To maintain intracellular redox homeostasis, genes encoding many endogenous antioxidants and phase II detoxification enzymes are transcriptionally upregulated upon deleterious oxidative stress through the cis- antioxidant responsive elements (AREs) in their promoter regions. Nrf2 has emerged as the pivatol transcription factor responsible for ARE-dependent transcription, and has been shown to play critical roles in hepatotoxicity, chemical carcinogenesis, pulmonary inflammatory diseases, neurodegenerative diseases and aging. Therefore, understanding the molecular mechanism of the Nrf2-dependent cytoprotective system is important for development of drugs for therapeutic intervention.Nrf2 is targeted by Keap1 for ubiquitin-mediated degradation under basal conditions. Upon oxidative stress, distinct cysteine residues of Keap1 are alkylated, leading to inhibition of Keap1 and activation of Nrf2. However, it was not clear how Nrf2 is re-entered into the repression status when redox homeostasis is re-achieved. In this dissertation, we establish that the post-induction repression of Nrf2 is controlled by the nuclear export function of Keap1 in alliance with the cytoplasmic ubiquitination/ degradation machinery. We show that a nuclear export sequence (NES) in Keap1 is required for termination of Nrf2 signaling; ubiquitination of Nrf2 is carried out in the cytosol; Keap1 nuclear translocation is independent of Nrf2; and the Nrf2-Keap1 complex does not bind the ARE. Collectively, these results suggest that Keap1 translocates into the nucleus to dissociate Nrf2 from the ARE and mediates nuclear export of Nrf2 followed by ubiquitination and degradation of Nrf2 in the cytoplasm.In addition to Keap1-mediated negative regulation, we identified a novel positive regulatory mechanism of Nrf2 mediated by transcription co-activator p300/CBP. We show that p300/CBP directly binds and acetylates Nrf2 in response to oxidative stress. We have identified multiple acetylated lysine residues within the Nrf2 Neh1 DNA-binding domain. Combined lysine-to-arginine mutations on the acetylation sites, with no effects on Nrf2 protein stability, compromised the DNA-binding activity of Nrf2 in a promoter-specific manner both in vitro and in vivo. These findings demonstrated that acetylation of Nrf2 by p300/CBP augments promoter-specific DNA binding of Nrf2 and established acetylation as a novel regulatory mechanism that functions in concert with Keap1-mediated ubiquitination in modulating the Nrf2-dependent antioxidant response.

The E2A-PBX1 fusion gene results from the t(1;19) chromosomal translocation that is found in 25% of pre-B-cell cases of acute lymphoblastic leukemia (ALL). The resulting encoded product contains the transactivation domains of E2A, a Class I basic helix-loop-helix transcription factor, and most of PBX1. PBX1 is a major cofactor for most members of the HOX family of homeodomain proteins and is necessary for regulating the essential role that HOX proteins play in development and tissue homeostasis. We have identified an interaction between the E2A-encoded portion of E2A-PBX1 and the CREB-binding domain (KIX) of the transcriptional coactivator CBP and demonstrated a requirement for this interaction in leukemia induction. Others have shown that HOX proteins and CBP also interact directly, with resulting inhibitory effects on the DNA-binding ability of HOX proteins and on the acetylation of substrate proteins by CBP. Several publications have also identified the interaction of HOX proteins with the PBX1 portion of E2A-PBX1 and the result is a potent transcriptional activator at PBX1/HOX target sequences. In an attempt to develop a molecular model for the induction of ALL by E2A-PBX1, we hypothesize that the addition of CBP interactive peptide elements encoded by E2A to PBX1 allows E2A-PBX1 to stabilize a ternary complex involving E2A-PBX1, HOX, and CBP resulting in the deregulated expression of critical PBX1 or HOX target genes. I demonstrate using in vitro protein-protein interactions that this ternary complex involving E2A-PBX1, HOXB4 (chosen as a representative member of the HOX family), and CBP does form. This direct interaction appears to reduce transcriptional activation by E2A-PBX1/HOXB4 heterodimers from PBX1/HOX enhancer elements. I also show that this suppression of transactivation appears to involve CBP antagonism of DNA binding by E2A-PBX1/HOXB4 heterodimers. My results are consistent with the idea that E2A-PBX1 contributes to ALL induction by promoting the redistribution of CBP away from DNA sites bound by E2A-PBX1/HOXB4 heterodimers and in favour of those sites bound by E2A-PBX1 homodimers. / Thesis (Master, Pathology & Molecular Medicine) -- Queen's University, 2008-09-29 13:57:25.324

