A brain-computer interface (BCI) is a method of communication that utilizes the scalp recorded electroencephalogram (EEG). A BCI requires no movement, making it a viable communication option for people who are severely disabled. Most BCI research has focused on improving BCI technology through advances in signal processing and paradigmatic manipulations. Research has recently begun to examine the influence of psychosocial factors on BCI performance. Examining psychosocial factors may be particularly important for disabled people who have several co-morbidities. The purpose of the current study is to examine the hypothesis that participants will be more motivated in a free spelling paradigm than in a copy spelling paradigm. Participants completed copy- and freespelling tasks, order was counterbalanced. Motivation was measured after each task. Preliminary data suggests an increase in motivation after the second task regardless of which task was performed second. No differences were observed in performance accuracy between the two tasks.

Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin’s B- cell lymphoma, accounting for about 30% of these lymphomas in the United States. Large-scale genome analyses of DLBCL have identified mutations in the related histone acetyltransferases (HATs) p300 and CBP in approximately 15% of patient samples and patient-derived cell lines. The research presented herein characterizes two human DLBCL cell lines, RC-K8 and SUDHL2, which express C-terminally truncated HAT domain-deficient p300 proteins, p300ΔC-1087 and p300 p300ΔC-820, respectively. It is shown that p300ΔC-820 localizes to sites of active transcription in the nucleus, interacts with NF-κB transcription factor REL, weakly enhances REL-dependent transactivation, and has a half-life similar to wild-type p300. Results demonstrate that knockdown of p300ΔC-820 in SUDHL2 cells reduces cell proliferation in vitro. In RC-K8 cells, p300ΔC-1087 suppresses expression of the NF-κB target genes A20 and IκBα, both of which are cytotoxic when overexpressed in RC-K8 cells. Microarray analysis of p300ΔC1087 knockdown compared to wild-type RC-K8 cells indicated that p300ΔC-1087 suppresses an NF-κB gene expression program and activates a MYC gene expression program in RC-K8 cells. Bioinformatic analysis demonstrated that cancer cell lines— regardless of tissue type—with truncating p300 mutations have altered expression of a MYC target gene set as compared to cancer cell lines with wild-type p300/CBP. Taken together, this research indicates that p300 truncations contribute to cell growth in DLBCL by modifying the transcriptional output of two lymphoid cell-specific oncoproteins, NF- κB and MYC, to optimal levels and suggests that p300 truncating mutations similarly modify the activity of oncogenic drivers in other cancer cell types. Based on this work, p300 truncation is proposed to represent a new class of oncogenic mutation that serves to optimize the activity of context-specific oncogenic transcription factors, and it is suggested that such oncogenic mutations be termed “cancer modifying” mutations. / 2017-09-30T00:00:00Z

