envolvimento dos defeitos no GHSR na etiologia do atraso constitucional do crescimento e desenvolvimento em uma parcela de pacientes com esta condição / Ghrelin, hormone secreted by gastric cells, stimulates growth hormone secretion by acting on its receptor GHSR, located in the hypothalamus and pituitary. Recently, mutations in the GHSR gene were described in patients with growth hormone deficiency (GHD) and idiopathic short stature (ISS). In the present study we analyzed the GHSR gene in patients with isolated GHD and patients with ISS, including a subgroup of patients with constitutional delay of growth and puberty (CDGP). We studied 14 GHD patients with normal pituitary magnetic resonance imaging and 96 patients with ISS, 31 of them with CDGP. We also studied 150 adults and in 197 children with normal stature. The entire coding region as well as the exon-intron boundaries of GHSR were PCR amplified in all patients and control group and PCR products were bidirectionally sequenced. Six different heterozygous variants in GHSR were identified: none of them were found in the control group and four of these amino acid substitutions occurred at a conserved position within the GHSR. One variant (p.Val249Leu) was found in a GHD patient and the other five (c.-6 G>C, p.Ser84Ile, p.Val182Ala, p.Ala169Thr e p.Ala358Thr) were found in patients with CDGP. The missense variants were submitted to functional studies. Two of these variants (p.Ser84Ile and p.Val182Ala) result in a decrease in basal activity that was in part explained by a reduction in cell surface expression. The p.Ser84Ile mutation was also associated with a defect in ghrelin potency. The p.Val249Leu variant, found in a female patient with isolated GHD, did not segregate with the phenotype in the family and had no functional impairment in vitro. This suggests that p.Val249Leu is not the cause of the GHD in the family and may be a rare allelic variant. The other variants (c.-6 G>C, p.Ser84Ile, p.Val182Ala, p.Ala169Thr e p.Ala358Thr) were identified only in patients with CDGP (3 male and 2 female). The frequency of allelic variants observed in this group (16%) was higher than expected by chance in contrast with ISS and GHD children, and the absence of other GHSR mutations in the large group of control children suggests that the association between GHSR mutations and CDGP phenotype is unlikely to be fortuitous. Functional studies revealed that two of the identified missense variants (p.Ser84Ile and p.Val182Ala) are functionally significant. These functional studies were performed in heterologous cell expression systems; therefore it is not possible to completely rule out that the other identified variants might cause some unrevealed impairment on GHSR function or expression in vivo. In conclusion, our data raise the possibility that abnormalities in ghrelin receptor function may be implicated in the ethiology of CDGP in some patients

O presente estudo é um subprojeto do Instituto de Psiquiatria do Desenvolvimento intitulado \"Novas Ferramentas na Compreensão do Desenvolvimento Infantil: a Interação Gene-Ambiente e Conectividade Neuronal\", financiado pela FAPESP e aprovado pela CAPPESQ com o número de protocolo 0054/09. Os primeiros anos são particularmente importantes no ciclo vital, é rápido o crescimento e desenvolvimento do cérebro, tornando-se vulnerável à exposição a diferentes fatores de risco biológicos e psicossociais. Os fatores biológicos, em geral, são acompanhados por fatores psicossociais e ambientais que potencializam o seu efeito. Essas condições adversas são fatores de risco e ameaça ao desenvolvimento infantil. Devido à importância e ao impacto dos atrasos no desenvolvimento sobre o futuro da criança, quanto mais precocemente forem identificadas as crianças de maior risco, menor o agravamento futuro. O objetivo dessa dissertação foi caracterizar o desenvolvimento neuropsicomotor de crianças de 6 a 9 meses através da Escala Bayley de Desenvolvimento, em uma amostra de base populacional. Estimou-se a prevalência de atraso e a identificou os fatores de risco psicossociais e ambientais associados. É um estudo epidemiológico de coorte de nascimento longitudinal, com três seguimentos. A primeira entrevista com a gestante, para coleta de dados socioeconômicos