Fundação de Amparo a Pesquisa no Estado do Rio Grande do Sul / Elephantopus mollis is a Asteraceae family species recently found in soybean crops / winter pastures in the central-western region of Rio Grande do Sul, Brazil. Its presence has reduced yields and increased the cost of production of these crops. In order to get the emergency pattern of the species throughout the year and its sensitivity to the main herbicide used in these crops it is that took place this work. To determine the emergency flow and the seed bank in the area two experiments were conducted in a rural area of the municipality of Tupanciretã, and for the response to herbicides were conducted five trials of dose-response curves to the herbicide glyphosate, 2, 4-D, metsulfuron-methyl, flumioxazin and saflufenacil. In the emergency experiments it have been demarcated two areas side by side. One kept uncroped and another subjected to the usual crop of the total area. In both areas, treatments were represented by twelve months of the year to carry out the count of emerged plants for each month. The samples to estimate the seed bank were collected in the month of August in each of the twelve portions of the area kept uncroped in the depths of 0 to 5 cm and 5 to 10 cm. In trays kept in a greenhouse (UFSM), counts were made of emerged plants, every 15 days for 150 days. For dose-response curves were established doses and represents the division multiple of the recommended dose of herbicide for similar species as 0; x / 8; x / 4; x / 2; x; 2x; 4x; 8x. For glyphosate x = 1440 g ha-1, 2,4-D x = 670 g ha-1, metsulfuron x = 2.4 g ai ha-1, flumioxazin x = 50 g ai ha-1 and saflufenacil x = 35 g ai ha-1. Herbicide treatments were applied to plants with 8 to 10 leaves. The variables were visual assessment of control (%) (range 0-100) at 3, 7, 14, 21 and 28 days after treatments and the mass of green and dry matter of roots and shoots, producing the total mass and relative, by its expression as a percentage of treatment without herbicide to 28 days. The results show that E. mollis emerges during all months of the year, with major emergencies in the months of November, February and May. But the seed bank pointed to the presence in the average of all samples of 400 seeds m2 of E. mollis in the 0 to 5 cm and inexpressive 5 to 10 cm. There was a weak correlation between the emerged plants and seed bank, proving to be the most intense emergency probably due to soil temperature for the months of November, February and May. It can be suggested that emergency peaks coincide with the time of implantation of cultures and thus represent the best opportunities to make up the control. The results found with the curves show that glyphosate and 2,4-D are not efficient in the control and can not conclude on the efficiency metsulfuron, flumioxazin and saflufenacil. / Elephantopus mollis é uma espécie da família Asteraceae recentemente encontrada em cultivos de soja/pastagens de inverno na região centro-oeste do Rio Grande do Sul, Brasil. Sua presença tem reduzido o rendimento e aumentado o custo de produção dessas culturas. Com o objetivo de conhecer o padrão de emergência da espécie ao longo do ano e sua sensibilidade aos principais herbicidas empregados nesses cultivos é que realizou-se o presente trabalho. Para determinar o fluxo de emergência e a estimativa do banco de sementes na área foram conduzidos dois experimentos em área rural do município de Tupanciretã, e para a resposta aos herbicidas foram conduzidos cinco ensaios de curvas de dose-resposta com os herbicidas glifosato, 2,4-D, metsulfuron-metil, flumioxazin e saflufenacil. Nos experimentos para a emergência foram demarcadas duas áreas próximas. Uma mantida sem cultivo e outra submetida ao cultivo usual da área total. Em ambas, os tratamentos foram representados pelos doze meses do ano para realizar a contagem das plantas emergidas para cada mês, com quatro repetições. As amostras para estimar o banco de sementes foram coletadas no mês de agosto, em cada uma das doze parcelas da área mantida sem cultivo, nas profundidades de 0 a 5 cm e de 5 a 10 cm. Em bandejas mantidas em casa de vegetação, foram efetuadas as contagens das plantas emergidas, a cada 15 dias, durante 150 dias. Para as curvas de dose-resposta foram estabelecidas doses representando a divisão e múltiplo da