National concern over traumatic brain injury (TBI) is growing rapidly. Recent focus is on mild TBI (mTBI), which is the most prevalent injury level in both civilian and military demographics. A preeminent sequelae of mTBI is cognitive network disruption. Advanced neuroimaging of mTBI victims supports this premise, revealing alterations in activation and structure-function of excitatory and inhibitory neuronal systems, which are essential for network processing. However, clinical neuroimaging cannot resolve the cellular and molecular substrates underlying such changes. Therefore, to understand the full scope of mTBI-induced alterations it is necessary to study cortical networks on the microscopic level, where neurons form local networks that are the fundamental computational modules supporting cognition. Recently, in a well-controlled animal model of mTBI, we demonstrated in the excitatory pyramidal neuron system, isolated diffuse axonal injury (DAI), in concert with electrophysiological abnormalities in nearby intact (non-DAI) neurons. These findings were consistent with altered axon initial segment (AIS) intrinsic activity functionally associated with structural plasticity, and/or disturbances in extrinsic systems related to parvalbumin (PV)-expressing interneurons that form GABAergic synapses along the pyramidal neuron perisomatic/AIS domains. The AIS and perisomatic GABAergic synapses are domains critical for regulating neuronal activity and E-I balance. In this dissertation, we focus on the neocortical excitatory pyramidal neuron/inhibitory PV+ interneuron local network following mTBI. Our central hypothesis is that mTBI disrupts neuronal network structure and function causing imbalance of excitatory and inhibitory systems. To address this hypothesis we exploited transgenic and cre/lox mouse models of mTBI, employing approaches that couple state-of-the-art bioimaging with electrophysiology to determine the structural- functional alterations of excitatory and inhibitory systems in the neocortex.

Thyroid disruptions by xenobiotics have been associated with a broad spectrum of severe adverse human health effects, such as impaired brain development and metabolic syndrome. Ingestion of indoor dust and contact with industrial chemicals are two significant human exposure routes of thyroid hormone disrupting chemicals (THDCs), raising serious concerns for human health. However, it is a laborious and costly process to identify THDCs using conventional experimental methods, due to the number of chemicals in commerce and the varieties of potential disruption mechanisms. In this thesis, we are aimed at in silico identification of novel THDCs targeting transthyretin (TTR) and thyroid hormone receptor (THR) among dust contaminants and commonly used industrial chemicals. In vitro assays were used to validate the in silico prediction results. Co-crystallization and molecular dynamics (MD) simulations were applied to reveal binding modes of THDCs at the studied biological targets and to explain their intermolecular recognition. The main findings presented in this thesis are: 1. Over 144 environmental pollutants have been confirmed as TTR-binders in vitro and these cover a wide range of environmental pollutants and show distinct chemical profiles including a large group of halogenated aromatic compounds and a second group of per- and polyfluoroalkyl substances. (Paper I) 2. In total 485 organic contaminants have been reported to be detected in household dust. The developed QSAR classification model predicted 7.6% of these dust contaminants and 53.1% of their metabolites as potential TTR-binders, which emphasizes the importance of metabolic bioactivation. After in vitro validation, four novel TTR binders with IC50 ≤ 10 µM were identified, i.e. perfluoroheptanesulfonic acid, 2,4,2',4'-tetrahydroxybenzophenone (BP2), 2,4,5-trichlorophenoxyacetic acid, and 3,5,6-trichloro-2-pyridinol. (Paper II) 3. The development of a robust structure-based virtual screening (VS) protocol resulted in the prediction of 31 dust contaminants as potential binders to THRβ1 including musk compounds, PFASs, and bisphenol A derivatives. The in vitro experiments confirmed four compounds as weak binders to THRβ1, i.e. 2,4,5-trichlorophenoxyacetic acid, bisphenol A (3-chloro-2-hydroxypropyl) (2,3-dihydroxypropyl) ether, 2,4,2',4'-tetrahydroxybenzophenone, and 2,4-dichlorophenoxyacetic acid. (Paper III) 4. We revealed the binding conformations of perfluorooctanesulfonic acid, perfluorooctanoic acid, and BP2 in the thyroxine binding sites (TBSs) of TTR by co-crystallizing TTR with the three compounds. A VS protocol was developed based on the TTR complex structures that predicted 192 industrial chemicals as potential binders to TTR. Seven novel TTR binders were confirmed by in vitro experiments including clonixin, 2,6-dinitro-p-cresol (DNPC), triclopyr, fluroxypyr, bisphenol S, picloram, and mesotrione. We further co-crystallized TTR with PBS, clonixin, DNPC, and triclopyr, and their complex structures showed that the compounds bind in the TBSs as proposed by the VS protocol. In summary, 13 indoor dust contaminants and industrial chemicals were identified as THDCs using a combination of in silico and in vitro approaches. To the best of our knowledge, none of these compounds has previously been reported to bind to TTR or THR. The identifications of these THDCs improve our understanding on the structure-activity relationships of THDCs. The crystal structures of TTR-THDC complexes and the information on THDC-Target intermolecular interactions provide a better understanding on the mechanism-of-actions behind thyroid disruption. The dataset compiled and in silico methods developed serve as a basis for identification of more diverse THDCs in the future and a tool for guiding de novo design of safer replacements.