e a entrevista para diagnósticos psiquiátricos, o segundo encontro para verificar diagnósticos psiquiátricos no puerpério, dados de nascimento e alimentação do lactente e por último aos 6 meses a aplicação da Escala Bayley. Avaliados 368 lactentes, encontramos 15,4% das crianças classificadas com atraso significativo em pelo menos um dos domínios, entre eles 10,87% tiveram atraso no desenvolvimento motor, com déficit de linguagem o total de 8,15% e 3,01% dos lactentes apresentaram atraso no desenvolvimento cognitivo aos 6 meses. Em analises constatou que o desenvolvimento cognitivo foi o fator com maior associação a fatores de estresse materno. Os transtornos, de humor durante a gestação, transtorno psicótico e transtorno de ansiedade no puerpério, a classe econômica, escolaridade materno, mãe adolescente e fumo durante a gestação, foram associados ao atraso no desenvolvimento mesmo após ajustes para fatores confundidores. Conclui-se que os transtornos psiquiátricos são preditores de atraso no desenvolvimento neuropsicomotor aos 6 meses de idade. Esse estudo mostra a importância da triagem para identificação de possíveis atrasos no desenvolvimento, para consequentes programas de intervenção a fim de evitar ou minimizar agravos futuros e possibilitar a criança desenvolver-se com todo seu potencial / This study is a subproject of Developmental Psychiatry Institute entitled \"New Tools in Child Development Understanding: Gene-Environment Interaction and Connectivity Neuronal\", funded by FAPESP and approved by CAPPESQ with protocol number 0054/09. It aims to characterize the neurological development of children aged 6 to 8 months by the Bayley scale in a population-based sample. It is expected, therefore, to estimate the prevalence of delay and the identification of psychosocial and environmental risk factors. The first years are particularly important in the life cycle, when is the rapid growth and development of the brain, making it vulnerable to exposure to different biological and psychosocial risk factors. Biological factors generally are accompanied by psychosocial and environmental factors that increase its effect. These adverse conditions are a risk factor and threat to child development. The importance and the impact of delays in the development of the child\'s future, the earlier identified the delay development, the risk could be smaller. The purpose of this thesis was to characterize the neurological development of children 6-9 months ago through the Bayley scale in a population-based sample, then estimate the prevalence of delay and identifying psychosocial and environmental risk factors. A longitudinal epidemiological study of birth cohort with three segments, the first interview with the pregnant woman, to collect socioeconomic data and the psychiatric diagnoses interview, the second meeting to check psychiatric diagnoses in the postpartum period, data of birth and infant feeding. At last, on six months, implementation the Bayley Scale of Development. Evaluated 368 infants, 15.4% children were classified as significant delay in at least one of the areas, among them 10.87% had delayed motor development, language delay total of 8.15% and 3.01 % of infants were delayed cognitive. In analysis, found that cognitive development was the factor with the largest association of maternal stress factors. Disorders, mood during pregnancy, psychotic disorder and anxiety disorder in the postpartum period, economic class, maternal education, teenage mother and smoking during pregnancy were associated with delayed development even after adjusting for confounding factors. It is concluded that, psychiatric disorders are predictors of delay in psychomotor development at 6 months of age. This study shows the importance of screening to identify possible developmental delays, for subsequent intervention programs to prevent or minimize future hazards and allow the child to develop to their full potential. Keywords: development; risk factors; infants

