A number of novel hydrocarbon cage systems have been designed and characterized using ab initio molecular orbital calculations at the MP2 and B3-LYP levels. In particular,equilibrium structures for five families of molecules, hemialkaplanes, hemispiroalkaplanes, alkaplanes, spiroalkaplanes and dimethanospiroalkaplanes, have been examined in detail with the aim of designing a saturated hydrocarbon with a planar-tetracoordinate carbon atom and with a view to identifying appropriate synthetic targets. ¶ The hemialkaplanes and hemispiroalkaplanes are constructed from a spiropentane or neopentane subunit, respectively, which is capped by a cyclic hydrocarbon. The hemispiroalkaplanes are predicted to contain a pyramidal-tetracoordinate carbon atom possessing a lone pair of electrons. Protonation at this apical carbon atom is found to be highly favorable, resulting in a remarkably high basicity for a saturated hydrocarbon. The proton affinities of the hemispiroalkaplanes are calculated to be more than 1170 kJ mol[superscript -1] , even greater than those for the diamine "proton sponges". ¶ The alkaplanes and the spiroalkaplanes, which are constructed by bicapping a neopentane or spiropentane subunit, respectively, with a pair of cyclic hydrocarbons, show unprecedented flattening of a tetracoordinate carbon atom. Linking the spiroalkaplane caps with methano bridges gives the dimethanospiroalkaplanes, two of which, dimethanospirooctaplane and dimethanospirobinonaplane, achieve exact planarity at the central carbon atom. They are the first neutral saturated hydrocarbons predicted to contain an exactly planartetracoordinate carbon atom. This has been achieved through structural constraints alone. The electronic structure at the central carbon atom results in a highest occupied molecular orbital corresponding to a p-type lone pair. Consequently, the adiabatic ionization energies for octaplane, spirooctaplane and dimethanospirooctaplane (approximately 5 eV) are predicted to be similar to those of lithium and sodium - incredibly low for a saturated hydrocarbon. ¶ Some consideration has been given to likely pathways for unimolecular decomposition for all species. Predicted structures, heats of formation and strain energies for all the novel hydrocarbons are also detailed. Tetramethylhemispirooctaplane and dimethanospirobinonaplane are identified as the preferred synthetic targets.

Over time astrocytes have been thought to function in an auxiliary manner, providing neurons with metabolic and structural support. However, recent research suggests they may play a fundamental role in the generation and propagation of focal epileptic seizures by causing synchronized electrical bursts in neurons. It would be helpful to have a simple mathematical model that represents this dynamic and incorporates these updated experimental results. We have created a two-compartment model of a typical neuron found in the hippocampal CA1 region, an area often thought to be the origin of these seizures. The focus is on properly modeling the astrocytic input to examine the pathological excitation of these neurons and subsequent transmission of the signals. In particular, we consider the intracellular astrocytic calcium fluctuations which are associated with slow inward currents in neighbouring neurons. Using our model, a variety of experimental results are reproduced, and comments are made about the potential differences between graded and “all-or-none” astrocytes.

Over time astrocytes have been thought to function in an auxiliary manner, providing neurons with metabolic and structural support. However, recent research suggests they may play a fundamental role in the generation and propagation of focal epileptic seizures by causing synchronized electrical bursts in neurons. It would be helpful to have a simple mathematical model that represents this dynamic and incorporates these updated experimental results. We have created a two-compartment model of a typical neuron found in the hippocampal CA1 region, an area often thought to be the origin of these seizures. The focus is on properly modeling the astrocytic input to examine the pathological excitation of these neurons and subsequent transmission of the signals. In particular, we consider the intracellular astrocytic calcium fluctuations which are associated with slow inward currents in neighbouring neurons. Using our model, a variety of experimental results are reproduced, and comments are made about the potential differences between graded and “all-or-none” astrocytes.

