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This thesis proposes some new model independent or nonparametric methods for estimating the dose-response curve and the effective dosage curve in the context of bioassay. The research problem is also of importance in environmental risk assessment and other areas of health sciences. It is shown in the thesis that our new nonparametric methods while bearing optimal asymptotic properties also exhibit strong finite sample performance. Although our specific emphasis is on bioassay and environmental risk assessment, the methodology developed in this dissertation applies broadly to general order restricted inference.

Submitted by MARINA GOMES DA SILVA null (marinags@hotmail.com.br) on 2016-08-04T16:07:16Z No. of bitstreams: 1 Diss_Agro_05 (002).pdf: 2170011 bytes, checksum: f477b7dc180f664f409a6c5baf8897fb (MD5) / Approved for entry into archive by Ana Paula Grisoto (grisotoana@reitoria.unesp.br) on 2016-08-09T14:18:34Z (GMT) No. of bitstreams: 1 silva_mg_me_jabo.pdf: 2170011 bytes, checksum: f477b7dc180f664f409a6c5baf8897fb (MD5) / Made available in DSpace on 2016-08-09T14:18:34Z (GMT). No. of bitstreams: 1 silva_mg_me_jabo.pdf: 2170011 bytes, checksum: f477b7dc180f664f409a6c5baf8897fb (MD5) Previous issue date: 2016-07-06 / Atualmente, insetos praga estão impactando a produção de soja e táticas de controle não estão sendo eficientes, por causa do uso inadequado no campo. Assim opções para manejo de pragas precisam ser desenvolvidas, tais como novos compostos químicos. Devido a disponibilidade de formulação recentemente desenvolvida (concentrado emulsionável – EC) de indoxacarbe, os objetivos com este estudo foram avaliar a eficiência desta formulação no controle de Helicoverpa armigera (Hübner) e Chrysodeixis includens (Walker) (Lepidoptera: Noctuidae) em soja. Um experimento a campo foi conduzido usando duas formulações (EC e solução concentrada – SC) de indoxacarbe (30 e 60 g i.a. ha-1) e testemunha. Após a pulverização, folíolos foram coletados das regiões mediana e superior das plantas em diferentes períodos. Os folíolos foram infestados com lagartas de 3°. instar de H. armigera e C. includens. As duas formulações do indoxacarbe foram eficientes no controle de ambas as pragas, independente da região da planta. As maiores dosagens causaram mortalidade > 80% em H. armigera somente 1h após a aplicação e em C. includens até 3 dias. No experimento de laboratório, folíolos recém-coletados de soja cultivada em casa-de-vegetação e imersos em soluções com concentrações crescentes das duas formulações de indoxacarbe para construção das curvas dose-resposta. Após secagem, os folíolos foram infestados com lagartas de 3°. instar de H. armigera e C. includens. As curvas dose-resposta foram similares para ambas as formulações. Para a espécie H. armigera, as formulações EC e SC de indoxacarbe apresentaram CL50 de 0,113 e 0,111 µg i.a. mL-1, enquanto que para a espécie C. includens, elas apresentaram CL50 de 0,065 e 0,127 µg i.a. mL-1, respectivamente. Para avaliar movimento translaminar de indoxacarbe, folíolos de soja foram tratados com as duas formulações de indoxacarbe (30 e 60 g i.a. ha-1) e foram então infestados com lagartas neonatas de C. includens. As formulações do indoxacarbe não apresentaram ação translaminar. A espécie C. includens mostrou ser mais sensível ao indoxacarbe do que H. armigera. De modo geral, a formulação EC é tão eficaz quanto a formulação SC no controle de H. armigera e C. includens em soja e pode ser utilizada como ferramenta no Manejo Integrado de Pragas. / Currently, insect pests are impacting soybean yield and control tactics are not efficient because of their inappropriate use in the field. Therefore, options for pest management ought to be developed, such as new chemical compounds. Because of the availability of recent developed formulation (emulsifiable concentrate - EC) of indoxacarb, the objectives of this study were to evaluate the effectiveness of this formulation for the control of Helicoverpa armigera (Hübner) and Chrysodeixis includens (Walker) (Lepidoptera: Noctuidae) in soybean. A field experiment was carried out using two formulations (EC and suspension concentrate - SC) of indoxacarb (30 and 60 g a.i. ha-1) and an untreated control. After spray, leaflets were collected from mid and upper regions of the plants at different times. The leaflets were infested with 3rd instar larvae of H. armigera and C. includens. The two indoxacarb formulations were effective in controlling both species, regardless of plant region. Higher doses caused > 80% mortality of H. armigera only 1h after application and of C. includens up to 3 days. In a lab experiment, fresh soybean leaflets were collected from greenhouse and immersed in solutions with increasing concentrations of the two indoxacarb formulations to build the dose-response curves. After drying, they were infested with 3rd instar larvae of H. armigera and C. includens. The dose-response curves were similar for both formulations. For H. armigera, the EC and SC indoxacarb formulations showed LC50 of 0.113 and 0.111 µg a.i. mL-1 while for C. includens, they showed LC50 of 0.065 and 0.127 µg a.i. mL-1, respectively. To evaluate translaminar movement of indoxacarb, soybean leaflets were treated with both indoxacarb formulations (30 and 60 g a.i. ha-1) and were then infested with neonate larvae C. includens. No translaminar movement was detected. The species C. includens was more sensitive to indoxacarb than H. armigera. Overall, the EC formulation is as effective as the SC formulation for the control of H. armigera and C. includes on soybean and can be used as a tool in Integrated Pest Management.