O presente estudo é um subprojeto do Instituto de Psiquiatria do Desenvolvimento intitulado \"Novas Ferramentas na Compreensão do Desenvolvimento Infantil: a Interação Gene-Ambiente e Conectividade Neuronal\", financiado pela FAPESP e aprovado pela CAPPESQ com o número de protocolo 0054/09. Os primeiros anos são particularmente importantes no ciclo vital, é rápido o crescimento e desenvolvimento do cérebro, tornando-se vulnerável à exposição a diferentes fatores de risco biológicos e psicossociais. Os fatores biológicos, em geral, são acompanhados por fatores psicossociais e ambientais que potencializam o seu efeito. Essas condições adversas são fatores de risco e ameaça ao desenvolvimento infantil. Devido à importância e ao impacto dos atrasos no desenvolvimento sobre o futuro da criança, quanto mais precocemente forem identificadas as crianças de maior risco, menor o agravamento futuro. O objetivo dessa dissertação foi caracterizar o desenvolvimento neuropsicomotor de crianças de 6 a 9 meses através da Escala Bayley de Desenvolvimento, em uma amostra de base populacional. Estimou-se a prevalência de atraso e a identificou os fatores de risco psicossociais e ambientais associados. É um estudo epidemiológico de coorte de nascimento longitudinal, com três seguimentos. A primeira entrevista com a gestante, para coleta de dados socioeconômicos e a entrevista para diagnósticos psiquiátricos, o segundo encontro para verificar diagnósticos psiquiátricos no puerpério, dados de nascimento e alimentação do lactente e por último aos 6 meses a aplicação da Escala Bayley. Avaliados 368 lactentes, encontramos 15,4% das crianças classificadas com atraso significativo em pelo menos um dos domínios, entre eles 10,87% tiveram atraso no desenvolvimento motor, com déficit de linguagem o total de 8,15% e 3,01% dos lactentes apresentaram atraso no desenvolvimento cognitivo aos 6 meses. Em analises constatou que o desenvolvimento cognitivo foi o fator com maior associação a fatores de estresse materno. Os transtornos, de humor durante a gestação, transtorno psicótico e transtorno de ansiedade no puerpério, a classe econômica, escolaridade materno, mãe adolescente e fumo durante a gestação, foram associados ao atraso no desenvolvimento mesmo após ajustes para fatores confundidores. Conclui-se que os transtornos psiquiátricos são preditores de atraso no desenvolvimento neuropsicomotor aos 6 meses de idade. Esse estudo mostra a importância da triagem para identificação de possíveis atrasos no desenvolvimento, para consequentes programas de intervenção a fim de evitar ou minimizar agravos futuros e possibilitar a criança desenvolver-se com todo seu potencial / This study is a subproject of Developmental Psychiatry Institute entitled \"New Tools in Child Development Understanding: Gene-Environment Interaction and Connectivity Neuronal\", funded by FAPESP and approved by CAPPESQ with protocol number 0054/09. It aims to characterize the neurological development of children aged 6 to 8 months by the Bayley scale in a population-based sample. It is expected, therefore, to estimate the prevalence of delay and the identification of psychosocial and environmental risk factors. The first years are particularly important in the life cycle, when is the rapid growth and development of the brain, making it vulnerable to exposure to different biological and psychosocial risk factors. Biological factors generally are accompanied by psychosocial and environmental factors that increase its effect. These adverse conditions are a risk factor and threat to child development. The importance and the impact of delays in the development of the child\'s future, the earlier identified the delay development, the risk could be smaller. The purpose of this thesis was to characterize the neurological development of children 6-9 months ago through the Bayley scale in a population-based sample, then estimate the prevalence of delay and identifying psychosocial and environmental risk factors. A longitudinal epidemiological study of birth cohort with three segments, the first interview with the pregnant woman, to collect socioeconomic data and the psychiatric diagnoses interview, the second meeting to check psychiatric diagnoses in the postpartum period, data of birth and infant feeding. At last, on six months, implementation the Bayley Scale of Development. Evaluated 368 infants, 15.4% children were classified as significant delay in at least one of the areas, among them 10.87% had delayed motor development, language delay total of 8.15% and 3.01 % of infants were delayed cognitive. In analysis, found that cognitive development was the factor with the largest association of maternal stress factors. Disorders, mood during pregnancy, psychotic disorder and anxiety disorder in the postpartum period, economic class, maternal education, teenage mother and smoking during pregnancy were associated with delayed development even after adjusting for confounding factors. It is concluded that, psychiatric disorders are predictors of delay in psychomotor development at 6 months of age. This study shows the importance of screening to identify possible developmental delays, for subsequent intervention programs to prevent or minimize future hazards and allow the child to develop to their full potential. Keywords: development; risk factors; infants

A ghrelina, hormônio secretado principalmente por células gástricas, liga-se ao seu receptor, o receptor de secretagogo de GH (GHSR - Growth hormone secretagogue receptor), localizado no hipotálamo e na hipófise, estimulando a síntese e secreção do GH. Recentemente foram identificadas mutações no gene GHSR em crianças com baixa estatura idiopática (BEI) e com deficiência isolada de GH (DGH). No presente estudo investigamos a presença de mutações no gene GHSR em crianças com DGH isolada de causa não identificada e crianças com BEI, incluindo um subgrupo de crianças com atraso constitucional de crescimento e desenvolvimento (ACCD). Foram selecionados 14 pacientes com deficiência isolada de GH sem alterações anatômicas da região hipotálamo-hipofisária e 96 pacientes com BEI, destes 31 (32%) apresentavam ACCD. Também foram estudados 150 controles adultos e 197 crianças controle com crescimento e puberdade normais. A região codificadora do GHSR foi amplificada utilizando-se oligonucleotídeos iniciadores específicos, seguida de purificação enzimática e seqüenciamento automático. Encontramos 6 variantes alélicas em heterozigose no GHSR: nenhuma delas presente nos controles estudados, e quatro destas variantes estão localizadas em regiões conservadas do gene. Uma variante foi encontrada em uma paciente do grupo DGH (p.Val249Leu) e as outras cinco (c.-6 G>C, p.Ser84Ile, p.Val182Ala, p.Ala169Thr e p.Ala358Thr) foram encontradas em pacientes do subgrupo ACCD do grupo BEI. As variantes missense foram submetidas a estudo funcional que evidenciou que as mutações p.Ser84Ile e p.Val182Ala possuem diminuição na atividade basal associadas à diminuição da expressão do receptor na superfície celular. Adicionalmente, a mutação p.Ser84Ile também apresenta redução na atividade do GHSR induzida pelo ligante. A variante p.Val249Leu foi encontrada em uma paciente do sexo feminino com diagnóstico de DGH isolado. A falta de segregação familiar associada à ausência de déficit funcional da variante nos estudos in vitro sugere que, neste caso, a variante p.Val249Leu não é a causa do fenótipo de DGH nesta família e trata-se de uma variante alélica rara. As 5 variantes alélicas no GHSR (c.-6 G>C, p.Ser84Ile, p.Val182Ala, p.Ala169Thr e p.Ala358Thr) encontradas nos pacientes com BEI foram identificadas apenas naqueles com puberdade atrasada, ou seja, pertencentes ao subgrupo ACCD (3 do sexo masculino e 2 do sexo feminino). A freqüência de variantes neste grupo de pacientes foi de 16%, significativamente maior que nos outros grupos, e a ausência de variantes gênicas novas no grupo de crianças obesas com altura normal e mesmo no grupo de crianças com BEI sem ACCD sugere que nosso achado não foi casual e que as alterações descritas podem estar associadas ao fenótipo de ACCD. Os estudos in vitro mostraram prejuízos funcionais em 2 destas variantes (p.Ser84Ile e p.Val182Ala) porém, devido à limitação dos estudos funcionais (celulas heterólogas) não podemos afastar que as demais não tenham algum impacto funcional in vivo. Em conclusão, nossos resultados sugerem um envolvimento dos defeitos no GHSR na etiologia do atraso constitucional do crescimento e desenvolvimento em uma parcela de pacientes com esta condição / Ghrelin, hormone secreted by gastric cells, stimulates growth hormone secretion by acting on its receptor GHSR, located in the hypothalamus and pituitary. Recently, mutations in the GHSR gene were described in patients with growth hormone deficiency (GHD) and