The human Class Ib gene, HLA-E inhibits both Natural Killer Cells and a subset of CD8+ cytotoxic T lymphocytes by engaging the CD94/NKG2A inhibitory receptor. IFN-γ induces the expression of HLA-E as well as Class Ia molecules, which are required for the killing of target cells. Since HLA-E has negative effects on immune killing of target cells, we have sought to identify locus specific mechanisms of IFN-γ induction in order to identify molecular targets for selective activation of Class Ia genes, but not HLA-E. We have previously identified a unique upstream IFN-γ response region in the HLA-E promoter and showed that GATA-1 is required for its function in the K562 leukemic cell line. We have now examined the effect of GATA family members on IFN-γ induction of HLA-E in other cell types. HLA-E CAT reporter gene assays demonstrate that tumor cells that express GATA factors as determined by western blot and quantitative PCR, mediate a 2.4 to 4.0 fold enhanced response to IFN-γ stimulation. Functional constructs containing mutations of the core nucleotides in the GATA binding site had a 4.8 fold decreased response to IFN-γ in A2780 cells and a 8.5 to 14.0 fold decreased response to IFN-γ in SKOV3 cells. Knockdown of GATA-6 using siRNA resulted in a 40% decrease in HLA-E induction in Seg1 cells and a 30% decrease in HLA-E induction in HCT116 cells. Tetracycline regulated shRNA knockdown of GATA-6 expression in the SKOV3 cell line revealed a 3 fold decrease in the IFN-γ response of HLA-E reporter driven constructs. Additionally we observed a decreased IFN-γ response in SKOV3 cells transfected with siRNA specific for CBP and IRF-9. We conclude that GATA factors play a tissue specific role in regulation of IFN-γ mediated HLA-E expression and that IRF-9 may be a target for the differential manipulation of classical MHC and HLA-E.

Le cerveau présente des fluctuations de son activité qui reflètent différents niveaux d’engagement avec le monde extérieur. Le traitement des stimuli externes n’est pas seulement associé avec une augmentation du métabolisme cérébrale, mais également avec une désactivation importante dans un ensemble des structures spécifiques connus sous le nom de ‘Default-Mode Network’ (DMN, réseau par défaut). Le rôle du DMN reste énigmatique en partie parce que ses corrélats électrophysiologiques et sa dynamique temporelle sont encore mal compris. En utilisant des enregistrements éléctrophysiologiques intracrânien chez le patient épileptique, nous démontrons que la population neuronale de ce réseau montre des suppressions de l’activité gamma (60-140 Hz). Plus important, nous montrons de quelle manière le profil temporale (en millisecondes) et l’amplitude de cette désactivation sont étroitement corrélés avec la difficulté de la tâche et la performance individuelle. Les résultats mettent également en évidence que pendant une tâche attentionnelle, une activation soutenue dans le temps de la bande gamma est présente dans un large réseau, alors que des activations transitoires sont spécifiques aux régions temporale et occipitale. Nos résultats révèlent ainsi un rôle essentiel des mécanismes d’activation et de désactivation des oscillations large bande gamma dans l’exécution d’un comportement orienté vers un but. / The brain displays moment-to-moment activity fluctuations that reflect various levels of engagement with the outside world. Processing external stimuli is not only associated with increased brain metabolism but also with prominent deactivation in specific structures, collectively known as the default-mode network (DMN). The role of the DMN remains enigmatic partly because its electrophysiological correlates and temporal dynamics are still poorly understood. Using unprecedented wide-spread depth recordings in epileptic patients, undergoing intracranial EEG during pre-surgical evaluation, we reveal that DMN neural populations display task-related suppressions of gamma (60-140 Hz) power and, critically, we show how millisecond temporal profile and amplitude of gamma deactivation tightly correlate with task demands and subject performance. The results show also that during an attentional task, sustained activations in the gamma band power are presented across large cortical networks, while transient activations are mostly specific to occipital and temporal regions. Our findings reveal a pivotal role for broadband gamma modulations in the interplay between activation and deactivation networks mediating efficient goal-directed behavior

