Prostate cancer is one of the leading causes of cancer-related deaths in men worldwide, with 10,000 new cases/year diagnosed in Sweden. In this context, there is an urgent need to identify new biomarkers to detect prostate cancer at an initial stage for earlier treatment intervention. Although how prostate cancer develops has not been fully established, the male sex hormone testosterone is a known prerequisite for prostate cancer development. High levels of transforming growth factor-β (TGFβ) are prognostically unfavorable in prostate cancer patients. TGFβ is a multifunctional cytokine that regulates a broad range of cellular responses. TGFβ signals through either the canonical Smad or the non-Smad signaling cascade. Cancerous cells develop different strategies to evade defense mechanisms and metastasize to different parts of the body. This thesis unveils one such novel mechanism related to TGFβ signaling. The first two articles provide evidence that TGFβ receptor type I (TβRI) is ubiquitinated by tumor necrosis factor receptor-associated factor 6 (TRAF6) and is cleaved at the ectodomain region by tumor necrosis factor alpha converting enzyme (TACE) in a protein kinase C zeta type-dependent manner. After TβRI is shed from the ectodomain, it undergoes a second cleavage by presenilin 1 (PS1), a γ-secretase catalytic subunit, which liberates the TβRI intracellular domain (TβRI-ICD) from the cell membrane. TRAF6 promotes TGFβ-dependent Lys63-linked polyubiquitination and recruitment of PS1 to the TβRI complex, and facilitates the cleavage of TβRI by PS1 to generate a TβRI-ICD. The TβRI-ICD then translocates to the nucleus, where it binds with the transcriptional co-activator p300 and regulates the transcription of pro-invasive target genes such as Snail1. Moreover, the nuclear translocated TβRI-ICD cooperates with the Notch intracellular domain (NICD), a core component in the Notch signaling pathway, to drive the expression of invasive genes. Interestingly, treatment with g-secretase inhibitors was able to inhibit cleavage of TβRI and inhibit the TGFβ-induced oncogenic pathway in an in vivo prostate cancer xenograft model. In the third article, we identified that Lysine 178 is the acceptor lysine in TβRI that is ubiquitinated by TRAF6. The TβRI K178R mutant was neither ubiquitinated nor translocated to the nucleus, and prevented transcriptional regulation of invasive genes in a dominant negative manner. In the fourth article, we show that TGFβ utilizes the E3-ligase TRAF6 and the p38 mitogen-activated protein kinase to phosphorylate c-Jun. In turn, the phosphorylated c-Jun activates p21 and Snail1 in a non-canonical Smad-independent pathway, and thereby promotes invasion in cancerous cells. In summary, we elucidate a new mechanism of TGFβ-induced oncogenic signal transduction in cancer cells in which TRAF6 plays a fundamental role. This opens a new avenue in the field of TGFβ signaling.

Des sons émotionnels furent présentés comme stimuli cibles lors d'une tâche auditive de type oddball. Les effets acoustiques furent départagés des effets émotionnels à l'aide d'une tâche contrôle similaire utilisant une version brouillée des sons originaux et dépourvue de propriétés émotionnelles. Les résultats du oddball émotionnel qui ont différé du oddball contrôle ont montré des effets de valence inversés dans les composantes électrophysiologiques P2 et P300; la valence négative ayant une amplitude plus grande dans la fenêtre de 130-270ms mais moins intense autour de 290-460ms, lorsque comparée aux valences positives et neutres. Les résultats P2 peuvent être interprétés comme une mobilisation attentionnelle précoce privilégiant les stimuli potentiellement dangereux, tandis que les résultats de la P300 pourrait indiquer une évaluation moins détaillée de ces stimuli. / In an auditory oddball task, negatively (disgust) and positively (laughter) valenced sounds were presented as rare targets. To disentangle acoustic effects from emotional ones, a control oddball was conceived with a non‐emotional scrambled version of the original target sounds as rare targets. Results from the emotional oddball that differed from the control oddball showed an inverse effect of valence in the P2 and P300 range, with negative valence having higher mean amplitude values in the 130‐270ms range, but lower values in the 290‐460 range when compared to ERPs elicited by positive and neutral valence. The P2 results are interpreted as early mobilization of attentional resources towards potentially threatening stimuli, while the P300 results could reflect less detailed evaluation of such stimuli.