Session ID: SA-B1-2 / SCIS & ISIS 2010, Joint 5th International Conference on Soft Computing and Intelligent Systems and 11th International Symposium on Advanced Intelligent Systems. December 8-12, 2010, Okayama Convention Center, Okayama, Japan

The incidence of stroke is increasing and is expected to continue to increase with the aging population, escalating rates of obesity and physical inactivity, and the rising prevalence of heart failure. Stroke is a leading cause of long-term disability, which includes approximately half of survivors that experience cognitive impairment. It is accepted that aerobic exercise can improve physical health in both healthy and stroke populations. Evidence also suggests aerobic exercise may positively affect cognitive function among healthy adults; however, whether there are similar beneficial effects among stroke survivors remains unclear. The purpose of this thesis was to examine whether a single session of moderate intensity aerobic exercise acutely improves cognitive function, specifically executive function, in comparison to a rest control among people with chronic stroke. Our first objective was to determine whether aerobic exercise alters cortical processing, as measured by P300 amplitude and latency during a modified Eriksen Flanker task. The second objective was to investigate whether aerobic exercise influences behavioral measures of response time and accuracy during a modified Eriksen Flanker task. Finally, the third objective was to examine the time course of effects up to 40 minutes after exercise cessation. In our sample, participants had shorter P300 latency and larger P300 amplitude 20 to 40 minutes after exercise cessation in comparison to rest. There were no significant behavioural changes. These findings suggest that aerobic exercise may enhance, or at least maintain cognitive processing speed and attention 20 to 40 minutes after exercise cessation, which otherwise deteriorated in the rest condition. Although results should be viewed cautiously due to a small sample size, these findings have potential implications for stroke rehabilitation. Our results suggest that aerobic exercise may be able to improve attentional focus during subsequent rehabilitation exercises for up to 40 minutes or more. Future research should examine whether the effects of various exercise doses and whether paired exercise and rehabilitation improves clinical outcomes.

The aim of this study is to explore advertising and in particular advertising reception as a significant part of contemporary social practice. Although advertising in some form has been a feature of a wide range of societies, historically and culturally, its economic and social importance has perhaps never been greater. Advertising, across the industrial period and in particular since the Second World War, has through the entrenchment of market economies and the development of different media technologies increased its reach and density through a variety of means. It has become a significant media form, received by audiences differentiated by social, economic, spatial and other factors. This study enquires into the nature of audience reception of advertising through an exploration and application of the encoding/decoding media model. The study argues that attention to the textual and formal elements of the model need to be given greater emphasis and the decoding aspect of the model broadened to deal with a complexity of contextual factors contributing to the process. Advertising media by their nature are comprised of different formal and presentational means. The study focuses on newsprint, television and billboard and other outdoor advertising. The public and private environments in which these forms appear can be characterised through the social and symbolic difference between the domestic environment in which much television is viewed and the outdoor urban environment in which much billboard advertising appears. These are recognised as contributory elements in the reception of advertising and any significance the advert may have for its audience. Audience decoding of advertisements is then a combination of producer intent and a complexity of contributory factors brought to or found in the decoding process. This includes a recognition of various ways of seeing associated with different media forms and social and spatial circumstances and the presentation and reception of adverts as part of a flow of advertising and of a wider social experience. The relation between adverts and other texts also has important intertextual consequences for reception. In the process of decoding, it will be argued that social groups can be understood to act as interpretive communities and a process of advertising diffusion can be observed. Three empirical case studies form a survey of mainly car or car related advertising, featuring television, billboard and newsprint advertising, and highlight a range of possible decodings. The significance of historical and social factors is confirmed as important in securing particular readings of advertisements, and spatial, environmental and contextual features are emphasised in this survey. The survey acknowledges the significance of advertising form and medium and highlights the circumstances in which negotiated and oppositional readings may occur. This study re-emphasises that advertising texts form their signification within a complex arrangement of synchronic and diachronic circumstances in which immediate social and environmental factors should be accorded further significance in the study of advertising. The study concludes with a reflection on its methods and procedures and a consideration of further work that might be carried out in the area of empirical advertising studies. In the interest of a richer understanding of advertising, further research would acknowledge the complexities of audience reception and might include an enquiry into further advertising contexts and environments.

Severe motor impairments can severely restrict interaction with one's surroundings. Brain computer interfaces combined with text-based communication systems, such as the P300 Speller, have allowed individuals with motor disabilities to spell messages with their EEG signals. Although providing full composition flexibility, they enable communication rates of only a few characters per minute. Utterance-based communication systems have been developed for individuals with disability and have greatly increased communication speeds, but have yet to be applied to BCIs. This paper proposes an utterance-based communication system using the P300-BCI in which words are organized in a network structure that facilitates rapid retrieval. In trials with able-bodied participants, the proposed system achieved greater message speeds, but rated lower in effectiveness than the P300 Speller. Nonetheless, subject preferences and reports of self-perceived effectiveness suggested an inclination towards the proposed word system and thus further investigation of word-based networks is warranted in brain-controlled AAC systems.