The work that I have produced during my graduate studies at the University of New Orleans addresses the impact that humans have on the environment in our contemporary world. A primary focus, but not exclusive, includes industrial materials or objects, their overwhelming presence that informs the juxtaposition of economic progress, and the reality of environmental disruption. Humor and metaphor are central themes of my work and reference my personal observations and experiences of living in the midst of these environments. Sources from Contemporary underground art have been filtered through my exposure to studio practice and art history, mainly the autonomous processes of Surrealism, resulting in a variety of influences that inform my work. I present imaginary images of architectural, biological, and mechanical transformations with the hopes of nudging the viewers' expectations and to create a better understanding of my opinion pertaining to the world and reality we all live in.

Environmental air pollution is one risk factor associated with the onset and progression of multiple sclerosis (MS). In this project, we investigated the effects of ubiquitous traffic-generated pollutants, namely a mixture of gasoline and diesel vehicle exhaust (MVE), on signaling pathways associated with the pathophysiology of MS in the central nervous system (CNS) of either ovary intact (ov+) or ovariectomized (ov-) female Apolipoprotein (Apo) E-/-. Specifically, we investigated whether a subchronic inhalation exposure to MVE (200 PM μg/m3; 6 hr/d, 7d/wk, 30d) vs. filtered air (FA) controls altered myelination, T cell infiltration, blood-brain barrier (BBB) integrity, or production of reactive oxygen species (ROS) and expression of neuroinflammation markers in the CNS ov+ and ov- Apo E-/- mice. Our results revealed that inhalation exposure to MVE resulted in increased demyelination and CD4+ and CD8+ T cell infiltration, associated with alterations in BBB integrity. Disruption of the BBB was evidenced by decreased tight junction (TJ) protein expression, increased matrix metalloproteinase (MMPs) activity, and increased permeability of immunoglobin (Ig) G, which were more pronounced in the MVE ov- group. Moreover, MVE-exposure also promoted ROS and neuroinflammatory signaling in the CNS of ov+ and ov- mice, compared to FA groups. To analyze mechanisms that may contribute to MVE-exposure mediated inflammatory signaling in the CNS, we examined the NF-κB signaling pathway components, namely IKK subunits, IKKα, and IKKβ, as well as RelA. MVE -exposure did not alter the expression of either IKKα and IKKβ or RelA. However, increased expression of IKKα and IKKβ mRNA was observed in both FA ov- and MVE ov- groups, indicating female sex steroid hormone signaling involvement. Investigation of hormone receptors expression revealed a reduction in cerebral ERα mRNA expression, compared to ov+ mice; however, MVE-exposure resulted in an even further decrease in expression of ERα mRNA, while ERβ and PRO A/B transcript expressions were unchanged across groups. Collectively, these study findings revealed that subchronic inhalation exposure to MVE mediates alterations in ER expression in the CNS of ApoE-/- female mice, associated with altered cerebrovascular integrity and increased ROS production and inflammatory signaling. These detrimental outcomes in the CNS, resulting from MVE-exposure, are further associated with increased CD4+/CD8+ infiltration and local demyelination in the CNS of female ApoE-/-mice, which are hallmarks of MS. Such findings suggest that exposure to ubiquitous traffic-generated air pollutants may contribute to pathologies that exacerbate demyelinating diseases in the CNS of females.