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Cette thèse est composée de deux parties. Dans la première partie, nous proposons une théorie pour l'interaction entre l'apprentissage par renforcement et les processus de régulation homéostatique. En fait, la régulation efficace de l'homéostasie interne et la défendre contre les perturbations a besoin des stratégies comportementales complexes pour obtenir des ressources physiologiquement épuisés. À cet égard, il est essentiel que les processus cérébraux de régulation homéostatique et les processus d'apprentissage associatifs travaillent de concert. Nous proposons une théorie computationnelle normative pour régulation homéostatique par l'apprentissage associatif, où la stabilité physiologique et l'acquisition de récompense s'avèrent les mêmes objectifs, réalisables simultanément. En théorie, le cadre résout la question de longue date de la façon dont le comportement manifeste est modulée par l'état interne, et comment les animaux apprennent à agir de manière prédictive pour empêcher des défis homéostasie potentiels (répondre par anticipation). Il fournit en outre une explication normative pour choix intertemporel, aversion au risque, la concurrence entre les systèmes de motivation, et le manque de motivation pour l'injection intraveineuse de produits alimentaires. Neurobiologiquement, la théorie suggère une explication pour le rôle de l'interaction par orexine entre les circuits hypothalamiques et les noyaux dopaminergiques du mésencéphale, comme une interface entre les états internes et les comportements motivés. Dans la deuxième partie de la thèse, nous utilisons le modèle présenté dans la première partie, comme base du développement d'une théorie de la dépendance à la cocaïne. Nous soutenons que la dépendance à la cocaïne provient du système de régulation homéostatique être détourné par les effets pharmacologiques de la cocaïne sur le cerveau. Nous démontrons que le modèle réussit à expliquer une variété des aspects comportementaux et neurobiologiques de la dépendance à la cocaïne , à savoir la grandissant de l’administration de cocaine sous les conditions de long accès a cocaïne, fonction dose-réponse pour la cocaïne , rechute à l'addiction à la cocaïne provoquée par amorçage, et l'interaction entre la disponibilité du récepteur de la dopamine D2 et dépendance à la cocaïne. / This thesis is composed of two parts. In the first part, we propose a theory for interaction between reinforcement learning and homeostatic regulation processes. In fact, efficient regulation of internal homeostasis and defending it against perturbations requires complex behavioral strategies to obtain physiologically-depleted resources. In this respect, it is essential that brains homeostatic regulation and associative learning processes work in concert. We propose a normative computational theory for homeostatically-regulated reinforcement learning (HRL), where physiological stability and reward acquisition prove to be identical objectives achievable simultaneously. Theoretically, the framework resolves the long-standing question of how overt behavior is modulated by internal state, and how animals learn to predictively act to preclude prospective homeostatic challenges (anticipatory responding). It further provides a normative explanation for temporal discounting of reward, and accounts for risk-aversive behavior, competition between motivational systems, taste-induced overeating, and lack of motivation for intravenous injection of food. Neurobiologically, the theory suggests a computational explanation for the role of orexin-based interaction between the hypothalamic circuitry and the midbrain dopaminergic nuclei, as an interface between internal states and motivated behaviors. In the second part of the thesis, we use the HRL model presented in the first part, as the cornerstone for developing an Allostatic Reinforcement Learning (ARL) theory of cocaine addiction. We argue that cocaine addiction arises from the HRL system being hijacked by the pharmacological effects of cocaine on the brain. We demonstrate that the model can successfully capture a wide range of behavioral and neurobiological aspects of cocaine addiction, namely escalation of cocaine self-administration under long- but not short-access conditions, U-shaped dose-response function for cocaine, priming-induced reinstatement of cocaine seeking, and interaction between dopamine D2 receptor availability and cocaine seeking.