dose recomendada dos herbicidas para espécies similares, na forma: 0; x/8; x/4; x/2; x; 2x; 4x; 8x. Para glifosato x = 1440 g ea ha-1, 2,4-D x = 670 g ea ha-1, metsulfuron x = 2,4 g ia ha-1, flumioxazin x = 50 g ia ha-1 e saflufenacil x = 35 g ia ha-1. Os tratamentos herbicidas foram aplicados sobre plantas com 8 a 10 folhas. As variáveis foram a avaliação visual de controle (%) (escala 0-100) aos 3, 7, 14, 21 e 28 dias após os tratamentos e a massa de matéria verde e seca das raízes e parte aérea, produzindo a massa total e relativa, por sua expressão em percentagem do tratamento sem herbicida aos 28 dias. Os resultados demonstram que E. mollis emerge durante todos meses do ano, com maiores emergências nos meses de novembro, fevereiro e maio. Já a estimativa do banco de sementes apontou para a presença, na média de todas amostras, de 400 sementes m2 de E. mollis na profundidade de 0 a 5 cm e inespressiva entre 5 a 10 cm. Houve uma fraca correlação entre as plantas emergidas e o banco de sementes, demonstrando ser a emergência mais intensa provavelmente devido à temperatura do solo dos meses de novembro, fevereiro e maio. Pode-se sugerir que os picos de emergência coincidem com os momentos de implantação das culturas e representam assim as melhores oportunidades para realizar-se o controle. Os resultados das curvas demonstram que glifosato e 2,4-D não são eficientes no controle e não se pode concluir sobre a eficiência de metsulfuron, flumioxazin e saflufenacil.

Hipóteses do estudo: 1) A magnitude da ação antimicrobiana difere entre os princípios ativos cloreto de cetilpiridíneo (CPC), digluconato de clorexidina (CHX), e óleos essenciais (OE) quando utilizados em dose única no bochecho pré-operatório. 2) A redução bacteriana é mais evidente nos pacientes periodontalmente doentes. Objetivos: Avaliou-se a ação antimicrobiana de bochechos pré-operatórios em dose única em diferentes condições periodontais. Método: Sessenta indivíduos saudáveis, sessenta com gengivite e sessenta com periodontite foram randomizados nos grupos: CPC 0,07%, CHX 0,12%, OE (timol 0,064%, mentol 0,042%, eucaliptol 0,092% e salicilato de metila 0,06%) e solução controle negativo. Para o diagnóstico periodontal foram avaliados índice de placa (IP), índice sangramento gengival (ISG), profundidade de sondagem (PS) e nível de inserção clínica (NIC). A quantificação da contagem bacteriana total e das espécies Porphyromonas gingivalis, Tannerella forsythia,Treponema denticola e Streptococcus oralis foi realizada pela PCR em tempo real (qPCR) em amostras de saliva. Os dados foram analisados utilizando-se os testes t pareado e t Student (p<0,05). Resultados: CHX, OE e CPC acarretaram reduções das contagens totais bacterianas e das espécies bacterianas específicas superiores ao controle negativo. A magnitude do efeito variou entre os agentes testados e foi influenciada pela condição periodontal. Para as reduções das contagens totais bacterianas OE exibiram os melhores resultados já que foram eficazes na saúde, gengivite e periodontite. CHX mostrou esse mesmo padrão, exceto no grupo gengivite. CPC não foi eficaz estatisticamente no grupo periodontite para esse parâmetro. As maiores reduções das espécies Gram negativas agrupadas no complexo vermelho (Pg, Td e Tf simultaneamente) foram observadas após o uso de CHX, no grupo saúde e OE, nos grupos gengivite e periodontite. Quanto às reduções da espécie Gram positiva So, elas foram maiores no grupo saúde após o uso de OE, no grupo gengivite após o uso de CHX e no grupo periodontite após o uso em dose única de CPC. Conclusões: O bochecho pré-procedimento tem ação antimicrobiana que sofre influência da condição periodontal e difere entre os agentes testados. Para pacientes saudáveis o clínico pode optar por CHX, OE ou CPC, mas para pacientes com doença periodontal OE ou CHX devem ser a primeira escolha. / The propouse of this study: 1) The extent the dimension of the antimicrobial action differs among the active agents cetylpyridinium chloride (CPC), chlorhexidine digluconate (CHX), and essential oils (EO) when used as a single dose in the preoperative rinse. 