Made available in DSpace on 2015-12-06T23:07:48Z (GMT). No. of bitstreams: 0 Previous issue date: 2006 / Objetivo: Comparar os valores de latência e amplitude do componente P300, em indivíduos que apresentam perda auditiva neurossensorial unilateral adquirida, antes e após a adaptação de prótese auditiva. Métodos: Foi realizado o Potencial Evocado Auditivo de Longa Latência (P300) em oito indivíduos, de ambos os sexos, portadores de perda auditiva neurossensorial unilateral (graus leve até moderadamente severo), antes da adaptação de prótese auditiva. Após seis meses de adaptação com a prótese, foi realizado novamente o P300, para comparação de seus componentes latência e amplitude. Resultados: Comparando-se a amplitude do P300, antes e depois do uso da prótese auditiva, foi observado aumento estatisticamente significante após o uso, nas três situações: comparação apenas entre as orelhas com perda auditiva, apenas entre as orelhas sem perda auditiva e de ambas orelhas juntas. Já comparando-se a latência do P300, antes e depois do uso da prótese auditiva, apesar de ter sido observada uma diminuição nos valores da latência, a diferença não foi estatisticamente significante, também analisada nas três situações. Quando comparadas as diferenças entre os indivíduos que possuem perda auditiva na orelha direita e os indivíduos que possuem perda auditiva na orelha esquerda, os valores de latência foram significantemente menores na orelha esquerda, tanto antes quanto depois do uso da prótese. Não houve diferença significante na latência e na amplitude entre os sexos feminino e masculino. Conclusões: Há aumento da amplitude do P300 com o uso da prótese auditiva por seis meses consecutivos, em pacientes com perda auditiva unilateral. A latência é menor para os indivíduos que possuem perda auditiva na orelha esquerda, em relação aos indivíduos que possuem perda auditiva na orelha direita. Não há diferença na latência e amplitude entre os sexos feminino e masculino. / Purpose: To compare P300 components - latency and amplitude in subjects with unilateral sensorineural hearing losses pre and post-hearing aid fitting. Method: Long Latency Auditory Evoked Potential – P300 – was registered in eight subjects with unilateral mild to moderate-to-severe sensorineural hearing loss, male and female, before hearing aid fitting. Six months after the fitting, the AEP was obtained again, so that the components of latency and amplitude could be compared with the first evaluation. Results: Considering amplitude there was a significant improvement after hearing aid fitting and use in three situations: comparing hearing impaired ears, comparing normal hearing ears and considering both ears. On the other hand when considering the latency before and after hearing aid fitting and use there were no significant differences in the same situations cited above. Latency was significant lower for the left ears, either before or after hearing aid fitting in comparison to the right ears in subjects with hearing impairment in the left or in the right ear, respectively. There were no significant differences in latency and amplitude between male and female subjects. Conclusions: P300 amplitude is increased by hearing aid use six months after fitting in patients with unilateral hearing loss. The latency is lower for subjects with hearing impairment in the left ear than for subjects with hearing impairment in the right ear. There is no difference in latency and amplitude considering gender as variable. / BV UNIFESP: Teses e dissertações

