The first part of the thesis describes a systematic function analysis that identified in vitro E2 partners for ten different HECT E3 ligase proteins. Using mass spectrometry, the linkage composition for the resulting autoubiquitylation products of a number of functional E2-HECT pairs was determined. HECT domains from different subfamilies catalyze the formation of very different types of Ub chains, largely independent of the E2 in the reaction. The second part of the thesis describes the characterization of the RAD6-interactome. Using affinity purification coupled with mass spectrometry, I identified a novel RAD6-interacting E3 ligase, KCMF1, which binds to a different surface on RAD6 than the other RAD6-associated E3 ligases. KCMF1 also recruits additional proteins to RAD6, and this new complex points to novel RAD6 functions. Interestingly, the RAD6A R11Q mutant polypeptide, found in X-linked mental retardation patients specifically loses the interaction with KCMF1, but not with other RAD6-associated E3 ligases.

An innovative mathematical architecture for modelling neuronal electrical activity is presented, called the cognitive rhythm generator (CRG), wherein the proposed architecture is a hybrid model comprised of three interconnected stages, namely: (1) a bank of neuronal modes; (2) a ring device (limit-cycle oscillator); and (3) a static output nonlinearity (mapper). Coupled CRG networks are employed to emulate and elucidate the dynamics of biological neural networks, including the recurrent networks in the hippocampus. Several species of ring devices are described and investigated, including the clock, labile clock, hourglass and multistable ring systems, and their applications to neuronal modelling explored. Complexity measures such as the maximum Lyapunov exponent, correlation dimension and detrended fluctuation analysis are applied to compare model and biological records and validate the CRG methodology. The basis of neural coding is also examined in mathematical detail, with particular regard to its description by Volterra-Wiener kernel formalism, from which the neuronal modes are derived. Applications to theta-gamma coding are discussed. Further on in the thesis, a CRG epileptiform network model of spontaneous seizure-like events (SLEs) is developed and used as a platform to test neuromodulation approaches for seizure abatement. (Neuromodulation mentioned here refers to methods involving electrical stimulation of neural tissue for therapeutic benefit). Spontaneous SLE transitions in the epileptiform network are shown to be related to the mechanism of intermittency, as determined by examining the state space dynamics of the model. The onset of SLEs is associated with increased network excitability and decreased stability, consistent with experimental results from the low-magnesium/high-potassium in vitro model of epilepsy. Lastly, a novel strategy for therapeutic neuromodulation is presented wherein a coupled CRG network (called the “therapeutic network”) is interfaced with the epileptiform network model, forming a closed loop for responsive, biomimetic neuromodulation of the epileptiform network. Relevance to clinical applications and future work is discussed.

The dynamic behaviour of high-rise buildings has become a critical design consideration as buildings are built taller and more slender. Large wind vibrations cause an increase in the lateral wind loads, but more importantly, they can be perceived by building occupants creating levels of discomfort ranging from minor annoyance to severe motion sickness. The current techniques to address these issues include stiffening the lateral load resisting system, reducing the number of stories, or incorporating a vibration absorber at the top of the building. All of which have consequences on the overall project cost. The dynamic response of high-rise buildings is highly dependent on damping. Full-scale measurements of high-rise buildings have shown that the inherent damping decreases with height and recent in-situ measurements have shown that the majority of buildings over 250 meters have levels of damping less than 1% of critical. Studies have shown that small increases in the inherent damping can lead to vast improvement in dynamic response. A new damping system, the viscoelastic (VE) Fork Configuration Damper (FCD), has been developed at the University of Toronto to address these design challenges. The proposed FCDs are introduced in lieu of coupling beams in reinforced concrete (RC) coupled wall buildings and take advantage of the large shear deformations at these locations when the building is subjected to lateral loads. An experimental study was conducted on 5 small-scale VE dampers to characterize the VE material behaviour and 6 full-scale FCD samples in an RC coupled wall configuration (one designed for areas where low to moderate ductility is required and one with built-in ductile structural “fuse” for areas where high ductility is required). The VE material tests exhibited stable hysteretic behaviour under expected high-rise loading conditions and the full-scale tests validated the overall system performance based on the kinematic behaviour of coupled walls, wall anchorage and VE material behaviour. Analytical models were developed that capture the VE material behaviour and the FCD system performance well. An 85-storey high-rise building was studied analytically to validate the design approach and to highlight the improvements in building response resulting from the addition of FCDs.

The induction of synaptic plasticity at CA1 synapses requires NMDAR activation. Modulation of NMDAR function by various GPCRs can shift the thresholds for LTP and LTD induction and contribute to metaplasticity. Here we showed that the activity of GluN2A- and GluN2B-containing NMDARs is differentially regulated by Gαi/o-coupled, Gαq- and Gαs-coupled receptors. Furthermore, enhancing the relative function of GluN2A-to-GluNB NMDAR activity by GPCRs can alter the balance of LTP and LTD induction and contribute to metaplasticity. In CA1 neurons, activation of the Gαs-coupled D1/D5R selectively recruited Fyn kinase and enhanced GluN2B-mediated NMDAR currents. Biochemical experiments confirmed that D1/D5R stimulation activates Fyn kinase and enhances the tyrosine phosphorylation of GluN2B subunits. In contrast, activation of the Gαq-coupled PAC1R selectively recruited Src kinase to enhance the function of GluN2A-containing NMDARs. Enhancing the functional ratio of GluN2A-to-GluN2B subunits by PAC1R activation lowered the threshold for LTP induction whereas enhancing the functional ratio of GluN2B-to-GluN2A subunits by D1/D5R activation increased the threshold for LTP induction. Unexpectedly, activation of the Gαi/o-coupled mGluR2/3 enhanced NMDAR-mediated function via a previously unidentified mechanism. Inhibition of the cAMP-PKA pathway via mGluR2/3 activation resulted in activation of Src via decreased phosphorylation of its C-terminal Tyr527 by Csk. Stimulation of mGluR2/3 selectively potentiated the function of GluN2A-containing NMDARs but whether it shifted the modification threshold θm to the left requires further investigation.

