Among the four valves of the heart, the aortic valve (AV) is frequently affected by disease. When progressive dilatation of the valve produces a leak when the valve should close (regurgitation), repair may be possible. AV repair is a desirable option because, contrary to AV replace-ment using a prosthesis, it does not require life-long anticoagulation treatment, and retains the original tissues that naturally combat structural degradation. All the AV repair procedures developed by cardiac surgeons require a good stabilization of the ventriculo-aortic junction (VAJ) diameter, through annuloplasty or reimplantation, for long-term success. In the present work, a preliminary design for a new type of annuloplasty ring is proposed that surgeons could tailor to the each valve’s shape and suture inside the VAJ. The design consists in wrapping a commonly available surgical biomaterial into a ring of controlled radial flexibility. For sizing and material selection, several models of increasing complexity were created to account for the anisotropic, hyperelastic nature of all the materials involved. First, an analytical model was programmed in MATLAB to assess the radial flexibility of annuloplasty rings formed with different biomaterials and select those that could match the physiological VAJ radial flexibility between systolic and diastolic pressures. The same program was also used to reproduce the experimental radial and longitudinal stretches of the human VAJ from 0 to 140 mmHg pressures. The analytical models were used to calibrate the parameters of independent finite element (FE) models of the VAJ and ring. Finally, the FE approach was extended to simulate the ring after suturing inside the VAJ, to determine the radial flexibility of the assembly under pulsatile pressure. Supple Peri-Guard® bo-vine pericardium patches used in transverse orientation emerged as the best currently available material option for the proposed ring, although a material providing more physiological radial flexibility would be desirable.

Les mémoires non-volatiles (MNV) sont l'objet d'un effort de recherche croissant du fait de leur capacité à limiter la consommation statique, qui obère habituellement la réduction des dimensions dans la technologie CMOS. Dans ce contexte, cette thèse aborde plus spécifiquement deux technologies de mémoires non volatiles : d'une part les jonctions tunnel ferroélectriques (JTF), dispositif non volatil émergent, et d'autre part les dispositifs à transfert de spin (TS) assisté par effet Hall de spin (EHS), approche alternative proposée récemment pour écrire les jonctions tunnel magnétiques (JTM). Mon objectif est de développer des modèles compacts pour ces deux technologies et d'explorer, par simulation, leur intégration dans les circuits non-volatiles.J'ai d'abord étudié les modèles physiques qui décrivent les comportements électriques des JTF : la résistance tunnel, la dynamique de la commutation ferroélectrique et leur comportement memristif. La précision de ces modèles physiques est validée par leur bonne adéquation avec les résultats expérimentaux. Afin de proposer un modèle compatible avec les simulateurs électriques standards, nous j'ai développé les modèles physiques mentionnés ci-dessus en langue Verilog-A, puis je les ai intégrés ensemble. Le modèle électrique que j'ai conçu peut être exploité sur la plate-forme Cadence (un outil standard pour la simulation de circuit). Il reproduit fidèlement les comportements de JTF. Ensuite, en utilisant ce modèle de JTF et le design-kit CMOS de STMicroelectronics, j'ai conçu et simulé trois types de circuits: i) une mémoire vive (RAM) basée sur les JTF, ii) deux systèmes neuromorphiques basés sur les JTF, l'un qui émule la règle d'apprentissage