Les interfaces cerveau-machine (ICM) permettent de contrôler une machine directement à partir de l'activité cérébrale. Le P300-Speller, en particulier, pourrait offrir à des patients complètement paralysés, la possibilité de communiquer sans l'aide de la parole ou du geste. Nous avons cherché à améliorer cette communication en étudiant la coadaptation entre cerveau et machine. Nous avons d'abord montré que l'adaptation d'un utilisateur peut être partiellement perçue, en temps-réel, à travers les modulations de sa réponse électrophysiologique aux feedbacks de la machine. Nous avons ensuite proposé, testé et évalué les effets sur l'utilisateur de plusieurs approches permettant d'améliorer l'interaction, notamment : - la correction automatique des erreurs, grâce à la reconnaissance en temps-réel des réponses aux feedbacks ; - une stimulation dynamique permettant de diminuer le risque d'erreur tout en réduisant l'inconfort lié aux stimulations ; - un processus automatique de décision adaptative, en fonction de l'état de vigilance du sujet. Nos résultats montrent la présence de réponses aux feedbacks spécifiques des erreurs et modulées par l'attention ainsi que par la surprise du sujet face au résultat de l'interaction. Par ailleurs, si l'efficacité de la correction automatique est variable d'un sujet à l'autre, le nouveau mode de stimulation comme la décision adaptative apparaissent comme très avantageux et leur utilisation a un effet positif sur la motivation. Dans la perspective d'études cliniques pour évaluer l'utilité des ICM pour la communication, ces travaux soulignent et quantifient l'intérêt de développer des interfaces capables de s'adapter à chaque utilisateur.

Προτείνουμε μια προσέγγιση για να αναλύσουμε τα δεδομένα που συλλέγουμε από το παράδειγμα του Ορθογράφου P300, χρησιμοποιώντας την τεχνική μηχανικής μάθησης, support vector machines. Στο συγκεκριμένο πλαίσιο κατηγοριοποίησης, πετύχαμε την σωστή λύση μετά από πέντε επαναλήψεις. Ενώ η κατηγοριοποίηση στους διαγωνισμούς BCI είναι για offline ανάλυση, η προσέγγιση μας μπορεί να θεωρηθεί ως μια online λύση για τον πραγματικό κόσμο. Είναι γρήγορη, απαιτεί λίγες (λιγότερες από 10) θέσεις ηλεκτροδίων, απαιτεί μόνο ένα μικρό ποσοστό προεπεξεργασίας και η επιλογή των τιμών για κρίσιμες παραμέτρους έχει αυτοματοποιηθεί. / We propose an approach to analyze data from the P300 speller paradigm using the machine-learning technique support vector machines. In a conservative classification scheme, we found the correct solution after five repetitions. While the classification within the BCI competition is designed for offline analysis, our approach is also well-suited for a real-world online solution: It is fast, requires few electrode positions (less than 10), demands only a small amount of preprocessing and selection of values for critical parameters is automated.