2) The bacterial reduction after the use of a single dose mouthwash is more evident in patients with periodontal diseases. Goals: The present study evaluated by microbiological parameters the antimicrobial effectiveness of the preoperative rinses in differents periodontal conditions. Method: Sixty periodontal healthy individuals, sixty individual with gingivitis, sixty individual with periodontitis were randomized into the following groups: CPC(0,07%), CHX(0,12%), EO(timol 0,064%,menthol 0,042%,eucalyptol 0,092%,methyl salicylate 0,06%) and negative control solution. Plaque index (IP), gingival bleeding index (IG), probing depth (PS) and clinical attachment level (NIC) were evaluated clinically. The bacterial identification and the quantification (Porphyromonas gingivalis, Tannerella forsythia,Treponema denticola, Streptococcus oralis) were realized for PCR real time(qPCR) on salivary samples. The data were analysed by the paired t-test and Student t-test(p<0,05). Results: CHX, EO and CPC have resulted in reduction in bacterial total counts and specifc bacterial species, wich were higher than the negative control. The magnitude of the effect varied between the tested agents and it was influenced by periodontal condition. The reductions in bacterial total counts EO showed the best results since they were effective in healthy, gingivitis and periodontitis. CHX showed the same pattern, except in the gingivitis group. CPC was not statistically effective in periodontitis group for this parameter. The largest reductions of the species Gram negative grouped in the red complex (Pg, Tf and Td simultaneously) were observed after the use of CHX in health, and EO in the gingivitis and periodontitis groups. The reductions in Gram positive species So, were higher in the group health after using EO, in the gingivitis group after the use of CHX and in the periodontitis group after using CPC. Conclusions: The pre-procedure rinses has antimicrobial action suffering influence of periodontal condition and varies from agents tested. In healthy patients the clinician may choose CHX, EO or CPC but for patients with periodontal disease EO or CHX should be the first choice.

Aujourd'hui les circuits intégrés commerciaux sont de plus en plus utilisés dans les satellites de télécommunication ou d'observation. En effet les contraintes économiques imposent l'usage de circuits non durcis aux radiations. Ceci, associé au fait que la technologie évolue entrainant une baisse de consommation et donc une diminution des marges de susceptibilité électromagnétique, les rendent plus sensibles à la fois aux interférences électromagnétiques et à la dose ionisante. Cet ensemble met en péril la mission des satellites. Ce travail de thèse est donc précurseur dans le domaine de la fiabilité combinée vis à vis de la dose ionisante et des signaux hautes fréquences (HF) sur des transistors bipolaires destinés aux applications basse fréquence. Nous avons tout d'abord observé la modification du comportement d'un transistor bipolaire discret lorsqu'il est soumis à une agression sinusoïdale continue (CW) dans la gamme 100 MHz - 5 GHz. Cette forme de signal nous a permis d'observer la réponse du transistor dans un régime établi. Il est important de noter que cette modification du comportement a lieu même pour des fréquences du signal d'interférence assez éloignées de la gamme de fréquence de fonctionnement du transistor. Nous avons pu alors mettre en évidence les différents mécanismes physiques mis en jeu. Ensuite nous avons étudié l'influence de différents paramètres : fréquence et puissance du signal d'interférence, boîtier du transistor, valeurs des éléments du circuit de polarisation, sur la réponse du transistor soumis à l'agression CW. Un critère simple permettant de prévoir le comportement du transistor sous agression CW est proposé. Nous avons ensuite étudié l'influence de la dose ionisante sur le comportement du transistor sous agression CW. Après avoir observé la modification du comportement statique du transistor suite à l'irradiation avec une source de cobalt 60, nous avons analysé l'évolution des grandeurs électriques du transistor sous agression HF, pour différentes valeurs de doses totales déposées. Nous avons donc pu monter que la dose ionisante influence effectivement le comportement du transistor sous agression. Enfin, nous avons soumis le transistor à une autre forme d'agression haute fréquence : un signal sinusoïdal modulé par un signal impulsionnel. Grâce à ce type de signal, nous avons pu faire une analyse