de la plasticité synaptique basée sur le décalage temporel des impulsions neuronale (STDP), l'autre mettant en œuvre l'apprentissage supervisé de fonctions logiques, iii) un bloc logique booléen basé sur les JTF, y compris la démonstration des fonctions logiques NAND et NOR. L'influence des paramètres de la JTF sur les performances de ces circuits a été analysée par simulation. Finalement, nous avons modélisé la dynamique de renversement de l'aimantation dans les dispositifs à anisotropie perpendiculaire à transfert de spin assisté par effet Hall de spin dans un JTM à trois terminaux. Dans ce schéma, deux courants d'écriture sont appliqués pour générer l'EHS et le TS. La simulation numérique basée sur l'équation de Landau-Lifshitz-Gilbert (LLG) démontre que le délai d'incubation de TS peut être éliminé par un fort EHS, conduisant à la commutation ultra-rapide de l'aimantation, sans pour autant requérir une augmentation excessive du TS. Nous avons appliqué cette nouvelle méthode d'écriture à la conception d'une bascule magnétique et d'un additionneur 1 bit magnétique. Les performances des circuits magnétiques assistés par l'EHS ont été comparés à ceux écrits par transfert de spin, par simulation et par une analyse fondée sur le modèle théorique. / Non-volatile memory (NVM) devices have been attracting intensive research interest since they promise to solve the increasing static power issue caused by CMOS technology scaling. This thesis focuses on two fields related to NVM: the one is the ferroelectric tunnel junction (FTJ), which is a recent emerging NVM device. The other is the spin-Hall-assisted spin-transfer torque (STT), which is a recent proposed write approach for the magnetic tunnel junction (MTJ). Our objective is to develop the compact models for these two technologies and to explore their application in the non-volatile circuits through simulation.First, we investigated physical models describing the electrical behaviors of the FTJ such as tunneling resistance, dynamic ferroelectric switching and memristive response. The accuracy of these physical models is validated by a good agreement with experimental results. In order to develop an electrical model available for the circuit simulation, we programmed the aforementioned physical models with Verilog-A language and integrated them together. The developed electrical model can run on Cadence platform (a standard circuit simulation tool) and faithfully reproduce the behaviors of the FTJ.Then, using the developed FTJ model and STMicroelectronics CMOS design kit, we designed and simulated three types of circuits: i) FTJ-based random access memory (FTRAM), ii) two FTJ-based neuromorphic systems, one of which emulates spike-timing dependent plasticity (STDP) learning rule, the other implements supervised learning of logic functions, iii) FTJ-based Boolean logic block, by which NAND and NOR logic are demonstrated. The influences of the FTJ parameters on the performance of these circuits were analyzed based on simulation results.Finally, we focused on the reversal of the perpendicular magnetization driven by spin-Hall-assisted STT in a three-terminal MTJ. In this scheme, two write currents are applied to generate spin-Hall effect (SHE) and STT. Numerical simulation based on Landau-Lifshitz-Gilbert (LLG) equation demonstrates that the incubation delay of the STT can be eliminated by the strong SHE, resulting in ultrafast magnetization switching without the need to strengthen the STT. We applied this novel write approach to the design of the magnetic flip-flop and full-adder. Performance comparison between the spin-Hall-assisted and the conventional STT magnetic circuits were discussed based on simulation results and theoretical models.