Submitted by Carla Santos (biblioteca.cp2.carla@bahiana.edu.br) on 2018-11-12T18:06:05Z No. of bitstreams: 1 Ana Borja.pdf: 4185815 bytes, checksum: 297a66e91e8ef188fac1ddc6e347bbae (MD5) / Approved for entry into archive by JOELMA MAIA (ebmsp-bibliotecacp2@bahiana.edu.br) on 2018-11-12T19:42:47Z (GMT) No. of bitstreams: 1 Ana Borja.pdf: 4185815 bytes, checksum: 297a66e91e8ef188fac1ddc6e347bbae (MD5) / Made available in DSpace on 2018-11-12T19:42:47Z (GMT). No. of bitstreams: 1 Ana Borja.pdf: 4185815 bytes, checksum: 297a66e91e8ef188fac1ddc6e347bbae (MD5) Previous issue date: 2018-07-10 / O transtorno de d??ficit de aten????o/hiperatividade (TDAH) ?? um dos transtornos psiqui??tricos mais comuns na inf??ncia e adolesc??ncia, causando preju??zos de graus vari??veis no funcionamento dos indiv??duos acometidos. Este estudo apresenta o resultado da investiga????o do efeito do metilfenidato (MFD) na lat??ncia e amplitude do potencial evocado auditivo de longa lat??ncia (P300) em crian??as portadoras de TDAH. Tamb??m investigou o potencial cognitivo P300 em crian??as com TDAH em compara????o com um grupo de crian??as sem TDAH. Metodologia: Foram desenvolvidos dois estudos: o primeiro, considerado quaseexperimental, de car??ter anal??tico, desenvolvido em indiv??duos portadores de TDAH, estimou a lat??ncia e a amplitude do P300 em fun????o do uso ou n??o de MFD. O segundo, um estudo descritivo, de car??ter explorat??rio, que estimou a lat??ncia e a amplitude do P300 em crian??as portadoras de TDAH em compara????o com crian??as sem sintomas de TDAH. Resultados: Os resultados indicam que o MFD reduz a lat??ncia do P300 em crian??as portadoras de TDAH. A amplitude n??o se mostrou efetiva como par??metro para avalia????o do uso do MFD no P300, pois os resultados apresentaram grande variabilidade nas respostas. O grupo TDAH possui lat??ncias maiores e amplitudes menores quando comparados com o grupo de controle, verificando-se signific??ncia estat??stica apenas para o grupo de maior faixa et??ria (11 a 16 anos). Indiv??duos na faixa et??ria de 7 a 10 anos apresentam lat??ncias maiores e amplitudes menores, independente do uso do MFD. Faixa et??ria, condi????o socioecon??mica, quociente de intelig??ncia, indicadores de boa sa??de, presen??a de comorbidades e escolaridade dos pais destacam-se como vari??veis que modificam a resposta do P300 com o uso do MFD. Conclus??o: Este estudo sugere que o uso do metilfenidato melhora o processo atentivo, segundo os par??metros do P300, favorecendo a discrimina????o auditiva e a tomada de decis??o. Sugere ainda que o P300 pode ser um instrumento ??til para triagem diagn??stica do TDAH.

Like other animals, humans explore to learn about the world, and exploit what we have learned in order to maximize reward. The trade-off between exploration and exploitation is a widely-studied topic that cuts across multiple domains, including animal ecology, economics, and computer science. This work approaches the explore-exploit dilemma from the perspective of cognitive neuroscience. In particular, how are our decisions to explore or exploit represented computationally? And how is that representation implemented in the brain? Experiment 1 examined neural signals following outcomes in a risk-taking task. Explorations – defined as slower responses – were preceded by an enhancement of the P300, a component of the human event-related brain potential thought to reflect a phasic release of norepinephrine from locus coeruleus. Experiment 2 revealed that the same neural signal precedes feedback in a learning task called a two-armed bandit. There, a reinforcement learning model was used to classify responses as either exploitations or explorations; exploitations were driven by previous rewards, and explorations were not. Experiments 3 and 4 extended these results in three important ways. First, evidence is presented that the neural signal observed in Experiments 1 and 2 was driven not only by the upcoming decision, but also by the preceding decision (perhaps even more so). Second, Experiments 3 and 4 involved increasingly larger action spaces. Experiment 3 involved choosing from among either 4, 9, or 16 options. Experiment 4 involved searching for rewards in continuous two-dimensional map. In both experiments, the feedback-locked P300 was enhanced following exploration. Third, exploitation was the more common strategy in Experiments 1 and 2. Thus, it was unclear whether the exploration-related P300 enhancement observed there was due to exploration per se, to exploration rate, or to the fact that exploration was rare compared to exploitation. Experiment 3 partially address this by eliciting different rates of exploration; the exploration-related P300 effect correlated with rate of exploration. In Experiment 4, exploration was more common than exploitation (in contrast to Experiments 1–3); even so, exploration was followed by a P300 enhancement. Together, Experiments 1–4 suggest the presence of a general neural system related to exploration that operates across multiple task types (discrete to continuous), regardless of whether exploration or exploitation is the more common task strategy. The proposed purpose of this neural signal is to interrupt one mode of decision-making (exploration) in favour of another (exploitation). / Graduate