idiopathic short stature (ISS). In the present study we analyzed the GHSR gene in patients with isolated GHD and patients with ISS, including a subgroup of patients with constitutional delay of growth and puberty (CDGP). We studied 14 GHD patients with normal pituitary magnetic resonance imaging and 96 patients with ISS, 31 of them with CDGP. We also studied 150 adults and in 197 children with normal stature. The entire coding region as well as the exon-intron boundaries of GHSR were PCR amplified in all patients and control group and PCR products were bidirectionally sequenced. Six different heterozygous variants in GHSR were identified: none of them were found in the control group and four of these amino acid substitutions occurred at a conserved position within the GHSR. One variant (p.Val249Leu) was found in a GHD patient and the other five (c.-6 G>C, p.Ser84Ile, p.Val182Ala, p.Ala169Thr e p.Ala358Thr) were found in patients with CDGP. The missense variants were submitted to functional studies. Two of these variants (p.Ser84Ile and p.Val182Ala) result in a decrease in basal activity that was in part explained by a reduction in cell surface expression. The p.Ser84Ile mutation was also associated with a defect in ghrelin potency. The p.Val249Leu variant, found in a female patient with isolated GHD, did not segregate with the phenotype in the family and had no functional impairment in vitro. This suggests that p.Val249Leu is not the cause of the GHD in the family and may be a rare allelic variant. The other variants (c.-6 G>C, p.Ser84Ile, p.Val182Ala, p.Ala169Thr e p.Ala358Thr) were identified only in patients with CDGP (3 male and 2 female). The frequency of allelic variants observed in this group (16%) was higher than expected by chance in contrast with ISS and GHD children, and the absence of other GHSR mutations in the large group of control children suggests that the association between GHSR mutations and CDGP phenotype is unlikely to be fortuitous. Functional studies revealed that two of the identified missense variants (p.Ser84Ile and p.Val182Ala) are functionally significant. These functional studies were performed in heterologous cell expression systems; therefore it is not possible to completely rule out that the other identified variants might cause some unrevealed impairment on GHSR function or expression in vivo. In conclusion, our data raise the possibility that abnormalities in ghrelin receptor function may be implicated in the ethiology of CDGP in some patients

This master’s thesis explores a space-division-multiplexing (SDM) platform fora delayed-choice experiment. SDM is a multiplexing technique for optical datatransmission that employs spatial modes in a multi- or few-mode fiber to increasethe transmission capacity. The spatial modes can thus be used as separate channels. SDM have shown great potential for quantum information systems, making it intriguing to investigate its broad applications by examining its use in adelayed-choice experiment. The delayed-choice experiment was proposed by J.A.Wheeler in 1978 explored the particle- and wave-like behavior of quantum particles and observe if the particle knows in advance if it should propagate as a waveor a particle through the experimental platform. Hence, it was suggested thatthe experiment should be changed after the particle entered the experimentalplatform. The experiment has afterward been realized in many different constellations but previous wave-particle delayed-choice experiments have not beendemonstrated with SDM nor with an all in fiber platform. The research involved modeling and constructing a SDM fiber-optic platform,only utilizing commercially available fiber optical telecommunication components. The platform was constructed with photonic lanterns, used as spatial division multiplexer and demultiplexer, and a two-input fiber Sagnac Interferometer,as a removable beam splitter. The system was tested with classical light but without difficulties, the platform could move to the quantum domain for performingthe delayed-choice experiment with single photons on the platform. The thesis resulted in a SDM platform with good performance for future measurement of bothparticle- and wave-like behavior of photons in a delayed-choice experiment.