The thesis focuses on designing and characterizing SiC 3.3 kV Diffused Metal-Oxide Semiconductor Field-Effect Transistor (DMOSFET)s with a Ron that is significantly lower than that of current commercial devices. The On-state resistance and breakdown voltage are then adjusted by adding a Super-Junction structure. Because of the pillar structure below the p-base area, the depletion will occur both vertically and horizontally and keeps the electric field distribution throughout the drift layer constant. The Super Junction Metal-Oxide Semiconductor Field-Effect Transistor (SJ MOSFET) has a good advantage compared to DMOSFETs. Due to its capacity to tolerate higher breakdown voltages and the fact that it does not require an increase in cell pitch to reach higher voltages, the Super-Junction approach is now the subject of effective research as compared to IGBTs and DMOSFETs. Silicon Carbide , a material with a wide bandgap that facilitates high temperature operation, high blocking voltage, high current flow and high switching frequency, is used to construct the device. In order to maintain a consistent electric field throughout the device, the concentration of the n and p pillars was chosen with a good charge balance between them. The outcomes of designing and simulating a DMOSFET, a Semi-SJ MOSFET, and a Full SJ MOSFET are compared in this research. The semi SJ device resulted in a Ron of 18.4 mΩcm2 and a Vb of 4.1 kV. The full SJ device reached a Ron of 12.4 mΩcm2 and a breakdown voltage of 4.2 kV. One optimized device was chosen from the semi SJ devices and used in several TCAD simulations, and the outcomes were evaluated based on the JFET width, pillar thickness, and charge imbalance between the p and n pillars. In this study, the device was also modelled for 6.5 kV and 10 kV SiC blocking voltage capabilities; the findings are also discussed. / Denna uppsats fokuserar på att utveckla och karakterisera 3.3 kV kiselkarbidbaserade DMOSFET-transistorer med betydligt lägre framspänningsfall jämfört med kommersiella halvledarkomponenter. Framspänningsfallet och spärrspänningen modifieras genom att använda en pelarliknande halvledarstruktur i drift regionen, dvs. en super-junction [SJ] struktur. På grund av pelarstrukturen under p-bas området, uppträder utarmningsområdet av laddningsbärare både vertikalt och horisontellt och ger ett konstant elektriskt fält genom drift-regionen. Super-junction transistorer har flera fördelar jämfört med komponenter i DMOSFET struktur. På grund av sin kapacitet att motstå högre spärrspänningar och genom att strukturen inte behöver en större enhetscellbredd för att nå högre spärrspänning, så är just nu super-junction strukturer i stort forskningsfokus jämfört med IGBT och DMOSFET komponenter. Kiselkarbid, ett material med ett brett bandgap, möjliggör komponenter för höga temperaturer, höga spärrspänningar, höga elektriska strömmar, samt höga växlingsfrekvenser, har använts för att bygga de undersökta komponenterna. För att generera ett konstant elektriskt fält över drift-regionen, så har dopningsnivåerna för n- och p- pelarna valts för att hålla en bra laddningsbalans mellan dem. Simuleringsresultaten av dessa komponentstrukturer, DMOSFET, halv-SJ MOSFET, och hel-SJ MOSFET är jämförda i detta projekt. Halv-SJ MOSFET transistorn resulterade i ett framspänningsfall på 18.4 mΩcm2 och når en spärrspänning av 4.1 kV. Hel-SJ MOSFET strukturen uppnår ett framspänningsfall på 12.4 mΩcm2 och med spärrspänning av 4.2 kV. En optimerad halv-SJ struktur valdes ut för att genomföra ytterligare TCAD simuleringsstudier om effekterna av JFET bredd, pelartjocklek, samt laddningsobalans mellan n- och p- pelarna. I den här studien simulerades även komponentstrukturer för 6.5 kV och 10 kV spärrspänningsklasser; även dessa resultat diskuteras i rapporten.

Doctor of Philosophy / Graduate Biochemistry Group / Dolores J. Takemoto / Eukaryotic cells possess a unique way to communicate with each other by passing metabolites and small molecules through protein pores that connect adjacent cells. Although there are many types and families of protein pores, connexins comprise a unique family. Six connexin monomers assemble into a hemichannel, which is transported to the cell membrane. An opposing cell membrane containing compatible connexin hemichannels is located and connected, forming an intercellular dodecameric protein complex. This results in a protein channel that connects two separate cytoplasmic compartments to each other. This type of channel is known as a gap junction. Connexin expression and function is commonly tissue specific. Of the 21 known human connexins, less than half are currently well characterized. Three connexins are expressed in the lens, connexin 43 (Cx43), 46 (Cx46), and 50 (Cx50). Of these three, Cx46 and Cx50 both have major functions in the mature lens. Cx46 functions as a major gap junction channel, which maintains mature lens homeostasis, while Cx50 possesses growth control properties in the lens. Cx46 expression is modulated in breast and bone tumors, and during ischemia. It is hypothesized that Cx46 provides resistance to hypoxia mediated cell death by prolonging survival. In this study, Cx46 expression was detected in human Y79 retinoblastoma cells. Decreasing the expression of Cx46 in nude mice carrying Y79 xenografts slowed early stage tumor growth. Y79 cells in culture survive for over 72 hours in 1% oxygen in vitro. C46 was upregulated in cultured lens cells when grown under hypoxia. Human lens epithelial cells, rabbit N/N1003A lens cells, and Y79 cells proliferated in 1% oxygen until Cx46 expression was depleted by use of siRNA. Protection from hypoxia-induced cell death was provided by transfection with the C-terminus of Cx46. We further determined that the promoter activity of Cx46 was increased in 1% oxygen. These results indicate that Cx46 would increase in response to hypoxia and suggest a role for Cx46 in protection from hypoxia. The studies demonstrate a novel function for Cx46 in cell survival during hypoxia.