As more and more people get in to video games. We look at what makes for a good experience. Psychological factors which enriches gameplay like flow and immersion. And Game design factors which provides conditions for flow and immersion. We gather knowledge and use these factors to implement a video game prototype with two versions for testing a scenario. In this scenario the player is set out in the world to fight terrorists in a top-down shooter. Version 1 keeps top-down shooter throughout the entire level while version 2 changes the combat system to a Japanese Role-Playing Game style on the end boss. We then sent out both versions to testers to measure their experience with both versions. Measurement is done with the Game Experience Questionnaire and interviews were held with the testers. The results from this study indicates that the experience is largely unaffected. This may however be due to many causes as, sample size, the scenario itself and more.

ABSTRACT The two disorders of Restless Legs Syndrome (RLS) and Periodic Limb Movements (PLM) are well recognised as fairly common neurological disorders. The presentation is of a sensory and motor component suggestive of a state of hyperexcitability of the nervous system. The underlying abnormality is believed to involve a dopamine deficiency but many of characteristics of the disorders have not been adequately described or quantified. I investigated, firstly, the possible reasons for the gender bias in the prevalence studies and found that women were more likely to have some associated conditions which may be related to RLS as well as a higher symptom load when compared to men subjects with RLS. I then looked at the problems of analysing the sensations occurring in RLS. Due to the lack of an adequate measuring tool and the possibility of a relationship between the sensations of RLS and those of pain, I used a validated descriptive pain questionnaire (the McGill pain questionnaire) to measure the sensations of RLS. Subjects with RLS were able to describe the sensations with the pain questionnaire and severity indices calculated from the McGill correlated well with measures of RLS severity but not with other intensity measures for pain. In the area of motor events I investigated the possibility of creating a classification system for the muscle activations documented as PLM. I recorded multiple muscle groups in the legs during sleep and devised a classification using sequence of activation and timing of activations from the different muscles. I also used the classification to show subtle changes in the leg activation patterns associated with change in sleep stage.

This research report attempts to establish the cognitive consequences of the disruption of schooling. Specifically the report investigates Vygotsky and Luna’s claim that formal schooling necessarily produces scientific concepts in learners, by examining the performance of learners who had been subjected to disrupted schooling. On the basis of empirical research conducted, the report challenges Vygotsky and Luria's claim about the cognitive consequences of schooling.

A desregulação endócrina induzida por contaminação ambiental está entre os principais problemas criados pela sociedade moderna de consumo, responsável pela inserção no ambiente de uma série de substâncias interferentes nos sistemas hormonais dos mais diversos organismos, incluindo o próprio homem. A ação destes compostos acarreta, entre outros efeitos, disfunções reprodutivas e estudos apontam que também podem ser indutores de cânceres. A legislação brasileira através do Conselho Nacional do Meio Ambiente (CONAMA) determina os padrões de qualidade das águas, porém muitas substâncias com potencial de desregulação endócrina não tem suas concentrações e emissões especificadas. O objetivo deste trabalho foi executar um levantamento da presença e possíveis conseqüências dos hormônios estrogênicos, uma das classes mais potentes de desreguladores endócrinos (ED), nos compartimentos água e sedimento do rio do Monjolinho. Este rio cruza parte da malha urbana da cidade de São Carlos - SP e recebe lançamentos localizados e difusos de esgotos domésticos e industriais. Portanto, amostras de água e sedimentos foram analisadas através de cromatografia líquida, e exemplares de peixes capturados no rio investigados quanto à presença da proteína vitelogenina (VTG) um biomarcador de exposição. Também ensaios ecotoxicológicos foram desenvolvidos em laboratório com diferentes abordagens para verificação de efeitos diversos. Em uma tentativa de abordar os dados gerados através de uma perspectiva ampla, foi delineada uma avaliação de risco ambiental discutindo as possíveis ameaças a biota e a população humana, já que concentrações de hormônios, principalmente o sintético etinilestradiol (concentração máxima de 30,1 ± 3,41 ng/L), a indução da VTG e efeitos em ensaios ecotoxicológicos foram confirmados. / The environmental endocrine disruption is among the main problems arrived with the modern society way of life. The hormonal systems of several organisms are injured by a number of chemicals disposal on hydric bodies in erroneous way. These compounds causes reproductive disturbs, and studies pointed it be cancer inductors. The Brazilian National Environmental Council (CONAMA) do not regulated standards for discharges and concentrations of these substances. This work aims to investigate the probable presence and effects of sexual estrogens hormones, one of the most powerful groups of endocrine disruptors (EDCs), at the Monjolinho river. This small urban river is placed in São Carlos; a town located in the São Paulo state, southwest Brazil, and receives concentrated and diffuse sewage effluents as industrials as domestics. Samples of water and sediments were analyzed by liquid chromatography, and male fishes captured were investigated to survey the vitellogenin protein (Vtg), a biomarker of exposition. To complement the study, ecotoxicological tests with different approaches were considered. Moreover an environmental risk analyze delineation was made because hormones concentrations, mainly the synthetic ethynilestradiol (EE2), VTG induction, and positive effects in ecotoxicity tests were found.