du comportement transitoire du transistor, et mettre en évidence l'importance des capacités, à la fois internes et externes au composant. Ici encore la dose ionisante influence les comportements. / Nowadays, economic constraints push space and aeronautical industries to use Commercial Off The Shelf (COTS) components, even though natural space environment constitutes a real challenge for electronic reliability due to ionizing particles. In addition to this problem, technological advancements lead to a decrease in device consumption inducing smaller electromagnetic susceptibility margins. Hence, integrated circuits are more sensitive to both Electromagnetic Interferences (EMI) and ionizing dose, which may threaten satellite missions. This thesis reveals precursor work in the field of combined ionizing dose and high frequency (HF) interferences on bipolar transistors designed for low frequency applications. Classical discrete low frequency bipolar transistors biased at integrated-circuit level of currents are put under study. A change of the voltage output when the device is subject to a continuous sine aggression (CW) in the range 100 MHz - 5 GHz is observed. This CW waveform allows an analysis of the response of the transistor in a steady state. It is important to note that the change in behavior of the transistor occurs even for interference frequency bands way higher than the operating frequencies of the device. We identified the different physical mechanisms involved during high frequency interference injection: rectification and current crowding. Then we studied the influence on the behavior under interference of different parameters: frequency and power of the interference signal, low frequency and RF frequency package of the transistor, values of elements of the bias circuit. A simple criterion to predict the way of change in the output voltage of the transistor is proposed. The same experiments were conducted on the transistors irradiated with a cobalt 60 source. We highlighted the importance for high-frequency susceptibility of the change induced by ionizing dose near the emitter base junction. Hence the susceptibility must be considered for different bias operations for different ionizing dose rates. Finally, our interest focused on another type of HF interference: a sine wave modulated by a pulse signal. With this type of signal, the transient behavior of the transistor under interference is analyzed. It highlights the importance of internal and external capacitances of the device on its response. Here again ionizing dose influences the electromagnetic susceptibility of the transistor.

Les doses secondaires neutroniques ne sont actuellement pas estimées lors de la planification de traitement dans les centres de protonthérapie puisque les logiciels de planification de traitement (TPS) ne le proposent pas tandis que les simulations Monte Carlo (MC) et les mesures sont inadaptées pour un environnement clinique. L’objectif de la thèse est de développer un modèle analytique dédié à l’estimation des doses secondaires neutroniques aux organes sains qui reste pratique et simple d’utilisation en routine clinique. Dans un premier temps, la géométrie existante de la gantry installée au Centre de protonthérapie d’Orsay (CPO) de l’institut Curie modélisée avec le code de calcul MCNPX a été étendue à trois configurations de traitement supplémentaires (énergie en entrée de ligne de 162, 192 et 220 MeV). Une approche comparative simulation-mesure a ensuite été entreprise afin de vérifier la capacité de ces modélisations à reproduire les distributions de doses (en profondeur et latérales) des protons primaires ainsi que le champ secondaire neutronique. Des écarts inférieurs à 2 mm ont été observés pour les protons primaires. Pour les neutrons secondaires, les écarts sont plus mitigés avec des rapports simulation sur mesure de ~2 et de ~6, respectivement pour la spectrométrie et les équivalents de dose dans un fantôme physique. L’analyse des résultats a permis d’identifier l’origine de ces écarts et de mettre en perspective la nécessité de conduire de nouvelles études pour améliorer à la fois les mesures expérimentales et les simulations MC. Dans un deuxième temps, une approche purement numérique a été considérée pour calculer les doses neutroniques aux organes sains de fantômes