The relationship between structure, dynamics, and function of neural networks in nervous systems is still an open question in the neuroscience community. Nevertheless, for certain areas of the mammalian nervous system we do have sufficient data to impose constraints on the organisation of the network structure. One of these areas is the medial entorhinal cortex which contains cells with hexagonally repeating spatial receptive fields, called grid cells. Another intriguing property of entorhinal cortex and other cortical regions is a population oscillatory activity, with frequency in the theta (4-10 Hz) and gamma (30-100 Hz) range. This leads to a question, whether these oscillations are a common circuit mechanism that is functionally relevant and how the oscillatory activity interacts with the computation performed by grid cells. This thesis deals with applying the continuous attractor network theory to modelling of the microcircuit of layer II in the medial entorhinal cortex. Based on recent experimental evidence on connectivity between stellate cells, and fast spiking interneurons, I first develop a two-population spiking attractor network model that is capable of reproducing the activity of a population of grid cells in layer II. The network was implemented with exponential integrate and fire neurons that allowed me to address both the attractor states and the oscillatory activity in this region. Subsequently, I show that the network can produce theta-nested gamma oscillations with properties that are similar to the cross-frequency coupling observed in vivo and in vitro in entorhinal cortex, and that these theta-nested gamma oscillations can co-exist with grid-like receptive fields generated by the network. I also show that the connectivity inspired by anatomical evidence produces a number of directly testable predictions about the firing fields of interneurons in layer II of the medial entorhinal cortex. The excitatory-inhibitory attractor network, together with the theta-nested gamma oscillations, allowed me to explore potential relationships between nested gamma oscillations and grid field computations. I show, by varying the overall level of excitatory and inhibitory synaptic strengths, and levels of noise, in the network, that this relationship is complex, and not easily predictable. Specifically, I show that noise promotes generation of grid firing fields and theta-nested gamma oscillations by the model. I subsequently demonstrate that theta-nested gamma oscillations are dissociable from the grid field computations performed by the network. By changing the relative strengths of interactions between excitatory and inhibitory neurons in the network, the power and frequency of the gamma oscillations changes without disrupting the rate-coded grid field computations. Since grid cells have been suggested to be a part of the spatial cognitive circuit in the brain, these results have potential implications for several cognitive disorders, including autism and schizophrenia, as well as theories that propose a cognitive role for gamma oscillations.

In this paper we analyze the behavior of the Gamma function at its critical points and points of discontinuity on the negative side of the x-axis. We will also explain the bluntness of the gamma function on this negative side.

A dissertation submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in fulfillment of the requirements for the degree of Master of Science in Medicine. Johannesburg, June 2017 / Introduction: Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease of unknown aetiology. There is growing evidence environmental factor(s) trigger the disease in the genetically susceptible host. Fragment crystallisable receptor (FCR) genes encode receptors that recognise the fragment crystallisable (Fc) portion of immunoglobulins (IgG) play an important role in the removal of antigen-antibody complexes from the circulation. Genes that code for these receptors have shown to be associated with susceptibility to SLE in various populations. The aim of the present study is to determine the role of single nucleotide polymorphisms (SNPs), allotypes and copy number variations of FC Gamma receptor genes IIIA and IIIB in susceptibility for the Black South Africans with SLE. Methods: DNA from 162 Black South African SLE patients and 155 matched controls were investigated using Taqman assays to determine SNP genotyping differences (FCGRIIIA) and copy number variation (CNV) number (FCGRIIIB). A PCR was optimised in order to determine the allotype differences (FCGRIIIB) via agarose gel electrophoresis. Statistical analyses were then performed on the data to see if the results displayed significance in susceptibility to SLE. Results: The minor allele of the allotypes (FCGRIIIB) and the rs396991 SNP (FCGRIIIA) were not statistically significant in conferring susceptibility