Autoimmunity is a failure to tolerate circulating or cell surface expressed self antigens,leading to activation of the immune system and attack of self tissues. Muscle-specific kinase (MuSK) myasthenia gravis (MG) is a disease caused by antibodies to MuSK and hallmarked by fatigable muscle weakness. MuSK is a tyrosine kinase that interacts with low-density lipoprotein receptor-related protein 4 (LRP4), resulting in maintenance of the high density of acetylcholine receptors (AChRs) at the neuromuscular junction; this high density is essential for efficient transmission of signals from nerve to muscle, and MuSK antibodies impair this transmission. MuSK antibodies are predominantly IgG4, a subclass that does not induce immunological damage. Thus how these antibodies cause neuromuscular junction dysfunction is not clear. Potential mechanisms of the MuSK antibodies were explored in in vitro experiments. Plasmas from fourteen MuSK-MG patients were studied. IgG antibodies and IgG subclass profiles were measured with flow cytometry. Total IgG, Fabs, IgG4 and IgG1-3 subclass antibodies were prepared and purified; these were used to investigate the effects on MuSK surface expression, binding of LRP4 to MuSK, and agrin-LRP4-MuSK-induced AChR clustering in C2C12 mouse myotubes. No evidence for MuSK endocytosis by MuSK IgG, IgG1-3 or IgG4 antibodies was found. The predominant IgG4 subclass, and the monovalent IgG Fabs, blocked binding between LRP4 and MuSK but both IgG4 and IgG1-3 subclass antibodies were equally able to disperse pre-formed and newly-induced AChR clusters in C2C12 myotubes. The block of LRP4-MuSK interaction by IgG4 antibodies is likely to be a major pathogenic mechanism in MuSK-MG, which may lead to disrupted signal transduction, reduced AChR aggregation and neuromuscular transmission failure at the neuromuscular junction. In addition, MuSK IgG1-3, until now described as nonpathogenic, may also contribute to the reduced AChR density and neuromuscular dysfunction in MuSK-MG. These results provide new evidence concerning the pathogenic antibodies and their mechanisms in MuSK-MG.