voxélisés représentant des patients d’un an, de dix ans et adulte, traités pour un craniopharyngiome. Une variation de chaque paramètre de traitement a été réalisée afin d’étudier leur influence respective sur les doses neutroniques. Ces paramètres ont pu être ordonnés par ordre décroissant d’influence : incidence de traitement, distance organe-collimateur et organe-champ de traitement, taille/âge des patients, énergie de traitement, largeur de modulation, ouverture du collimateur, etc. Des suggestions ont également été avancées pour réduire les doses neutroniques.Dans un troisième temps, un modèle analytique a été conçu de façon à être utilisable en routine clinique, pour tous les types de tumeur et toutes les installations de protonthérapie. Son entraînement séparé pour trois incidences de traitement a montré des écarts inferieurs à ~30% et ~60 µGy Gy⁻¹ entre les données d’apprentissage (doses neutroniques calculées aux organes sains) et les valeurs prédites par le modèle analytique. La validation a consisté à comparer les doses neutroniques estimées par le modèle analytique à celles calculées avec MCNPX pour des conditions différentes des données d’apprentissage. Globalement, un accord acceptable a été observé avec des écarts moyens de ~30% et ~100 µGy Gy⁻¹. La flexibilité et la fiabilité du modèle analytique ont ainsi été mises en évidence. L’entraînement du modèle analytique à partir d’équivalents de dose neutroniques mesurés dans un fantôme solide au Centre Antoine Lacassagne a confirmé son universalité, bien qu’il requière néanmoins quelques ajustements supplémentaires pour améliorer sa précision. / Stray neutron doses are currently not evaluated during treatment planning within proton therapy centers since treatment planning systems (TPS) do not allow this feature while Monte Carlo (MC) simulations and measurements are unsuitable for routine practice. The PhD aims at developing an analytical model dedicated to the estimation of stray neutron doses to healthy organs which remains easy-to-use in clinical routine. First, the existing MCNPX model of the gantry installed at the Curie institute - proton therapy center of Orsay (CPO) was extended to three additional treatment configurations (energy at the beam line entrance of 162, 192 and 220 MeV). Then, the comparison of simulations and measurements was carried out to verify the ability of the MC model to reproduce primary proton dose distributions (in depth and lateral) as well as the stray neutron field. Errors within 2 mm were observed for primary protons. For stray neutrons, simulations overestimated measurements by up to a factor of ~2 and ~6 for spectrometry and dose equivalent in a solid phantom, respectively. The result analysis enabled to identify the source of these errors and to put into perspective new studies in order to improve both experimental measurements and MC simulations. Secondly, MC simulations were used to calculate neutron doses to healthy organs of a one-year-old, a ten-year-old and an adult voxelized phantoms, treated for a carniopharyngioma. Treatment parameters were individually varied to study their respective influence on neutron doses. Parameters in decreasing order of influence are: beam incidence, organ-to-collimator and organ-to-treatment field distances, patient’ size/age, treatment energy, modulation width, collimator aperture, etc. Based on these calculations, recommendations were given to reduce neutron doses. Thirdly, an analytical model was developed complying with a use in clinical routine, for all tumor localizations and proton therapy facilities. The model was trained to reproduce calculated neutron doses to healthy organs and showed errors within ~30% and ~60 µGy Gy⁻¹ between learning data and predicted values; this was separately done for each beam incidence. Next, the analytical model was validated against neutron dose calculations not considered during the training step. Overall, satisfactory errors were observed within ~30% and ~100 µGy Gy⁻¹. This highlighted the flexibility and reliability of the analytical model. Finally, the training of the analytical model made using neutron dose equivalent measured in a solid phantom at the center Antoine Lacassagne confirmed its universality while also indicating that additional modifications are required to enhance its accuracy.