to SLE in cases or controls. The rs10127393 SNP (FCGRIIIA) was shown to be monomorphic within both cases and controls for the T allele and is not associated with SLE. The cumulative percentage of copy numbers (FCGRIIIB) ≤2 copies were 0.6% larger in cases than seen in controls. Although this was not significant, this was what has been previously suggested in the literature. Almost half of the cases (43.8%) had lupus nephritis (LN). Upon investigation the NA1/NA2 alleles were found to confer susceptibility to LN (p=0.018), whereas the rs396991 G allele did not (p=0.643). Conclusion: In this study the allotypes, SNPs and CNV investigated were not found to confer susceptibility to SLE. However, subtle trends suggest that further studies are required with larger sample sizes to acquire more data. Almost half of the cases were diagnosed with LN and the NA2 allele was shown to be a risk factor in developing LN. / MT2017

Orientador: Daniel Marcos Bonotto / Banca: Marcos Aurélio Farias de Oliveira / Banca: Antenor Zanardo / Banca: Boaventura Freire dos Reis / Banca: Francisco Yukio Hiodo / Resumo: Os radioelementos naturais U, Th e K foram caracterizados na área do Projeto Rio Preto (GO), executado pela extinta Nuclebrás, após a realização de etapa de campo para reconhecimento da área e amostragem de corpos litológicos das formações aflorantes na área. Sua determinação foi efetuada por espectrometria gama que possibilitou a mensuração dos nuclídeos 40K, 214Bi e 208Tl. Para o universo total de amostras (n = 288) também foram efetuadas análises químicas dos óxidos SiO2, TiO2, Al2O3, Fe2O3, MgO, MnO, K2O, Na2O, CaO e P2O5 com o intuito de se proceder a caracterização química das rochas da região. Os valores de concentração de óxidos e de nuclídeos permitiram a confecção de mapas de sua distribuição pela área de estudo. Para amostras selecionadas foram realizadas leituras de espectrometria alfa para a determinação dos isótopos de U presentes. As razões 234U/238U e eU/U, relativas às leituras por espectrometria alfa e gama, respectivamente, foram determinadas para avaliar a situação de equilíbrio radioativo na cadeia natural de decaimento do urânio. Foi utilizada também a autorradiografia para identificar a presença de minerais radioativos em lâminas de xistos e gnaisses da Formação Ticunzal. / Abstract: The natural radioelements U, Th and K were characterized in the area of the Rio Preto project held by Nuclebrás, after recognizing the area and sampling the rocks occurring there. The determination was performed by gamma spectrometry that allowed to quantify the nuclides 40K, 214Bi and 208Tl. All rock samples (n = 288) were chemically analyzed in terms of the oxides SiO2, TiO2, Al2O3, Fe2O3, MgO, MnO, K2O, Na2O, CaO and P2O5. The values of concentration of oxides and nuclides were used to generate distribution maps in the studied area. Alpha spectrometry was utilized for selected samples in order to determine the U-isotopes. The 234U/238U and eU/U ratios relative to the alpha and gamma spectrometry readings, respectively, were determined to evaluate the radioactive equilibrium condition in the natural uranium series decay. Autorradiography was also used to identify the presence of radioactive minerals in shales and gneisses from Ticunzal Formation. / Doutor

L'objet de ce travail de thèse est l'étude théorique et numérique des quelques problèmes relevants de l'analyse et de la modélisation de forme. Les problèmes considérés sont issus d'applications modernes comme la modélisation de décollement de membrane par mouvements minimisants, des inégalités isopérimétriques et de traitement d'image. Analyse et optimisation de formes des valeurs propres de l'opérateur de conductivité. Dans un ouvert de mesure finie on considère le Laplacian avec conditions aux bord de type conductivité, i.e. Constantes localement ou globalement, avec constantes libres. Cet opérateur intervient dans le processus de détection de défauts par mesures au bord et a fait l'objet d'une première analyse par Greco et Lucia dans le cadre globalement constant. Nous étudions des propriétés qualitatives des valeurs propres en relation avec la géométrie, des inégalités isopérimétriques générales par réarrangement et/ou [gamma]-convergence, et nous implémentons un algorithme génétique pour déterminer les formes minimisantes pour les valeurs propres d'ordre petit, à mesure constante, La génération des formes est basée sur les niveaux des séries de Fourier tronquées, contrôlées par les coefficients. Simulation numérique du décollement d'un membrane. On étudie le modèle de décollement d'une membrane adhésive proposé par Bucur, Buttazzo et Lux, dans le cadre des mouvements minimisantes