Abstract Title: The Ticking of the “Biological Clock”: Worry about Future Fertility in Nulliparous Women By: Karen Kersting, M.A., M.S. A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at Virginia Commonwealth University. Virginia Commonwealth University, 2013. Major Director: Kathleen M. Ingram, J.D., Ph.D. Associate Professor of Psychology Department of Psychology Modern women are waiting until later in their lives to have children than women of previous generations, a trend influenced by a number of factors including financial stability, dating norms, and career goals and responsibilities. As women age, their fertility may decline in ways that make it less likely that they will be able to become pregnant and increase the odds having a child born with a birth defect. Some women are known to experience worry about whether they will be able to become pregnant when they are ready to try. The primary purpose of this study was to assess how much women are worrying, what demographic and cultural factors predict higher levels of worry, and if worry about future fertility is related to symptoms of distress. Through online recruitment, 598 nulliparous women between the ages of 25 and 40 years completed a cross-sectional, self-report survey. Mean scores on measures of future fertility worry revealed a low-to-moderate, but consistently present level of worry. As hypothesized, multiple regression analysis showed that higher levels of endorsement of the personal importance of motherhood were related to higher levels of future fertility worry, as was age and the interaction of age and importance, but to a lesser extent. Knowledge of fertility was not related to increased worry. Additionally, higher levels of future fertility worry were shown to be related to higher levels of symptoms of depression and symptoms of anxiety. And an open-ended question revealed that women hold a variety of reasons for not wanting to become pregnant presently, including career, relationship, and financial concerns. Overall, the study contributes rigorous findings to a previously unstudied research question and population: How much do nulliparous women who have not experienced infertility worry about their fertility? And what influences that worry? The findings imply that media, researchers, practitioners, the general public, and even women themselves may have held errant assumptions about the thoughts and feelings of nulliparous women, and that worry about fertility is complex, generally moderate, and closely related to personal values.

Depuis leur découverte dans les années 1930, les polyuréthanes (PU) ont connu un essor important et représentent aujourd’hui un marché supérieur à 10 millions de tonnes par an. Ces matériaux sont préparés par réaction de polyaddition d'un polyol sur un polyisocyanate en présence d’un catalyseur. Des complexes organométalliques, notamment à base d’étain, sont communément employés pour accélérer cette réaction. Cependant, leur toxicité et leur nocivité envers l’environnement vont prochainement conduire à leur interdiction. Dans le cadre d’un projet pluridisciplinaire, nos efforts se sont concentrés sur le développement de catalyseurs potentiellement plus respectueux de l’environnement. Nous avons tout d’abord réalisé un criblage d’organocatalyseurs pour la synthèse de carbamates. Cette étude préliminaire a mis en évidence l’efficacité des guanidines bicycliques telles que le 7-méthyl-1,5,7-triazabicyclo[4,4,0]déc-5-ène (MTBD). De nouveaux analogues du MTBD ont été préparés et utilisés comme catalyseurs pour la synthèse de PU. Une étude mécanistique a également été conduite. Elle a permis d’expliquer les comportements catalytiques contrastés d’espèces chimiques pourtant très proches, à l’image du MTBD, du TBD, du DBU et du DBN. Ces travaux ont notamment mis en évidence la nucléophilie du MTBD qui réagit avec deux équivalents d’isocyanate pour former des composés tricycliques originaux. Ces nouveaux hétérocycles présentent des propriétés attrayantes de catalyseurs à effet retard thermo-activables pour la synthèse de PU. / Polyurethanes (PU) constitute an important market, estimated around 10 wt% of the current synthetic polymer production. They are usually prepared by the most straightforward route involving the addition of polyols to polyisocyanates in the presence of a catalyst. Tin based organometallic complexes are the most active catalysts currently in use, but environmental concerns should lead in not too distant a future to a ban of these reagents. In the context of a multidisciplinary project, we focused our efforts on the design of environmentally more acceptable organocatalysts that could advantageously replace metal-based catalysts. A screening of organocatalysts was therefore carried out, from which bicyclic guanidines such as 7-methyl-1,5,7-triazabicyclo[4,4,0]dec-5-ene (MTBD) emerged as the most efficient. New analogues of MTBD were prepared and successfully used as catalysts for the synthesis of PU. Mechanistic studies were also performed. The catalytic behaviour of structurally similar compound such as MTBD, TBD, DBU or DBN was rationalised. The nucleophilic reaction between MTBD and isocyanates was highlighted and original compounds in which two equivalents of isocyanate are incorporated onto the guanidine scaffold were isolated. These novel heterocycles exhibit appealing thermally-triggered delayed-action catalytic properties for the synthesis of PU.