Le développement majeur de la thèse a été consacré au problème d’optimisation du choix de dose dans les essais de recherche de dose, en phase II. Nous avons considéré ce problème sous l’angle des fonctions d’utilité. Nous avons alloué une valeur d’utilité aux doses, le problème pour le sponsor étant de trouver la meilleure dose, c’est-à-dire celle dont l’utilité est la plus élevée.Dans ce travail, nous nous sommes limités à une seule fonction d’utilité, intégrant deux composantes: une composante liée à l’efficacité (la POS=puissance d’un essai de phase III de 1000 patients de cette dose contre placebo) et une autre liée à la safety. Pour cette dernière, nous avons choisi de la caractériser par la probabilité prédictive d’observer un taux de toxicité inférieur ou égal à un certain seuil (que nous avons fixé à 0.15) en phase III (toujours pour un essai de 1000 patients au total). Cette approche a l’avantage d’être similaire aux concepts utilisés dans les essais de phase I en oncologie qui ont notamment pour objectif la recherche de la dose liée à une toxicité limite (notion de ”Dose limiting Toxicity”).Nous avons retenu une approche bayésienne pour l’analyse des données de la phase II.Mis à part les avantages théoriques connus de l’approche bayésienne par rapport à l’approche fréquentiste (respect du principe de vraisemblance, dépendance moins grande aux résultats asymptotiques, robustesse), nous avons choisi l’approche bayésienne pour plusieurs raisons:• Combinant, par définition même de l’approche bayésienne, une information a priori avec les données disponibles, elle offre un cadre plus flexible la prise de décision du sponsor: lui permettant notamment d’intégrer de manière plus ou moins explicite les informations dont il dispose en dehors de l’essai de la phase II.• L’approche bayésienne autorise une plus grande flexibilité dans la formalisation des règles de décision.Nous avons étudié les propriétés des règles de décisions par simulation d’essais de phase II de différentes tailles: 250, 500 et 1000 patients. Pour ces deux derniers design nous avons aussi évalué l’intérêt de d’effectuer une analyse intermédiaire lorsque la moitié des patients a été enrôlée (c’est-à-dire avec respectivement les premiers 250 et 500 patients inclus). Le but était alors d’évaluer si, pour les essais de phase II de plus grande taille, s’autoriser la possibilité de choisir la dose au milieu de l’étude et de poursuivre l’étude jusqu’au bout si l’analyse intermédiaire n’est pas concluante permettait de réduire la taille de l’essai de phase II tout en préservant la pertinence du choix de dose final. / The main development of the thesis was devoted to the problem of dose choice optimization in dose-finding trials, in phase II. We have considered this problem from the perspective of utility functions. We have allocated a utility value to the doses itself, knowing that the sponsor’s problem was now to find the best dose, that is to say, the one having the highest utility. We have limited ourselves to a single utility function, integrating two components: an efficacy-related component (the PoS = the power of a phase III trial - with 1000 patients - of this dose versus placebo) and a safety-related component. For the latter, we chose to characterize it by the predictive probability of observing a toxicity rate lower or equal to a given threshold (that we set to 0.15) in phase III (still for a trial of 1000 patients in total). This approach has the advantage of being similar to the concepts used in phase I trials in Oncology, which particularly aim to find the dose related to a limiting toxicity (notion of "Dose limiting Toxicity").We have adopted a Bayesian approach for the analysis of phase II data. Apart from the known theoretical advantages of the Bayesian approach compared with the frequentist approach (respect of the likelihood principle, less dependency on asymptotic results, robustness), we chose this approach for several reasons:• It provides a more flexible framework for the decision-making of the sponsor because it offers the possibility to combine (by definition of the Bayesian approach) a priori information with the available data: in particular, it offers the possibility to integrate, more or less explicitly, the information available outside the phase II trial.• The Bayesian approach allows greater flexibility in the formalization of the decision rules.We studied the properties of decision rules by simulating phase II trials of different sizes: 250, 500 and 1000 patients. For the last two designs (500 and 1000 patients in phase II), we have also evaluated the interest of performing an interim analysis when half of the patients are enrolled (i.e. with the first 250and the first 500 patients included respectively). The purpose was then to evaluate whether or not, for larger phase II trials, allowing the possibility of choosing the dose in the middle of the study and continuing the study to the end if the interim analysis is not conclusive, could reduce the size of the phase II trial while preserving the relevance of the final dose choice.