Temporal pulse shaping based on integrated Bragg gratings is investigated in this work to achieve arbitrary output waveforms. The grating structure is simulated based on the sidewall-etching geometry in an AlGaAs platform. The inverse scattering employin the Gel'fan-Levithan-Marchenko theorem and the layer peeling method provides a tool to determine grating structures from a desired spectral reflection response. Simulations of pulse shaping considered flat-top and triangular pulses as well as one-to-one and one-to-many pulse shaping. The suggested grating profiles revealed a compromise between performance and grating length. The integrated grating, a few hundred microns in length, could generate flat-top pulses with pulse durations as short as 500 fs with rise/fall times of 200 fs; the results are comparable to previous work in free-space optics and fiber optics. The theories and the devised algorithms could serve as a design station for advanced grating devices for, but not restricted to, optical pulse shaping.

The first part of the thesis describes a systematic function analysis that identified in vitro E2 partners for ten different HECT E3 ligase proteins. Using mass spectrometry, the linkage composition for the resulting autoubiquitylation products of a number of functional E2-HECT pairs was determined. HECT domains from different subfamilies catalyze the formation of very different types of Ub chains, largely independent of the E2 in the reaction. The second part of the thesis describes the characterization of the RAD6-interactome. Using affinity purification coupled with mass spectrometry, I identified a novel RAD6-interacting E3 ligase, KCMF1, which binds to a different surface on RAD6 than the other RAD6-associated E3 ligases. KCMF1 also recruits additional proteins to RAD6, and this new complex points to novel RAD6 functions. Interestingly, the RAD6A R11Q mutant polypeptide, found in X-linked mental retardation patients specifically loses the interaction with KCMF1, but not with other RAD6-associated E3 ligases.

科学研究費補助金 研究種目:基盤研究(C) 課題番号:11680482 研究代表者:庄司 多津男 研究期間:1999-2001年度

THz and mm-wave technology has become increasingly significant in a very diverse range of applications such as spectroscopy, imaging, and communication as a consequence of a plethora of significant advances in this field. However to achieve a mass production of THz systems, all the commercial aspects should be considered. The main concerns are attributed to the robustness, compactness, and a low cost device. In this regard, research efforts should be focused on the elimination of obstacles standing in the way of commercializing the THz technology. To this end, in this study, low cost fabrication technologies for various parts of mm-wave/THz systems are investigated and explored to realize compact, integrated, and rugged components. This task is divided into four phases. In the first phase, a robust fiber-based beam delivery configuration is deployed instead of the free beam optics which is essential to operate the low cost THz photomixers and photoconductive antennas. The compensation of different effects on propagation of the optical pulse along the optical fiber is achieved through all-fiber system to eliminate any bulky and unstable optical components from the system. THz measurements on fiber-coupled systems exhibit the same performance and even better compared to the free beam system. In the next phase, the generated THz wave is coupled to a rectangular dielectric waveguide through design of a novel transition with low insertion loss. The structure dimensions are reported for various range of frequencies up to 650GHz with insertion loss less than 1dB. The structure is fabricated through a standard recipe. In third phase, as consequence of the advent of high performance active device at mm-wave and THz frequency, a transition is proposed for coupling the electromagnetic wave to the active devices with CPW ports. Different approaches are devised for different frequencies as at higher frequencies any kind of metallic structure can introduce a considerable amount of loss to the system. The optimized structures show minimum insertion loss as low as 1dB and operate over 10% bandwidth. The various configurations are fabricated for lower frequencies to verify the transition performance. The last phase focuses on the design, optimization, fabrication and measurements of a new dielectric side-grating antenna for frequency scanning applications. The radiation mechanism is extensively studied using two different commercial full-wave solvers as well as the measured data from the fabricated samples. The optimized antenna achieves a radiation efficiency of 90% and a gain of 18dB. The measured return loss and radiation pattern show a good agreement with the simulation results.

On this thesis work, design and construction of an up to date complete RF excitation system was intended. This excitation system is mainly based on highly efficient switching power generators and proper coupling of the power to the object plasma. This new excitation system design should answer the demands of today&#039 / s progressed CO2 lasers on various power ranges. Though it could be used by a large variety of applications including RF plasma and RF heating, on the first occasion in order to define design considerations, this system is to be exploited by RF excited fast flow and RF excited slab CO2 laser constructions.

Wideband and dual band stacked microstrip patch antennas are investigated for the new wideband and dual band applications in the area of telecommunications. In this thesis, aperture-coupled stacked patch antennas are used to increase the bandwidth of the microstrip patch antenna. By this technique, antennas with 51% bandwidth at 6.1 GHz and 43% bandwidth at 8 GHz satisfying S11&lt / -15 dB are designed, manufactured and measured. A dual-band aperture coupled stacked microstrip patch antenna operating at 1.8 GHz with 3.8% bandwidth and at 2.4 GHz with 1.6% bandwidth is designed, produced and measured for mobile phone and WLAN applications. In addition, an aperture coupled stacked microstrip patch antenna which operates at PCS frequencies in 1.7-1.95 GHz band is designed. Dual and circularly polarized stacked aperture coupled microstrip patch antennas are also investigated. A triple band dual polarized aperture coupled stacked microstrip patch antenna is designed to operate at 900 MHz, at 1.21 GHZ and at 2.15 GHz. Mutual coupling between aperture coupled stacked microstrip patch antennas are examined and compared with the coupling of aperture coupled microstrip patch antennas