quasi-statiques. Suivant la dissipation de l'énergie, le décollement consiste en une évolution de domaines ou une évolution de mesures. Mon travail a consisté dans la simulation associées à des stratégies évolutionnaires en relation avec la dérivée de forme, méthodes des lignes de niveaux et la dérivation des mesures. Etude numérique du problème de localisation optimale. Nous nous intéressons à l'analyse numérique des différents problèmes de localisation optimale tels que le problème de chois optimal des pixels d'appui pour l'interpolation d'image ou la minimisation de la compliance (cadre linéaire ou non linéaire). Différentes méthodes sont utilisées, tels que le gradient topologique, les algorithmes génétiques et le calcul asymptotique par [gamma]-convergence / We are interested in a few problems which can be viewed in the framework of shape optimization like : the conductivity eigenvalue problem. In an open set of finite measure we considers the Laplacian with conductivity boundary conditions, i.e., constants locally or globally with free constants. The operator intervenes in the process of the defect identication of a material by electrostatic boundary measurements and was the subject of a first properties of the eigenvalues in relation with the geometry, general isoperimetric inequalities by rearrangement and/or [gamma]-convergence, and we implement a genetic with constant measure. The generation of the forms is based on the levels of truncated Fourier series, controlled by the coefficeints. Numerical implementation for debonding membranes. We study the model of quasistatic evolution of an adhesive membrane subjected to a debonding force proposed by Bucur, Buttazzo and Lux, within the framwork of the minimizing movements. According to the dissipation of energy the debonding process consisted in the numerical simulation of the debonding process in the two situations. Methods of descent are associated with the evolution strategies in relation to the shape derivative ; level set method and the mesure derivation. Numerical results for a few problem of optimal location. We are interested in the numeraical analysis of the various problems of optimal location such as the problem of best alternative of the pixels of support for the image interpolation or minimization of compliance (framework linear and not linear). Various methods are used, such as the topological gradient, the genetic algorithms and asymptotic calculation by [gamma]-convergence

En este trabajo buscamos un método para diferenciar entre lluvias de partículas producidas por rayos cósmicos y por rayos gamma a energías de TeV, utilizando simulaciones CORSIKA. Este método intenta resolver el problema que existe en la búsqueda de señales de rayos gamma medidos por diversos experimentos frente a un fondo de flujo dominante de hadrones. Los resultados de este trabajo pueden aplicarse al estudio de Explosiones de Rayos Gamma (GRBs). Los GRBs emiten fotones muy energéticos, que al interactuar con la atmósfera terrestre, producen una gran cascada electromagnética de partículas secundarias, las cuales son detectables. El procedimiento sería simular eventos producidos por fotones, la señal, y protones, el fondo, que son las partículas más abundantes de los rayos cósmicos. Extraemos varios parámetros de los perfiles longitudinales de las lluvias de partículas, caracterizando las lluvias simuladas. Algunos de los parámetros de ajuste más importantes son el m_aximo de lluvia (Xmax), el ancho de la lluvia FWHM, el parámetro de asimetría, el número máximo de partículas Nmax y el comienzo de lluvia XStart. Existen diferentes experimentos utilizando tanques Cherenkov de agua y detectores de fluorescencia que pueden medir estos parámetros de las lluvias. Hemos probado dos métodos. El primero se basa en cortes simples, mientras que el segundo se basa en un análisis multivariado utilizando el paquete TMVA, que mejora los cortes individuales. El primer método se aplicó a las energías simuladas separadas de 102, 103, 104 y 105 GeV para encontrar cortes adecuados. Encontramos que Xmax, FWHM, Xstart y Nmax dependen de la energía. Posteriormente aplicamos estos cortes dependientes de la energía y otros cortes fijos a una muestra realista, que consiste en 104 eventos de señales (fotones) y 106 eventos de fondo (protones) que cubren un rango de energía de 102 a 105 GeV con diferentes espectros. Además, se introdujo un error en la energía simulada para simular la eficiencia de reconstrucción de energía de un detector. El resultado obtenido deja 54% eventos de señal y 12% eventos de fondo. Aplicando el análisis multivariado TMVA, encontramos que el método Boosted Decision Trees (BDT) era