Made available in DSpace on 2015-12-06T23:46:31Z (GMT). No. of bitstreams: 0 Previous issue date: 2014 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Introdução: As alteracoes de fala e linguagem podem estar associadas com alteracoes no processamento da informacao recebida via o sentido da audicao. Estudos demonstraram que existe uma correlacao entre o processamento das informacoes auditivas, as vias visuais e a dificuldade de linguagem expressiva, a qual pode ter manifestacao na fluencia da fala e ser caracterizada como gagueira. Para a avaliacao dos processos neuroaudiologicos envolvidos na gagueira, pode-se realizar a avaliacao comportamental do processamento auditivo, potencial evocado auditivo de curta e longa latencia. Objetivo: Caracterizar e comparar as medidas eletrofisiologicas e comportamentais do processamento auditivo em individuos com e sem gagueira. Metodo: Foram selecionados 41 adultos (18 a 46 anos de idade), sendo que 20 individuos diagnosticados com gagueira, com grau de severidade de muito leve a severo que foram comparados com individuos sem gagueira, de mesma escolaridade e genero. Os individuos com gagueira realizaram avaliacao especifica da gagueira, e todos os individuos (com e sem gagueira) realizaram a avaliacao audiologica (audiometria tonal, vocal, imitanciometria e pesquisa dos reflexos acusticos), avaliacao comportamental do processamento auditivo, avaliacao eletrofisiologica (potencial evocado auditivo de curta e longa latencia). Os dados foram submetidos a analise estatistica, com nivel de significancia 0,05. Utilizando os testes de Fisher, Mann-Whitney, Qui quadrado e McNemar. Resultados: Os individuos com gagueira apresentaram maior ocorrencia de alteracoes no processamento auditivo, sendo os testes em que foram encontradas diferencas estatisticas significantes quanto a alteracao foram teste dicotico nao verbal na etapa de atencao livre e escuta direcionada a direita e a esquerda, o teste SSW, o teste de memoria sequencial nao verbal e o teste dicotico consoante vogal. Na avaliacao do potencial evocado auditivo de curta latencia os individuos com gagueira apresentaram maior ocorrencia de alteracao neste potencial, sendo a alteracao mais encontrada de tronco encefalico baixo. Na avaliacao do potencial evocado auditivo de longa latencia, os individuos com gagueira apresentaram maior ocorrencia de alteracao, sendo a alteracao mais encontrada a ausencia do componente N2. Conclusao: Os individuos com gagueira apresentam maior ocorrencia de alteracoes no processamento auditivo, no potencial evocado auditivo de curta e longa latencia / BV UNIFESP: Teses e dissertações

Prescription opioid (PO) abuse is a growing public health concern worldwide as evidenced by an increasing number of opioid-related hospital admissions with a striking lack of research examining the neural basis underlying cognitive symptomatology. Drugs of abuse, through their impact on the dopaminergic system, are thought to disrupt the cognitive network regulating impulse control and incentive salience through inhibition of goal-oriented behaviour and drug-induced attentional biases. The objective of the present study is to examine neurocognitive processes in PO abusers (vs. healthy controls) by relying on the enhanced temporal resolution (1ms) of event-related potentials (ERPs) to track information processing abnormalities associated with cognitive control. In a naturalistic clinical study, 16 patients actively using prescription opioids and 16 healthy controls (matched for age, gender, educational level and smoking status) were assessed using a Go/NoGo and cue reactivity paradigm. Analysis revealed no significant differences in N2 or P3 amplitude, measures of inhibitory control, between groups after successful NoGo trials and no significant differences in ERN or Pe amplitude, measures of error processing, between groups after unsuccessful NoGo trials. Cue reactivity analysis of attention-related ERP components in patients demonstrated significantly (p<0.005) smaller P2 amplitudes, indexing the commencement of attentional processing, for drug pictures compared to neutral and affective pictures. Furthermore, stimulus type did not significantly modulate LPP amplitudes, indexing sustained attention, in patients however arousal ratings for drug pictures were positively correlated with LPP amplitudes in patients. These ERP results of altered cognitive control and incentive salience suggest the neural mechanisms underlying these cognitions are affected by chronic opioid abuse. Investigating the cognitive abnormalities experienced by PO abusers is an important factor in understanding the neural correlates of substance abuse and in predicting successful outcomes to ensure the best chance at long-term recovery for addicted individuals.

Visual snow syndrome is a persistent visual disturbance characterized by rapid flickering dots in the entire visual field. Hypothesized to arise from reduced inhibition of sensory cortex, visual snow has recently been linked to potentiation (enhancement) of the P100, an event-related potential (ERP) component associated with early visual processing. Here, we investigate whether this potentiation in visual snow is specific to visual responses, by comparing ERPs linked to early, bottom-up perceptual versus late, top-down cognitive processes. Specifically, we examined two components, the N170 and P300, associated respectively with rapid face categorization and attentional orienting towards targets. We predicted that if visual snow predominantly reflects diminished inhibition of perceptual areas, there should be stronger potentiation for the earlier perceptual N170 component. ERPs associated with the N170 (Face > House) and P300 (Target > Nontarget) were recorded in a 22 year-old male with a 2-year history of visual snow symptoms and a set of age- and gender-matched controls. Although N170 and P300 responses in all participants showed appropriate face- and target-selectivity, respectively, the visual snow patient demonstrated consistent potentiation relative to controls, particularly for the early N170 response. Bootstrapped estimates of mean amplitude computed within participants similarly revealed larger and more variable ERP amplitudes in the visual snow patient, especially for the N170 component. These results support an early perceptual locus of ERP potentiation in visual snow, further supporting the idea that this condition arises from diminished inhibition of sensory cortices.