Rett Syndrome (RTT) is a neurodevelopmental disorder primarily caused by mutations in the X-linked gene methyl-CpG-binding protein 2 (MECP2). The mosaic brain environment in heterozygous (MECP2+/-) females consists of both MeCP2-wildtype (MeCP2+) and Mecp2-mutant (MeCP2-) neurons. To separate possible cell autonomous and cell non-autonomous effects three-dimensional morphological analysis was performed on individually genotyped layer V pyramidal neurons in the primary motor cortex of heterozygous (Mecp2+/-) and wild-type (Mecp2+/+) mature female mice (>8 months old) from the Mecp2tm1.1Jae line. Mecp2+/+ neurons and Mecp2+ were found to be indistinguishable while Mecp2- neurons have significantly reduced basal dendritic length (p<0.05), predominantly in the region 70-130 μm from the cell body, culminating in a total reduction of 15%. Mecp2- neurons have three (17%) fewer total branch points, lost specifically at the second and third branch orders. Thus the reduced total dendritic length in Mecp2- neurons is a result of fewer higher-order branches. Soma and nuclear areas of 30 Mecp2+/- female mice (5-21 months) with X chromosome inactivation (XCI) ratios ranging from 12% to 56% were analyzed. On average Mecp2- somata and nuclei were 15% and 13% smaller than Mecp2+ neurons respectively. The variation observed in the soma and nuclear sizes of Mecp2- neurons was not due to age, but was found to be correlated with the XCI ratio. Animals with a balanced XCI ratio (approximately 50% Mecp2-) were found to have Mecp2- neurons with a less severe cellular phenotype (11-17% smaller than Mecp2+). Animals with a highly skewed XCI ratio favouring expression of the wild-type allele (less than 30% Mecp2-) were found to have a more severe Mecp2- cellular phenotype (17-22% smaller than Mecp2+). These data support indicate that mutations in Mecp2 exert both cell autonomous and cell non- autonomous effects on neuronal morphology. / Graduate

Pesquisas in vivo e in vitro, têm estabelecido uma correlação entre alterações na morfologia dendrítica e a epilepsia. No entanto, ainda não se conhecem em detalhe as consequências dessas modificações, sobre a eletrofisiologia e o padrão de disparo. Também existe um fenômeno que não tem sido completamente explicado, conhecido como o paradoxo do dendrito epiléptico, no qual neurônios piramidais, mesmo com a diminuição dramática do principal lugar de inervação glutamatérgica (como consequência de, por exemplo, uma redução do diâmetro e comprimento das árvores dendríticas), inesperadamente apresentam um estado de hiperexcitabilidade crônica. Nesta pesquisa foram aproveitadas as vantagens de uma abordagem neurocomputacional, para induzir sistematicamente alterações na arquitetura dendrítica do mesmo tipo às observadas na epilepsia, e avaliar os seus efeitos sobre a eletrofisiologia e o padrão de disparo. Para isso foi construído um modelo computacional biologicamente realista, de um neurônio piramidal do neocórtex. O código-fonte do modelo está na linguagem do NEURON, e foi baseado em dados eletrofisiológicos (i.e. propriedades da membrana e condutâncias iônicas) e morfométricos, obtidos in vitro previamente por outros pesquisadores. A análise foi feita com base em parâmetros eletrofisiológicos do padrão de disparo. O nosso modelo sugere uma influencia muito forte da morfologia dendrítica sobre a eletrofisiologia, a geração de potencias de ação e o padrão de disparo. Os resultados obtidos mostram que, mesmo mantendo constantes todos parâmetros biofísicos (que têm a ver com as dinâmicas elétricas dos canais iônicos), é possível induzir um aumento grande no comportamento elétrico e na geração de potenciais de ação, a partir da redução do diâmetro e comprimento das ramificações das árvores dendríticas. Estes resultados, também permitem contribuir no fornecimento de uma explicação para o paradoxo mencionado. / In vivo and in vitro studies had found a correlation between dendritic morphology alterations and epilepsy. Nevertheless, it has not been established in detail the consequences of those modifications, over the electrophysiology and firing pattern. There is also a phenomenon still not completely understood, known as the epileptic dendrite paradox, in which pyramidal neurons with a dramatic reduction in the principal place of glutamatergic innervation (due to, for example, a loss in dendritic trees\' diameter and length), unexpectedly present a chronic hyperexcitable state. In this study we took advantage of a neurocomputational approach, to systematically induce dendritic alterations of the same type as observed in Epilepsy, and evaluate their effect over the electrophysiology and firing behavior. With that purpose in mind, we constructed a biologically realistic computational model of a pyramidal neuron of the neocortex. For this model, it was implemented the programming language (hoc) of the NEURON software, and was elaborated based on electrophysiological data (i.e. membrane properties and ionic conductances), and morphological measurements, taken in vitro previously by other investigators. The analysis was done from electrophysiological parameters of the firing pattern. Our model suggests a great influence of dendritic morphology over the electrophysiology, spike generation and firing pattern. The results obtained show that, even when all the biophysical parameters involved in ion channel dynamics are maintained constant, it is possible to induce a strong increase in electric behavior and spike firing, from a reduction in the length and diameter of the dendritic trees\' ramifications. These results, also contribute to a explanation of the mentioned paradox.