el mejor para distinguir la señal del fondo. El resultado para una eficiencia de señal similar fue 0:7% de eventos de fondo. Por último, utilizando cortes más estrictos en la BDT para mejorar la significancia, el resultado fue 1 evento de fotón por cada 1000 eventos de protón. Dada la proporción de flujo inicial, significa una capacidad de rechazo de fondo de 103. Por lo tanto, la viabilidad de la separación gamma/hadrón requiere una mejora adicional. / In this work we search for a method to differentiate between particle showers produced by cosmic rays and by gamma rays at TeV energies, using CORSIKA simulations. This method tries to solve the dominant hadron flux background problem when looking for gamma-ray signals measured by different experiments. The results of this work can be applied to the study of Gamma-Ray Bursts (GRBs). GRBs emit very energetic photons, which after interacting in the Earth's atmosphere, produce a large detectable electromagnetic cascade of secondary particles. The procedure will be to simulate events produced by photons, the signal, and protons, the most abundant cosmic-ray background. We extract several parameters from fitting particle air-shower longitudinal profiles, characterizing the simulated showers. Some of the most important _t parameters are the shower maximum (Xmax), the width of the shower FWHM, the asymmetry parameter, the maximum number of particles Nmax and the shower start Xstart. There are different experiments using water Cherenkov tanks and fluorescence detectors which can measure these shower parameters. We tested two methods. The first relies on simple cuts, while the second is based on a multivariate analysis using the TMVA package, which improves individual cuts. The first method was applied to single simulated energies of 102, 103, 104 and 105 GeV to find adequate cuts. We found that Xmax, FWHM, Xstart and Nmax depend on the energy. Later we applied these energy-dependent cuts and other fixed cuts to a realistic sample, which consists of 104 signal events (photons) and 106 background events (protons) covering an energy range from 102 to 105 GeV with different spectra. Moreover, we introduced an energy smearing to simulate a detector energy reconstruction efficiency. The obtained result leaves 54% signal events and 12% background events. Applying the multivariate analysis TMVA, we found that the Boosted Decision Trees (BDT) method was the best for distinguishing signal from background. The result for a similar signal efficiency was 0:7% of background events. Finally using tighter cuts on the BDT to improve the significance results in 1 photon event for every 1000 protons. Given the initial ux proportion, it means a 103 background rejection capability. Thus the feasibility of gamma/hadron separation requires further improvement. / Trabajo de investigación

This thesis set out to investigate the electrophysiological correlates of maths anxiety (MA). Research has shown that those with high MA (HMA) tend to have poorer accuracy and increased reaction time on maths based tasks and that high maths anxious individuals avoid situations where they might have to use maths. This can impact on their future by restricting their degree or job prospects. Previous research has identified the behavioural cognitive and psychological effects of MA and recently studies have begun to examine the associated underlying mechanisms in the brain. Chapter one outlines the background MA behavioural and measurement research before evaluating the neurophysiological methods used in cognitive neuroscience and the use of electroencephalography (EEG) in chapter two. Chapter three continues by outlining previous research concerning the neurophysiological processing of maths and number before evaluating relevant neurophysiological research concerning MA. Four experimental studies are conducted, exploring the neurophysiological underpinnings of MA research using EEG. Each of these recruits 30 participants and measures of electro-cortical (Event Related Potentials (ERPs), Global Field Power, Frequency etc.) and questionnaire measures are implemented. The first study aimed to identify whether the behavioural effects of MA (poorer accuracy and increased reaction time) are consistent with ERP differences (component amplitude and latency differences) in the brain and to understand why these effects are experienced. This revealed no significant comparisons between ERP components and behavioural responses involving low and high maths anxious individuals, but this may have been due to the lack of an anxious response by using a verification task, rather than requiring calculation. Study two introduces the measurement