Um injetor de pastilhas (pellets) de impurezas foi projetado, construído e instalado junto ao tokamak TCABR do Instituto de Física da Universidade de São Paulo - USP. O injetor é basicamente constituído por uma câmara com gás a alta pressão cuja vazão é controlada por uma bobina de acionamento rápido. Uma fonte de alta tensão (7kV) e alta corrente (6kA) foi construída para alimentar a bobina. Ao ser disparada, o gás propulsor (N2 ou He) acelera a pastilha para o interior do vaso do tokamak, sem que gás penetre no mesmo. Pastilhas de grafite cilíndricas com diâmetro de 0,4mm a 0,9mm, e comprimento de 0,5mm a 1mm, foram utilizadas para investigar a possibilidade de se mitigar os e*feitos de uma disrupção maior O processo de ablação da pastilha no TCABR foi investigado através de simulações que consideraram, de uma maneira simplificada, o resfriamento sofrido pelo plasma devido à propagação da pastilha no seu interior. O modelo, ao ser aplicado aos dados experimentais do tokamak T-10, por exemplo, apresentou resultados bastante encorajadores. Na maioria dos casos em que houve a injeção das pastilhas no TCABR, o plasma terminou devido ao surgimento de uma disrupção maior. Analisando a taxa de queda da corrente de plasma em dois instantes próximos ao fim da descarga, tanto para pulsos que sofreram uma disrupção natural quanto aos que sofreram um disrupção induzida (devido à injeção de pastilhas de grafite), constatou-se que a corrente de plasma decresce mais lentamente nos casos em que houve o disparo do injetor. Isto significa uma menor sobrecarga nos sistemas eletro-mecânicos do tokamak, em resultado à ocorrência da disrupção. A análise da atividade MHD foi realizada no entorno da disrupção causada pela injeção de pastilha. Observou-se, em conseqüência, uma redução da velocidade de rotação das ilhas magnéticas após o início da interação da pastilha com o plasma. Também constatou-se, em todos os disparos analisados, um aumento significativo da atividade MHD. Um outro resultado interessante foi a constatação de que a emissão de raios-X de altas energias decresce significativamente no final das descargas nas quais ocorre a injeção de pastilhas. / An impurity pellet injector has been projected, built and installed in the TCABR tokamak, at the Physics Institute of Physics of the University of São Paulo - USP. Basically, the injector is composed of a high pressure gas chamber, in which the gas flow (N2 or He) is controlled by a fast switch valve. An high voltage (7kA) and high electric current (6kA) power supply has been built to provide energy for the valve. When fired, the propellant gas move the pellet into the interior of the tokamak vessel. During this process, the gas is properly collected before reaching the tokamak vacuum chamber. For this work, cylindrical carbon pellets with 0,4mm to 0,9mm in diameter and 0,5mm to 1mm in length were chosen as to investigate how the hazardous effects of a major disruption could be mitigated. The pellet ablation process in TCABR was studied trough running simulations that take into account, in a simplified way, the cooling of the plasma by the propagating pellet. The model, when applied to the T-10 tokamak experimental data, for example, exhibited very encouraging results. For the TCABR tokamak, in most of the cases in which pellets were injected, the plasma was terminated because of the advent of a major disruption. By analyzing the plasma current decay rate in two time intervals - within the end of plasma discharges, with and without the injection of pellets, it was observed that the plasma current decays significantly slower when pellets are injected. Consequently the load on the tokamak\'s electromechanical systems is reduced. Fourier analysis has been carried out to investigate the MHD activity near the disruption time, caused by the pellet injection. It could be noticed a reduction on the magnetic island\'s velocity rotation, after the pellet-plasma interaction initiates. Also, for all discharges analyzed, the MHD activities increased in amplitude after the pellet-plasma interaction. Another interesting result refers to the fact that the hard X-ray emission was observed to decrease significantly within the end of discharges in which pellets were injected