Basische Helix-Loop-Helix (bHLH)-Proteine bilden eine diverse Gruppe evolutionär gut konservierter Transkriptionsfaktoren. Viele transaktivierende bHLH-Proteine werden zelltyp- oder gewebespezifisch exprimiert und fungieren als wichtige Schlüsselregulatoren zellulärer Determinations- und Differenzierungsprozesse. Die eng verwandten neuronalen bHLH-Gene Neurod1, Neurod2 und Neurod6 werden in differenzierenden Pyramidenneuronen des sich entwickelnden zerebralen Kortex exprimiert und stehen schon lange im Verdacht, deren Reifung zu steuern. In der Vergangenheit wurde jedes der drei Gene in Mäusen inaktiviert. Untersuchungen an den einfach-defizienten Tieren konnten jedoch keine wichtigen Funktionen in embryonalen Pyramidenneuronen identifizieren. Da die Aminosäuresequenzen und die Expressionsmuster der Faktoren sehr ähnlich sind, wurde angenommen, dass sie sich redundante Funktionalität teilen. Um dies zu überprüfen, habe ich Neurod2/6-doppel-defiziente Tiere gezüchtet und unter besonderer Berücksichtigung der Differenzierung von Pyramidenneuronen und der Konnektivität des zerebralen Kortex analysiert: Die Experimente zeigen, dass Neurod2 und Neurod6 tatsächlich mehrere bisher unbekannte gemeinsame Funktionen haben, wobei jeder Faktor für den Verlust des jeweils anderen kompensieren kann. Zumindest eines der beiden Gene ist notwendig für (1) die Kontrolle der radialen Migration eines Teils der Pyramidenneurone, (2) die frühe Regionalisierung des zerebralen Kortex und (3) die Bildung kortikaler Projektionen vom Neokortex zum Striatum, zum Thalamus und zur kontralateralen Hemisphäre. Callosale Axone bilden in Neurod2/6-doppel-defizienten Mäusen Faserbündel die tangential in den medialen Kortex einwachsen, aber noch vor Erreichen des ipsilateralen Cingulums und vor dem Kontakt mit der Mittellinie stoppen und defaszikulieren. Es resultiert eine neue Variante der callosalen Agenesie, die nahelegt, dass es bisher nicht identifizierte Wachstumssignale im medialen Kortex gibt. Die Expression von Neurod1, welche sich normalerweise auf die Subventrikularzone beschränkt, persistiert in radial migrierenden Pyramidenneuronen der Intermediärzone und der Kortikalplatte von Neurod2/6-doppel-defizienten Mäusen. Diese ektopische Neurod1-Expression kann dort den Verlust von Neurod2 und Neurod6 kompensieren. In einem weiteren Schritt habe ich konditionale Neurod1/2/6-tripel-defiziente Mäuse gezüchtet. In diesen Tieren wird das Neurod1-Gen durch selektive genetische Rekombination in all jenen Zellen, die über Neurod6-Promoteraktivität verfügen, irreversibel entfernt: Wie erwartet, teilt sich Neurod1 weitere gemeinsame Funktionen mit Neurod2 und Neurod6. Zumindest eines der drei Gene ist notwendig für die Differenzierung hippokampaler Pyramidenzellen und die Hemmung des programmierten Zelltods der unreifen Neuronen des Cornu Ammonis. Während die gemeinsame Inaktivierung von Neurod1/2/6 zur Aplasie des Hippocampus führt, überlebt ein Großteil der neokortikalen Pyramidenzellen. Die terminale neuronale Differenzierung ist jedoch auch im Neokortex gestört und die neokortikale Konnektivität sehr stark reduziert. Diese Arbeit zeigt, dass die Transkriptionsfaktoren der NeuroD-Familie gemeinsam die Differenzierung, das Überleben, die Migration und das axonale Wachstum von pyramidalen Neuronen des sich entwickelnden zerebralen Kortex steuern. Während der Embryonalentwicklung ergeben sich folgende, teils überschneidende Funktionen der NeuroD-Gene: Die Differenzierung und das Überleben von hippocampalen Körnerzellen ist abhängig von Neurod1. Die frühen Schritte der Differenzierung von hippocampalen Pyramidenneuronen und deren Überleben sind eine Funktion von wahlweise Neurod1, Neurod2 oder Neurod6. Spätere neuronale Differenzierungsschritte, die Regionalisierung des Neokortex und das gezielte Wachstum wichtiger neokortikaler Faserzüge basieren auf Funktionen von Neurod2 oder Neurod6, aber nicht von Neurod1. Der postnatale Umbau des somatosensorischen Kortex und die funktionale Integration thalamischer Afferenzen wurden bereits als strikt Neurod2-abhängig beschrieben.