of gamma activity as a neurophysiological measure of anxiety and threat processing and brings three core areas of anxiety research together: Previous studies outline high anxiety in connection with gamma modulation, also showing gamma band activity is associated with the amygdala and finally, that the amygdala is responsible for the processing of threat perception and anxiety. This research has not been brought together when studying MA. Results produced similar ERP findings to the previous study but the introduction of gamma activity into the research provided the first differences between high and low MA (LMA) groups, showing significantly greater gamma activity levels in HMA individuals. However, this study only used numerically-based tasks, thus the third study implemented a non-numerical condition to act as a control. Study three replicates the findings showing a reduced level of gamma activity in high MA individuals for the non-numerical based task, however, this was also reduced for the simple maths task. It was theorised that it is more likely to be the initial threat perception that represents the anxious response and gamma activity increases. To test this and remove any working memory demands, the fourth study implements the presentation of single digit observation (using single digit numbers and letters). Even though there was no demand on working memory, high maths anxious participants displayed similar levels of gamma activity as low maths anxious individuals during letter observation. However, they had significantly greater levels during the observation of number. Findings suggest that HMA individuals may not only struggle with the processing of maths stimuli, but may have a threat-related response to the simple observation of numerical stimuli. This implies that HMA individuals consistently apply an avoidance technique due to a threat response associated with increased levels of gamma activity. The findings of the each study are finally discussed in terms of their contribution to the neurophysiological underpinnings of MA, the first exploration of this using gamma activity, future research and the extent that number anxiety may act as a precursor or sine qua non to MA.

Prefrontal cortex (PFC) is critical to behavioral flexibility and, hence, the top-down control over bottom-up sensory information. The mechanisms underlying this capacity have been hypothesized to involve the propagation of alpha/beta (8-30 Hz) oscillations via feedback connections to sensory regions. In contrast, gamma (30-160 Hz) oscillations are thought to arise as a function of bottom-up, feedforward stimulation. To test the hypothesis that such oscillatory phenomena embody such functional roles, we assessed the performance of nine monkeys on tasks of learning, categorization, and working memory concurrent with recording of local field potentials (LFPs) from PFC. The first set of tasks consisted of two classes of learning: one, explicit and, another, implicit. Explicit learning is a conscious process that demands top-down control, and in these tasks alpha/beta oscillations tracked learning. In contrast, implicit learning is an unconscious process that is automatic (i.e. bottom up), and in this task alpha/beta oscillations did not track learning. We next looked at dot-pattern categorization. In this task, category exemplars were generated by jittering the dot locations of a prototype. By chance, some of these exemplars were similar to the prototype (low distortion), and others were not (high distortion). Behaviorally, the monkeys performed well on both distortion levels. However, alpha/beta band oscillations carried more category information at high distortions, while gamma-band category information was greatest on low distortions. Overall, the greater the need for top-down control (i.e. high distortion), the greater the beta, and the lesser the need (i.e. low distortion), the greater the gamma. Finally, laminar electrodes were used to record from animals trained on working memory tasks. Each laminar probe was lowered so that its set of contacts sampled all cortical layers. During these tasks, gamma oscillations peaked in superficial layers, while alpha/beta peaked in deep layers. Moreover, these deep-layer alpha/beta oscillations entrained superficial alpha/beta, and modulated the amplitude of superficial-layer gamma oscillations. These laminar distinctions are consistent with anatomy: feedback neurons originate in deep layers and feedforward neurons in superficial layers. In summary, alpha/beta oscillations reflect top-down control and feedback connectivity, while gamma oscillations reflect bottom-up processes and feedforward connectivity.