Automatic exposure control (AEC) is effective at reducing potentially harmful radiation doses without sacrificing image quality for many types of computed tomography (CT) scans. However, there is a need for more information regarding the use of AEC for CT head scans. This study was conducted at Johnson County Community Hospital in Mountain City, TN. Preexisting adult CT head scans (n)60 were randomly selected to form 2 stratified samples, (n)30 each. One sample used a standard protocol, and the other used a protocol with a mA-modulated AEC system, Siemens CARE Dose 4D. Causal-comparative analyses were conducted, and it was determined that AEC was effective at maintaining subjective image quality while reducing radiation doses an average of 38% for adult CT head scans. It was concluded that using AEC was an effective tool to optimize radiation doses for adult CT head scans in one particular setting, but more research on this topic is needed.

Human and animal studies show significant delays in neurobehavioral development in offspring after prolonged prenatal exposure to moderate and high ethanol doses resulting in high blood alcohol concentration (BECs). However, none have investigated the effects of lower ethanol doses given acutely during specific developmental time periods. Here, we sought to create a mouse model for modest and circumscribed human drinking during the 3rd and 4th weeks of pregnancy.We acutely treated mice during embryo gastrulation on gestational day (GD) 7 or neurulation on GD8 with a low or moderate ethanol dose given via gavage that resulted in BECs of 107 and 177. mg/dl, respectively. We assessed neonatal physical development (pinnae unfolding, and eye opening); weight gain from postnatal day (PD) 3-65; and neurobehavioral maturation (pivoting, walking, cliff aversion, surface righting, vertical screen grasp, and rope balance) from PD3 to 17. We used a multiple linear regression model to determine the effects of dose, sex, day of treatment and birth in animals dosed during gastrulation or neurulation, relative to their vehicle controls.We found that ethanol exposure during both time points (GD7 and GD8) resulted in some delays of physical development and significant sensorimotor delays of pivoting, walking, and thick rope balance, as well as additional significant delays in cliff aversion and surface righting after GD8 treatment. We also found that treatment with the low ethanol dose more frequently affected neurobehavioral development of the surviving pups than treatment with the moderate ethanol dose, possibly due to a loss of severely affected offspring. Finally, mice born prematurely were delayed in their physical and sensorimotor development.Importantly, we showed that brief exposure to low dose ethanol, if administered during vulnerable periods of neuroanatomical development, results in significant neurobehavioral delays in neonatal mice. We thus expand concerns about alcohol consumption during the 3rd and 4th weeks of human pregnancy to include occasional light to moderate drinking.

Les insectes présentent une étonnante diversité morphologique dans les organes de vol, et cette évolution a conduit à leur rayonnement au sein du règne animal. L'une des modifications les plus frappantes est la transformation des ailes postérieures en structures d'équilibrage très réduites, appelées haltères. Des travaux pionniers chez la drosophile ont montré que la spécification des haltères est sous le contrôle du gène Hox Ultrabithorax (Ubx). En revanche, la formation des ailes antérieures est décrite pour être indépendante des gènes Hox, mais cette observation est controversée chez d’autres insectes. Au cours de mon doctorat, j'ai réexaminé le rôle des gènes Hox pour la spécification des organes du vol chez la drosophile. Mes travaux montrent que la protéine Hox Antennapedia (Antp) est exprimée à un niveau faible dans des cellules spécifiques du primordium de la marge et est nécessaire à la formation correcte de l’aile adulte. De manière étonnante, Antp peut également fonctionner comme Ubx et former un haltère quand la protéine est exprimée à des niveaux similaires à ceux de Ubx. Ainsi, la formation d’organes de vol divergents chez la drosophile est directement contrôlée par une dose spécifique de protéine Hox et non par une protéine Hox spécifique. Les gènes Hox sont intrinsèquement liés à l'évolution de la diversité morphologique chez les animaux. Par conséquent, le rôle de la dose des protéines Hox a également été testé d'un point de vue évolutif