Diploma thesis "Delayed School Attendance in the Region of Říčany" deals with survey of the region of Říčany with respect to opinions and experience of kindergarten and primary school teachers. The work is divided into two parts. The theoretical part contains information on delay school attendance issues necessary for successful realisation of a pedagogical research. The practical part is focused on answering of defined survey questions and on verification or falsification of the hypothesis. The research is based on the quantity method of questioning (by means of questionnaire and interview) and qualitative method of observation. The survey took place at 24 kindergartens and 7 primary schools taking into account 54 kindergarten teachers and 15 primary school teachers in the region of Říčany. It was found out, that the number of delayed school attendance in the region of Říčany is lower than the average value in the entire Czech Republic. Further, kindergarten and primary school teachers agree, that children often have problems with communication and concentration. Other important findings are that teachers don't feel any difference between children with and without delayed school attendance; they have individual approach to children on the basis of their abilities and needs. The end of the work contains...

Le vieillissement des populations est corrélé à l’augmentation des pathologies neurodégénératives liées à l’âge, plus particulièrement la maladie d’Alzheimer. La recherche de marqueurs précoces de la maladie ainsi que l’élaboration de nouvelles stratégies thérapeutiques constituent un enjeu de taille. Parmi les mécanismes moléculaires de la formation des plaques amyloïdes actuellement explorés, les formes oligomériques tronquées de peptide amyloïde (Aß), notamment le peptide Aß3(?pE)??42? retrouvé à des stades précoces de la maladie, joueraient un rôle déterminant. Ces travaux de thèse ont permis de montrer, dans un premier temps, que l’injection intracérébrale de ce peptide chez la souris entraîne des altérations de la mémoire de travail et des capacités d’apprentissage, associées à une accumulation d’espèces réactives dérivées de l’oxygène dans des régions cérébrales spécifiques (hippocampe et bulbes olfactifs) de ces animaux. Des essais menés in vitro sur des cultures primaires de neurones de souris montrent leur implication dans les voies apoptotiques impliquant l’activation des caspases et la cascade métabolique de l’acide arachidonique. La seconde étape de ces travaux a constitué en l’étude des effets protecteurs d’un peptide antiapoptotique d’origine endogène, l’humanine (HN) et son variant S14G (HNG). In vitro, un effet protecteur de ces peptides a été mesuré après traitement de neurones en culture par le peptide A[bêta]3?(pE)42.??? Les résultats les plus marquants résident dans les observations faites in vivo : en effet, ces peptides inhibent l’effet délétère de l’injection intracérébroventriculaire du peptide Aß3?(pE??)42?? en restaurant les performances mnésiques des animaux dans les tests comportementaux. A la lumière de ces résultats, les peptides HN pourraient constituer de nouveaux outils thérapeutiques dans le traitement ou la prévention des dommages cellulaires précoces liés à la présence des oligomères solubles du peptide Aß / Aging of population is correlated to the increase of neurodegenerative disease, more particularly Alzheimer disease. Defining early diagnostic markers and new therapeutic strategies are highly relevant. Among the molecular pathways which are currently developed, N-terminal-truncated forms of amyloid-ß (Aß) peptide have been recently suggested to play a pivotal role in the disease. Among them, Aß3(?pE)42 ?peptide is the dominant Aß species in amyloid plaques. We first investigated the effects of soluble oligomeric Aß3(pE) 42 after intracerebroventricular injection on mice learning capacities and the molecular mechanisms of in vitro neurotoxicity. Mice injected with soluble Aß3(pE) 42 displayed impaired spatial working memory and delayed memory acquisition. These cognitive alterations were associated with free radical overproduction in hippocampus and olfactory bulbs. In vitro, Aß3(pE) 42 oligomers induced a redox-sensitive neuronal apoptosis involving caspase activation and an arachidonic acid-dependent pathway. The second goal of this work was to investigate the protective effects of the apoptosis rescue endogenous peptide humanin (HN) and its S14G mutant (HNG). In vitro, we measured their inhibitory effect on neuronal death and apoptotic events resulting from soluble Ab oligomer treatment. What’s of particular interest is the in vivo restoration of soluble Aß3(pE) 42 oligomer-induced mnesic impairment. Thus, HN peptides might serve as new drug candidates for treatment or prevention of early cellular damages linked to soluble A[bêta] oligomers