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Recientemente ha comenzado a surgir evidencia que relaciona a p300 con el cáncer. Sin embargo, aún no está claro cuál es el rol de la proteína en esta patología ya que hay evidencia que indica que puede funcionar como un supresor tumoral o como una oncoproteína. La información disponible sobre la relación entre p300 y el carcinoma mamario está basada generalmente en estudios en líneas celulares siendo escasos los trabajos en modelos animales o utilizando biopsias humanas. En este trabajo de tesis se pudo demostrar que la inhibición de la actividad acetilasa de p300 disminuye la supervivencia celular de las líneas LM3 y MDA-MB-231 e induce apoptosis en la línea celular LM3. Además se demostró que dicha inhibición disminuye la migración celular de las líneas LM3 y MDA-MB-231 y disminuye la invasión celular y la formación de lamelipodios en la línea celular LM3. En el modelo murino de trasplante singeneico de células LM3 se demostró que la inhibición de p300 reduce la carga tumoral, la invasión a la cavidad abdominal y el número de metástasis pulmonares. La reducción del tamaño tumoral fue acompañada de una disminución del índice mitótico y de los niveles de Ki-67 y de un incremento de la expresión de Bax. Al estudiar la expresión de p300 en el modelo murino transgénico MMTV-PymT y en el de carcinogénesis inducida con DMBA en rata se observó que p300 se encuentra altamente expresado y en una localización citoplasmática en las células del tumor comparado con las de la glándula mamaria normal. Además se observó que parte del p300 citoplasmático se encuentra en estructuras con características de agresomas en las células tumorales de un cultivo primario derivado de este último modelo animal, pero no en las células normales del mismo cultivo. En biopsias humanas de carcinomas mamarios se ha podido demostrar una mayor expresión de p300 en tejidos tumorales que en las zonas histológicamente normales adyacentes al tumor y que en el tejido mamario no maligno. También se detectó la inusual localización citoplasmática de p300 en los tejidos malignos y se pudo demostrar que esta localización se asocia con un menor tamaño tumoral, menor tasa de recaída y mayor sobrevida global de las pacientes y en los tumores triple negativos también con menor estadio tumoral. En conjunto, los resultados de esta tesis sugieren que la acción oncogénica de p300 se realiza en el núcleo a través de su acción sobre la regulación de la transcripción génica y que al ser trasladado al citoplasma esta acción no puede realizarse porque está fuera del núcleo, porque además en el citoplasma es degradado y/o secuestrado en agresomas y posiblemente también por que ejerce nuevas funciones específicas de su ubicación citoplasmática que pueden tener efectos antitumorales. También indican que la localización de p300 puede ser de potencial interés como factor pronóstico y señalan la necesidad de continuar investigando los mecanismos celulares y moleculares que la desregulación de esta proteína podría estar afectando, contribuyendo así al desarrollo del cáncer de mama. / Recently, an increasing body of evidence indicates that p300 could play a role in cancer. Nonetheless, the role of the protein in this disease remains unclear, since there is evidence indicating that it can function both as a tumor suppressor and as an oncoprotein. The available information about the relationship between p300 and breast carcinoma is usually based on studies in cell lines although there have been few studies using animal models or human biopsies. In this thesis we demonstrated that the inhibition of the p300 acetyltransferase activity decreases cellular viability in LM3 and MDA-MB-231 cell lines and induces apoptosis in LM3 cell line. Furthermore, we demonstrated that p300 inhibition reduces cellular invasion in LM3 and MDA-MB-231 cell lines and decreases the invasiveness and lamellipodium formation in LM3 cells. In a syngeneic murine model of subcutaneous transplantation of LM3 cells, we demonstrated that inhibition of p300 reduces tumor burden, tumor invasion into the abdominal cavity and lung metastases. This reduction in tumor burden was accompanied by a decrease in the mitotic index and Ki-67 levels and an increase in Bax expression. When we have studied the expression of p300 in the MMTV-PymT transgenic murine model and in the DMBA-induced rat model, we observed stronger expression and a cytoplasmic localization in the tumor cells in comparison with normal mammary glands. In addition, we have observed that cytoplasmic p300 is partially localized in aggresome-like structures in tumor- but not in normal mammary gland-derived primary cell cultures from the rat animal model. Moreover, the analysis of p300 expression in human breast cancer samples showed that p300 immunoreactivity is significantly higher in the cancerous tissues than in the non-malignant mammary tissues and in the histologically normal adjacent tissues. Interestingly, p300 was observed in the cytoplasm, and María Eugenia Fermento Página 9 the rate of cytoplasmic p300 was higher in breast cancer than in non-tumor tissues. Importantly, we found that cytoplasmic localization of p300 is associated with a reduced tumor size, lower recurrence rates and an increase in the overall survival time of patients. Furthermore, in triple negative breast cancer cytoplasmic p300 is also associated with lower tumor stage. Together, the results obtained in this thesis suggest that p300 acts as an oncogene when localized in the nucleus through its action upon the regulation of gene transcription. When p300 is translocated to the cytoplasm, its oncogenic action cannot be performed because it is outside of the nucleus, because it is degraded and/or sequestered in aggresomes and probably also because it may exert cytoplasmic specific functions which might have antitumor effects. Also, the results obtained in this thesis suggest that p300 localization could be potentially interesting as a prognostic factor and indicate the necessity to continue studying the cellular and molecular mechanisms in which the p300 is involved and whose deregulation could contribute to breast cancer development.