A growing body of evidence shows that presynaptic nerve terminals throughout the nervous system are vulnerable to a range of traumatic, toxic and disease-related neurodegenerative stimuli. The aim of this study was to further characterise this vulnerability by examining the response of mouse α-motor nerve terminals at the neuromuscular junction (NMJ) to hypoxia-reperfusion injury. To address this aim, a novel model system was generated in which ex vivo skeletal muscle preparations could be maintained in an hypoxic environment, at an O2 concentration below in vivo normoxic values (<0.25% O2), for 2hr followed by 2hr reperfusion (2H-2R). Using this model system combined with quantitative assessment of immunohistological preparations as well as some ultrastructural observations, I present evidence to show that α-motor nerve terminals are rapidly and selectively vulnerable to hypoxia-reperfusion injury with no apparent perturbations to postsynaptic endplates or muscle fibres. I show that the severity of α-motor nerve terminal pathology is age and muscle type/location dependent: in 8-12wk old mice, nerve terminals in fast-twitch lumbrical muscles are more vulnerable than predominantly slow-twitch transversus abdominis and triangularis sterni. In 5-6 week old mice however, there is an age dependent increase in vulnerability of α-motor nerve terminals from the predominantly slow-twitch muscles while the fast-twitch lumbricals remained unaffected by age. The functional, morphological and ultrastructural pathology observed in α-motor nerve terminals following 2H-2R is indicative of selective and ongoing nerve terminal disassembly but, occurs via a mechanism distinct from Wallerian degeneration, as the neuroprotective slow Wallerian degeneration (Wlds) gene did not protect nerve terminals from these pathological changes. I also provide provisional evidence to show that 1A/II muscle spindle afferents and γ-motor nerve terminals are more resistant to hypoxia-reperfusion injury compared with α-motor nerve terminals. In addition to this, I also report preliminary finding that indicate that the oxygen storing protein, neuroglobin, maybe expressed at the mouse NMJ and report the difficulties of using mice that express yellow fluorescent protein (YFP) in their neurons for repeat/live imaging studies. Overall, these data show that the model of hypoxia-reperfusion injury developed in this study is robust and repeatable, that it induces rapid, quantitative changes in α-motor nerve terminals and that it can be used to further examine the mechanisms regulating nerve terminal vulnerability in response to hypoxia-reperfusion injuries. These findings have clinical implications for the use of surgical tourniquets and in the aetiology of many neurodegenerative diseases and neuropathic sequelae where mechanisms relating to hypoxia and hypoxia-reperfusion injury have been implicated.

As the size of modern transistors is continuously scaled down, challenges rise in almost every component of a silicon device. Formation of ultra shallow junction (USJ) with high activation level is particularly important for suppressing short channel effects. However, the formation of low resistance USJ is made difficult by dopant Transient Enhanced Diffusion (TED) and clustering-induced deactivation. In this work, we proposed a novel point defect engineering solution to address the arsenic TED challenge. By overlapping arsenic doped region with silicon interstitials and vacancies, we observed enhanced and retarded arsenic diffusion upon anneal, respectively. We explain this phenomenon by arsenic interstitial diffusion mechanism. In addition, we implemented this interstitial-based mechanism into a kinetic Monte Carlo (kMC) simulator. The key role of interstitials in arsenic TED is confirmed. And we demonstrated that the simulator has an improved prediction capability for arsenic TED and deactivation. As a long time unsolved process challenge, arsenic segregation at SiO₂/Si interface was investigated using density functional theory (DFT) calculation. The segregation-induced arsenic dose loss not only increases resistance but also may induce interface states. We identified three arsenic complex configurations, [chemical formula] , [chemical formula] and [chemical formula], which are highly stabilized at SiO₂/Si interface due to the unique local bonding environments. Therefore, they could contribute to arsenic segregation as both initial stage precursors and dopant trapping sites. Our calculation indicates that arsenic atoms trapped in such interface complexes are electrically inactive. Finally, the formation and evolution dynamics of these interface arsenic-defect complexes are discussed and kMC models are constructed to describe the segregation effects. A potential problem for the p-type USJ formation is the recently found transient fast boron diffusion during solid phase epitaxial regrowth process. Using DFT calculations and molecular dynamics simulation, we identified an interstitial-based mechanism of fast boron diffusion in amorphous silicon. The activation energy for this diffusion mechanism is in good agreement with experimental results. In addition, this mechanism is consistent with the experimentally reported transient and concentration-dependent features of boron diffusion in amorphous silicon. / text

No description available.