parmi plusieurs lignages d'insectes. Les résultats montrent que la dose de protéines Hox est à peu près la même entre les primordia antérieur et postérieur d’un insecte à quatre ailes comme Bombyx mori. Dans l’ensemble, mes résultats démontrent que la spécification des organes de vol n’est pas un programme Hox-indépendant et que la variation de la dose des protéines Hox est un moyen de modifier la taille et la forme de l’aile, pouvant ultimement aboutir à la création d’un tout nouvel organe d’équilibrage au cours de l’évolution des insectes. Enfin, au cours de mon doctorat, j'ai également participé à plusieurs projets parallèles visant à identifier et à caractériser le rôle des nouveaux cofacteurs des protéines Hox dans différents contextes développementaux, notamment la spécification de l’haltère et la répression de l'autophagie. Ces travaux s'appuient en partie sur la complémentation de fluorescence bimoléculaire (BiFC), une méthode que nous avons récemment couplée à la panoplie d'outils génétiques de la drosophile pour réaliser des criblages d'interactions protéine-protéine à grande échelle in vivo. / Insects display an astonishing array of diversity in flight appendage morphologies and theirevolution led to the catalyzed radiation of insects in the animal kingdom. The first definite modellinking the Hox genes to morphological evolution was demonstrated in Drosophila. One of themost striking modifications is the transformation of hindwings into highly reduced balancingstructures called halteres. Work in Drosophila established that the specification of halteres isunder the control of a single Hox gene, Ultrabithorax (Ubx). In contrast, the formation of forewingshas been described to be Hox-independent. During my Ph.D., I reconsidered the role of Hox genesfor flight appendage specification in Drosophila. I show that the Hox protein Antennapedia (Antp)is expressed at a low level in specific cells of the wing blade primordium and required for theproper formation of the adult wing. Moreover, Antp works like Ubx to form a haltere whenexpressed in the levels of Ubx. Thus, the formation of divergent flight organs in Drosophila is notdependent on a specific Hox protein but on a specific Hox dose.Hox genes are intrinsically linked to the evolution of morphological diversity in animals.Therefore the role of the Hox dose was also tested from an evolutionary point of view amongseveral insect lineages. Results show that the Hox dose is for example pretty much the samebetween the forewing and hindwing primordia of the four-wing insect species Bombyx mori.Altogether, my results demonstrate that the specification of flight appendages is not aHox-independent developmental program and that the variation in the Hox dose is a way tomodify the wing size and shape, ultimately leading to a completely new balancing organ duringinsect evolution.

Die Nephrotoxizität ist die wichtigste Nebenwirkung bei Applikation von Radioimmunkonjugaten zur Konditionierung des Knochenmarks bei der Leukämiebehandlung. Die Auswirkungen der Unsicherheiten bei der Dosisbestimmung der Niere, insbesondere durch individuelle Nierenmasse und regionale Aktivitätsunterschiede, wurden untersucht. Die biologische Strahlenwirkung wurde als Biologisch Effektive Dosis unter Berücksichtigung des Zeitverlaufs der Dosisapplikation quantifiziert. Berechnungen wurden neben 188Rhenium auch für andere therapierelevante Radionuklide durchgeführt.

Methods for testing commercial off-the-shelf (COTS) digital devices at varying levels of complexity is presented and discussed as well as the results for testing a COTS SRAM, FRAM, and SoC using these methodologies in a pulsed dose rate environment at Little Mountain Test Facility (LMTF) and neutron testing at Los Alamos Neutron Science Center (LANSCE). Investigations at LMTF revealed a dependence in all three devices on the integrated dose of a single pulse of radiation, implying that the duration of radiation plays a significant role in the response. The test infrastructure necessary to dynamically access an FRAM at LMTF and time the access with the pulse of radiation allowed for the discovery of a new FRAM failure mode where an entire word of the FRAM becomes corrupted as well as selecting between two different failure modes based on the timing of the pulse. A novel component-based testing methodology for testing complicated SoCs is presented and used to report on the cross-sections of several components on the Xilinx MPSoC, including its DMA which has not previously been reported.