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Significant efforts have been made in the last decades to decrease the world’s dependency to fossil fuels. One of the fronts which has shown major improvement is gas turbine efficiency. To this end, components such as recuperators have been developed to recover heat that is usually trapped and wasted in the exhaust gases of combustion processes. Brayton Energy Canada has recently developed a promising compact heat exchanger that could be used as a recuperator in gas turbines. Nevertheless, this novel type of wire mesh heat exchanger still has room for improvement, especially regarding the way that its fin arrays are manufactured due to the fact that the technique presently used is time consuming and consequently costly. The present research aims to manufacture near-net shaped pin fin arrays using cold gas dynamic spray as an additive manufacturing technique by selectively covering the substrate by the means of a mask. Moreover, this research work studies the feasibility of using CGDS as an additive manufacturing technique to produce pin fin arrays, the thermal and hydrodynamic performances of this new type of pin fin created, the effect of geometric parameters such as fin density and height on the performances, the viability of the sprayed pin fins in a real environment by means of finding mechanical properties such as adhesion strength, the possibility of producing a streamwise material anisotropic fin arrays, and finally the different adhesion mechanisms by means of numerical modeling of the relevant impact physics.

Kainic acid induced excitotoxicity causes pyramidal cell death in the CA3a/b region of the hippocampus. Electrical synapses, gap junctional communication, and single membrane channels in non-junctional membranes (hemichannels) composed of connexin36 (Cx36) have been implicated in both seizure propagation and the spread of excitotoxic cell death. In rats, Cx36 protein is expressed by pyramidal neurons. Localization of protein in mouse, however, is highly controversial. Expression is reported to be restricted to hippocampal interneurons yet the same excitotoxic mechanisms (electrical and metabolic coupling between pyramidal neurons) are invoked to explain the role of Cx36 in excitotoxic pyramidal loss in murine brain. To address this controversy, I show by confocal immunofluorescence and in situ hybridization that Cx36 protein expression is restricted to interneurons and microglia in murine hippocampus and is not expressed by, or is below level of detection in pyramidal neurons. Using behavioural and electrophysiological measures, seizure propagation was found to be moderately enhanced in the absence of Cx36 likely due to the loss of interneuron-mediated synchronous inhibition of the pyramidal cells. Further, CA3a/b neurons die post kainic acid injury in the presence of Cx36 but are protected in Cx36-/- mice. When delayed excitotoxic cell death is maximal, Cx36 is primarily expressed by activated microglia as demonstrated by confocal immunofluorescence, in situ hybridization, and Western blotting. These activated microglia are located in the direct vicinity of, and surrounding cells in the damaged Ca3a/b region. Finally, I show that loss of Cx36 from activated microglia in mice is sufficient to prevent excitotoxic cell death in the CA3a/b with surviving neurons functional as assessed by both electrophysiological and behavioural measures. Together, these data identify a new mechanism of excitotoxic injury, mediated by neuronal-glial interactions, and dependent on microglial Cx36 expression.

Axon guidance receptors such as deleted in colorectal cancer (DCC) contribute to the normal formation of neural circuits, and their mutations can be associated with neural defects. In humans, heterozygous mutations in have been linked to congenital mirror movements, which are involuntary movements on one side of the body that mirror voluntary movements of the opposite side. In mice, obvious hopping phenotypes have been reported for bi-allelic mutations, while heterozygous mutants have not been closely examined. We hypothesized that a detailed characterization of heterozygous mice may reveal impaired corticospinal and spinal functions. Anterograde tracing of the motor cortex revealed a normally projecting corticospinal tract, intracortical microstimulation (ICMS) evoked normal contralateral motor responses, and behavioral tests showed normal skilled forelimb coordination. Gait analyses also showed a normal locomotor pattern and rhythm in adult mice during treadmill locomotion, except for a decreased occurrence of out-of-phase walk and an increased duty cycle of the stance phase at slow walking speed. Neonatal isolated spinal cords had normal left-right and flexor-extensor coupling, along with normal locomotor pattern and rhythm, except for an increase in the flexor-related motoneuronal output. Although mice do not exhibit any obvious bilateral impairments like those in humans, they exhibit subtle motor deficits during neonatal and adult locomotion.