Previous literature has suggested an apparent P300 sensitivity to self-relevant stimuli. To further explore this relationship, we asked participants to submit 10 photos, each of a particular category (e.g. footwear, plants), to be used as either targets or distractors in a given condition of an oddball task. Furthermore, we attempted to see whether the effect of self-relevance on the P300 could be induced in a participant by allowing them to study a set of unique photos which would then be used as targets. Our analysis suggested that P300 amplitude elicited in response to self-relevant stimuli used as targets was statistically significantly greater than all other conditions’ targets. This effect was not correlated with the participant sentiment toward their own photos as assessed by the Revised Personal Involvement Inventory. In light of this, we suggest a generalized effect of self-relevance on the P300. Limitations and future directions are discussed.

A Brain Computer Interface (BCI) provides a means, to control external devices, through the electrical activity of the brain, bypassing motor movement. Recent years have seen an increase in the application of P300 cognitive potential as a control and/or communication signal for the motor restoration in paralyzed patients, such as those in the later stages of ALS (Amyotrophic lateral sclerosis). Although many of these patients are in locked-in state i.e. where motor control is not possible, their cognition is known to remain intact. The P300 speller paradigm explored in this study relying on this cognition represented by the P300 peak potential in EEG (Electroencephalography) signals to restore communication. The conventional visual oddball paradigms used to elicit P300 potential may not be the optimum choice due to their need for precise eye-gazing, which may be challenge for many patients. This study introduces a novel paradigm with motor imagery as a secondary after-stimulus task in a traditional visual oddball paradigm for P300 Speller application. We observed increased P300 peak amplitude as well as the event-related desynchronization (ERD) associated with motor imagery in six healthy novice subjects. Acceptable detection accuracy was obtained in the five-trial averaged signals from 250 ms to 750 ms after the visual stimulation, whereby the early visual evoked potentials were excluded from classification. As an enhancement, efforts are being made to assess implementation by motor imagery embedded in an auditory oddball paradigm which would minimize the need for eye-gazing further. We can conclude from the results of this study that the proposed paradigm with motor imagery embedded in a traditional visual oddball paradigm might be a feasible option for communication restoration in paralyzed patients.

Au-delà de sa présence sur les microtubules stables, l'acétylation de l’-tubuline peut être augmentée après exposition des cellules aux UV ou après une carence en nutriments, phénomène que l’on appelle « hyperacétylation ». Cependant, le mécanisme d’induction de cette hyperacétylation est encore inconnu. Dans cette étude, nous montrons que l’hyperacétylation de la tubuline est une réponse générale aux stress cellulaire, et nous avons cherché à caractériser cette réponse, à identifier la voie de signalisation activée par le stress et conduisant à cette réponse, et à étudier la signification biologique de ce phénomène rapide et réversible. Nous avons trouvé que MEC-17/-TAT1, l’acétyltransférease majeure de l’ tubuline, est une enzyme nécessaire à l’induction de l’hyperacétylation en réponse aux stress, et qu'elle est régulée, à l’état basal par une autre acétyltransférase appelée p300. Au cours du stress, nous montrons que l'augmentation de la production des espèces réactives de l'oxygène (ROS), conduit à l'activation de la kinase « AMP-activated protein kinase (AMPK) », qui, à son tour provoque la phosphorylation de MEC-17, et probablement son activation. Enfin, nous montrons que l’hyperacétylation de la tubuline induite par le stress, participe à la survie des cellules dans des conditions de stress et à l'induction de l'autophagie de survie. / Beyond its presence in stable microtubules, -tubulin acetylation can be boosted after UV exposure or after nutrient deprivation but the mechanisms of this hyperacetylation are still unknown. In this study, we show that tubulin hyperacetylation is a general cell stress response, and aimed to characterize this response, to identify the stress-activated signaling pathway leading to its induction and the biological significance of this rapid and reversible phenomenon. We found that the major tubulin acetyltransferase MEC-17/-TAT1 is the main enzyme required for mediating tubulin hyperacetylation upon stress, and that it is regulated under normal conditions by the acetyltransferase p300. Upon stress, we show that the increased production of reactive oxygen species (ROS), leads to the activation of AMP-activated protein kinase (AMPK), which in turn mediates MEC-17 phosphorylation, and probably its subsequent activation. Finally, we show that tubulin hyperacetylation induced upon stress participate in cell survival under stress conditions and in the induction of protective autophagy.