Factors that confer predisposition and vulnerability for alcoholism and other substance abuse disorders may be described usefully within the gene-environment interplay framework. Thus, it is postulated that heritability provides a major contribution not only to alcohol but also to other substances of abuse. Studies of evoked potential amplitude reduction have provided a highly suitable and testable method for the assessment of both environmentally-determined and heritable characteristics pertaining to substance use and dependence. The different personal attributes that may co-exist with parental influence or exist in a shared, monozygotic relationship contribute to the final expression of addiction. In this connection, it appears that personality disorders are highly prevalent co-morbid conditions among addicted individuals, and, this co-morbidity is likely to be accounted for by multiple complex eti-ological relationships, not least in adolescent individuals. Co-morbidity associated with deficient executive functioning may be observed too in alcohol-related aggressiveness and crimes of violence. The successful intervention into alcohol dependence and craving brought about by baclofen in both human and animal studies elucidates glutamatergic mechanisms in alcoholism whereas the role of the dopamine transporter, in conjunction with both the noradrenergic and serotonergic transporters, are implicated in cocaine dependence and craving. The role of the cannabinoids in ontogeny through an influence upon the expression of key genes for the development of neurotransmitter systems must be considered. Finally, the particular form of behaviour/ characteristic outcome due to childhood circumstance may lie with biological, gene-based determinants, for example individual characteristics of monoamine oxidase (MAO) activity levels, thereby rendering simple predictive measures both redundant and misguiding.

<p>Deep learning has been increasingly adopted in a multitude of settings. Yet, its strong performance relies on processing data during inference that is in-distribution with its training data. Deep learning input data during deployment, however, is not guaranteed to be in-distribution with the model's training data and can often times be distorted, either intentionally (e.g., by an adversary) or unintentionally (e.g., by a sensor defect), leading to significant performance degradations. In this dissertation, we develop algorithms for a variety of applications to improve the performance of deep learning models in the presence of distorted data. We begin by first designing feature engineering methodologies to increase classification performance in noisy environments. Here, we demonstrate the efficacy of our proposed algorithms on two target detection tasks and show that our framework outperforms a variety of state-of-the-art baselines. Next, we develop mitigation algorithms to improve the performance of deep learning in the presence of adversarial attacks and nonlinear signal distortions. In this context, we demonstrate the effectiveness of our methods on a variety of wireless communications tasks including automatic modulation classification, power allocation in massive MIMO networks, and signal detection. Finally, we develop an uncertainty quantification framework, which produces distributive estimates, as opposed to point predictions, from deep learning models in order to characterize samples with uncertain predictions as well as samples that are out-of-distribution from the model's training data. Our uncertainty quantification framework is carried out on a hyperspectral image target detection task as well as on counter unmanned aircraft systems (cUAS) model. Ultimately, our proposed algorithms improve the performance of deep learning in several environments in which the data during inference has been distorted to be out-of-distribution from the training data. </p>

Acute sleep loss may lead to elevated fatigue, decreased energy, and diminished cognitive performance. Traditionally, sleep extension is used to restore mood and cognitive function to baseline levels following insufficient sleep, yet this method may not be feasible or preferred. Acute exercise may serve as an affordable and relatively safe intervention to reduce detriments to daytime functioning following sleep loss. The primary purpose of this study was to examine the effects of moderate-intensity aerobic exercise on neurocognitive function following acute sleep restriction. A secondary aim was to examine the effects of exercise in subjective reports of fatigue, energy, and sleepiness following acute sleep restriction. Fifty-six participants, matched by sex, age, and chronotype, were randomly assigned to either an exercise (EX) or seated control (SC) condition. Following a 4-hour sleep restriction protocol, participants completed the oddball paradigm before and after 20 minutes of exercise or stationary sitting. P3 amplitude and latency, arousal, sleepiness, energy, and fatigue were assessed during the experiment. After controlling for pre-test differences, P3 latency was significantly faster following exercise relative to the control group. No significant P3 amplitude differences were observed between conditions. The EX group displayed significant improvements in arousal, sleepiness, energy, and fatigue compared to the SC group. Findings suggest that 20 minutes of moderate-intensity aerobic exercise following acute sleep restriction may improve cognitive processing speeds, as well as improve arousal, sleepiness, energy, and fatigue.

No description available.