Gammaaminosmörsyrareceptorer typ A (GABAAR) är pentameriska ligandstyrda kloridkanaler som uppvisar neurohämmande egenskaper. Därmed är de primära läkemedelsmål för flera ångestdämpande och lugnande läkemedel som används för att minska förekomsten av aktionspotential i neuroner. Trots vikten av dessa receptorer har strukturen av öppen receptor för GABAAR inte lösts hittills, på grund av deras snabba desensibiliseringskinetik. Diazepambindande hämmare (DBI) är en neuropeptid som tidigare rapporterats vara en positiv modulerare för α5β3 GABAAR. I denna studie framställdes DBI genom rekombinant proteinexpression, och den positiva moduleringen undersöktes och karakteriserades med hjälp av voltage-clamp med två elektroder på Xenopus laevis oocyter. För att kunna studera DBI moduleringen skapades GABA dos-responskurvan, och dess karakteristik undersöktes. Baserat på resultaten verkar den positiva moduleringen av DBI vara koncentrationsberoende. Vidare orsakar moduleringen en 2,16-faldig ökning av GABA-framkallad ström vid dess maximala modulationskoncentration. Trots att ström signaler från voltage-clamp uppvisar en viss grad av variabilitet stämmer resultaten överens med tidigare rapporterade observationer som utredde DBI moduleringen respektive GABA dos-responskurvan för α5β3 GABAAR. Dessa resultat kan utnyttjas för att stödja framtida strukturella studier av GABAAR genom att använda denna kunskap om DBI för att potentiellt kunna stabilisera den öppna receptorn, såväl som för att förstå mekanismen för interaktionen mellan DBI och GABAAR. / γ-Aminobutyric acid type-A receptors (GABAARs) are pentameric ligand-gated chloride channels which exhibit neuro inhibitory effects. Hence, they are the primary drug-targets of multiple anxiolytic and sedative drugs used to inhibit the firing rate of neurons. Despite the importance of these receptors, the open structure of GABAAR has not been resolved, owing to their rapid desensitization kinetics. Diazepam binding inhibitor (DBI) is a neuropeptide previously reported to positively modulate the α5β3 GABAARs. In this study, DBI was recombinantly expressed, and this positive modulation was further investigated and characterized by using two-electrode voltage clamp of Xenopus oocytes. For the purpose of studying DBI modulation, GABA dose-response curve was generated, and its characteristics were assessed. Based on the results, the positive modulation of DBI appears to be concentration dependent. Furthermore, the modulation causes a 2.16-fold increase in GABA-elicited current at its maximum modulatory concentration. Although the current traces present some degree of variability, the results are supported by being consistent with previously reported findings investigating DBI modulation and the dose-response curve for α5β3 GABAARs, respectively. These findings can be used to support future structural studies of GABAARs by utilizing this knowledge of DBI to potentially stabilize the open structure of the receptor, as well as in understanding the mechanism of interaction between DBI and GABAARs.

Le benzo-a-pyrène (BaP) est un cancérogène reconnu pour l'homme, contaminant présent dans notre environnement. Il cause des dommages à l'ADN que nous avons mesurés dans les lymphocytes exposés à de faibles concentrations de BaP, provenant de 20 jeunes volontaires non fumeurs et en santé. Suite à l’exposition, la fréquence des micronoyaux (MN) augmente significativement et décrit une courbe dose-réponse non linéaire, suggérant le déclenchement du processus de détoxification et la réparation de l’ADN. Des différences entre les individus et entre les sexes sont présentes dans la réponse génotoxique produite par le BaP. Le test des aberrations chromosomiques montre que le pourcentage de chromosomes cassés augmente significativement dans les cellules exposées au BaP. Combinés avec l'augmentation de la fréquence des MN, nos résultats confirment l'effet clastogène du BaP déjà rapporté dans la littérature. L’hybridation in situ en fluorescence (FISH) des MN avec une sonde pancentromérique est aussi utilisée pour établir leur mécanisme de formation. La FISH révèle que la majorité des MN formés après une exposition au BaP contient un centromère et plus, ce qui est significativement différent de la condition non exposée. Plus précisément, dans nos conditions expérimentales, les MN induits par le BaP contiennent surtout trois centromères et plus, indiquant également la présence d'un effet aneugène. L'effet clastogène du BaP est relié à son rôle d'initiateur dans la cancérogenèse, alors que l'effet aneugène le relierait à l'étape de progression. Ces résultats sont importants puisque l'exposition aux composés de la classe du BaP est de longue durée (cigarette, air pollué). / Benzo-a-pyrene (BaP) is a known human carcinogen, contaminating all spheres of our environment. In human cells, BaP can induce various genotoxic effects on DNA, such as micronuclei (MNs) and chromosomal aberrations (CAs). MNs and CAs are measured in human lymphocytes in vitro exposed to low BaP concentrations, taken from 20 young healthy non-smoking subjects. Following BaP exposure, MN frequency increases significantly and shows a non-linear dose-response curve, suggesting the induction of detoxification process and/or DNA repair. Also, interindividual and sex differences in BaP-induced genotoxic damages are present. CA test shows that chromosome breaks increase significantly in cells exposed to BaP even at low concentrations. Combined to the observed MN frequency increase, our results confirm the clastogenic properties of BaP, as already reported in literature. In addition, fluorescence in situ hybridization (FISH) on MN using a pancentromeric probe is done to assess MN content. FISH reveals that most BaP-induced MNs contain centromeres, and specifically three or more centromeres. This difference is significant when compared to the unexposed condition, and suggest presence of an aneugenic effect. Clastogenic effect of BaP is associated with initiation step of carcinogenesis, while the aneugenic effect would link it with cancer progression. These results could be particularly important because exposure to BaP and other member of its chemical class usually last for decades (smoking, air pollution, etc.), and need to be confirm in future studies.

No description available.