O glifosato-Roundup é um herbicida amplamente utilizado em diversas culturas agrícolas. Sua toxicidade reprodutiva está relacionada com a inibição da proteína StAR e da enzima aromatase, causando in vitro redução significativa da produção de testosterona e estradiol. Este trabalho teve como objetivo verificar esse efeito in vivo, utilizando-se ratos Wistar machos pré-púberes como modelo experimental. Utilizou-se 68 machos tratados dos 23 aos 53 dias de idade com as doses de 0, 5, 50 e 250 mg/kg de peso vivo por gavagem uma vez ao dia. Foram avaliados a progressão da puberdade, o desenvolvimento corporal, a produção hormonal de testosterona, estradiol e corticosterona, morfologia testicular e da glândula adrenal, função renal e hepática e histopatologia renal e hepática. As análises estatísticas utilizadas foram a análise de variâncias de uma via ANOVA, de duas vias MANOVA ou Kruskall-Walis e pós-testes de Tukey-Kramer, Fisher ou de Dun. O herbicida glyphosate-Roundup alterou de forma significativa a progressão da puberdade de forma dose dependente, bem como se observou a redução na produção de testosterona e alterações na morfologia dos túbulos seminíferos. A morfologia da glândula adrenal e a produção de corticosterona não foram afetadas pelas doses utilizadas nesse estudo. Observou-se comprometimento da função renal e alterações patológicas nesse órgão. Não foram evidenciadas alterações hepáticas. O crescimento corporal dos animais não foi influenciado pelo tratamento. Pode-se concluir que esse herbicida é um potente disruptor endócrino in vivo, causando distúrbios no desenvolvimento reprodutivo e na produção hormonal dos animais. / The glyphosate-Roundup is a widely pesticide used in several culturas agrícolas. Its reproductive toxicity is associated to inhibition of StAR protein and aromatase enzime that cause in vitro significantly reduction in testosterone and estradiol production. The objective of this study was to evaluate the in vivo effects of inhibition of StAR protein and aromatase enzyme, using prepubertal male Wistar rats like experimental model. 68 animals were exposed once a day by gavage to glyphosate-Roundup in following doses: 0, 5, 50 or 250 mg/kg of body weight. The end points were puberty progression, body development, testosterone, estradiol and corticosterona productions and testicular and adrenal morphology, renal and liver function and histopatology. The statistical analysis used were one-way ANOVA, multi-way ANOVA or Kruskall-Walis and posthoc tests of Tukey-Kramer, Fisher or Dun. The herbicide glyphosate-Roundup changed significantly the puberty progression in dose-dependent manner, as well reduction in testosterone production and alterations in testicular morphology. There were not observed alterations in adrenal morphology or corticosterone production in the doses used in this study. The renal function and histopatology were altered in treated groups while liver function wasn\'t. The body development was not influenced by the exposure. In conclusion, glyphosate-Roundup is a potent endocrine disruptor in vivo that cause problems in reproductive development and hormonal synthesis in exposure animals.