In this doctoral thesis the two dimensional material graphene has been studied in depth with particular respect to Zener tunnelling devices. From the hexagonal structure the Hamiltonian at a Dirac point was derived with the option of including an energy gap. This Hamiltonian was then used to obtain the tunnelling properties of various graphene nano-devices; the devices studied include Zener tunnelling potential barriers such as single and double graphene potential steps. A form of the Landauer formalism was obtained for graphene devices. Combined with the scattering properties of potential barriers the current and conductance was found for a wide range of graphene nano-devices. These results were then compared to recently obtained experimental results for graphene nano-ribbons, showing many similarities between nano-ribbons and infinite sheet graphene. The methods studied were then applied to materials which have been shown to possess three dimensional Dirac cones known as topological insulators. In the case of Cd3As2 the Dirac cone is asymmetrical with respect to the z-direction, the effect of this asymmetry has been discussed with comparison to the symmetrical case.

L'acide rétinoïque (AR) régule la myogénèse embryonnaire. Dans le cadre de ce projet de thèse, nous avons d'une part utilisé l'AR pour moduler la myogénèse embryonnaire, dans la perspective d'étudier les conséquences de cette modulation sur le potentiel ultérieur de croissance et identifier les mécanismes moléculaires mobilisés.D'autre part, nous avons étudié la fonction de deux gènes régulés par l'AR et susceptibles de participer au contrôle de la myogénèse embryonnaire.La première partie du travail a été réalisée sur les modèles truite et poisson-zèbre. Nous avons montré que chez la truite comme chez le poisson zèbre, une incubation dans l'AR entrainait une activation de l'expression de Fgf8et de la différenciation des fibres musculaires rapides. Toutefois, chez la truite, nous n'avons pas pu mettre en évidence de régulation des MRF, indiquant qu'une autre voie est utilisée pour activer la myogénèse chez cette espèce.Dans la seconde partie de ce travail, la fonction de deux gènes régulés par l'AR et exprimés dans le mésoderme a été étudiée chez le poisson-zèbre. Le gène vertnin est exprimé essentiellement dans le tailbud. Quand il est inactivé par injection d'un oligo nucléotide morpholino antisens, on observe une altération de la formation des somites (mais pas de modification apparente du processus de segmentation) et une altération de l'intégrité des fibres lentes. Les fibres lentes sont en effet irrégulièrement espacées et les espaces au niveau des myoseptes verticaux peuvent être anormalement larges et les jonctions myotendineuses mal formées. Le gène arrestine β2aest exprimé dans les somites néo-formés puis également dans le mésoderme présomitique et le tailbud. Son inactivation par injection d'OM antisens entraine l'apparition du phénotype U-type et une altération de la morphologie des fibres lentes avec des fibres qui se détachent des jonctions myotendineuses. / Retinoic acid (RA) regulates embryonic myogenesis. During this thesis project, we first used RA to modulate embryonic myogenesis in order to study consequences of this modulation on the future potential for growth and to identify the underlying molecular mechanisms. Second part deals with the characterisation of the function of two genes regulated by the RA which may be involved in the control of embryonic myogenesis.The first part of the work was performed on the trout and zebrafish models. We have shown that in trout as in zebrafish, incubation in RA produced an activation of Fgf8 expression and differentiation of fast muscle fibers.However in trout, we did not observed regulation of MRF expression indicating that an alternative pathway isused to activate myogenesis in this species.In the second part of this work, the function of two genes regulated by the RA and expressed in the mesodermwas studied in zebrafish. The vertnin gene is expressed primarily in the tailbud. When it is inactivated by injection of antisense morpholino oligonucleotide, there is an alteration in the somites morphogenesis (but no apparent change in the process of segmentation) and impairment of the integrity of the slow muscle fibers. Slowfibers are indeed irregularly spaced and the vertical myosepta can be abnormally large. In addition myotendinous junctions display some abnormal branches. The arrestin β 2a gene is expressed in last formed somites and then also in the presomitic mesoderm and the tailbud. Its inactivation by injection of antisense MO leads to the appearance of the U-type phenotype and alteration of the slow muscle fibers morphology which detach frommyotendinous junctions