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An analytical threshold criterion in approximation has been developed for the basic phase-locked loop demodulator utilizing quasi-linearization technique. The analysis is based on assumptions that the loop is excited by an input FM signal and additive white Gaussian noise. This paper defines the threshold criterion by the characteristics of maximum demodulating sensitivity limit. Finally, the effects of the modulation indeces and loop parameters on the threshold characteristics are discussed from a theoretical and practical point of view. / Master of Science

Yes / R-loops are by-products of transcription that must be tightly regulated to maintain genomic stability and gene expression. Here, we describe a mechanism for the regulation of the Rloop- specific helicase, senataxin (SETX), and identify the ubiquitin specific peptidase 11 (USP11) as an R-loop regulator. USP11 de-ubiquitinates SETX and its depletion increases SETX K48-ubiquitination and protein turnover. Loss of USP11 decreases SETX steady-state levels and reduces R-loop dissolution. Ageing of USP11 knockout cells restores SETX levels via compensatory transcriptional downregulation of the E3 ubiquitin ligase, KEAP1. Loss of USP11 reduces SETX enrichment at KEAP1 promoter, leading to R-loop accumulation, enrichment of the endonuclease XPF and formation of double-strand breaks. Overexpression of KEAP1 increases SETX K48-ubiquitination, promotes its degradation and R-loop accumulation. These data define a ubiquitination-dependent mechanism for SETX regulation, which is controlled by the opposing activities of USP11 and KEAP1 with broad applications for cancer and neurological disease. / Wellcome Trust Investigator Award, Lister Institute of Preventative Medicine Fellowship

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Ataxia-telangiectasia mutated gene product (ATM) is a 350 kDa Serine/Threonine kinase belonging to the family of Phosphatidylinositol-3 kinase like kinases. ATM functions as a key element in DNA Damage Response (DDR), a mechanism that maintains genomic integrity within the cells. ATM is activated after double stranded DNA damage and initiates signalling cascades that determine the process of decision-making of cell fate and involves the participation of multiple proteins. This vital protein acts first by sensing double stranded DNA breaks and second by transducing the signal and activating other downstream proteins of the repair pathway via its kinase function. This provides an important link between signals generated after DNA damage, the cell cycle pathway and apoptotic machinery. This function is crucial for mammalian cells which are constantly challenged by genotoxic agents from a variety of sources and therefore require a robust sensing and repair mechanism to maintain cell vitality. Cells lacking ATM are hypersensitive to cytotoxic insults, particularly genotoxic stress, induced through radiation or radiomimetic drugs. This thesis describes the discovery and characterisation of novel autoregulatory feedback loops of ATM kinase in human cells. Firstly, I have discovered that inhibition of ATM kinase activity causes induction of ATM protein expression followed by time dependent oscillations. This novel autoregulatory mechanism was demonstrated in cell cycle independent manner and both in the absence and presence of DNA damage. ATM promoter assay revealed that this autoregulation was governed at the transcriptional level. Furthermore, this autoregulatory induction of ATM was also accompanied by a transient upregulation of P53, pATR and E2F1 levels. Elucidation of the underlying trafficking mechanism of ATM during such autoregulation and in DDR also revealed a novel ATM sub-cellular trafficking mechanism which was dependent on its own kinase activity. This trafficking mechanism involved DNA damage induced Golgi to nuclear transport of phosphorylated ATM S-1981 to elicit DDR. This was found to be a conserved pathway required during the initiation of DDR and was demonstrated in multiple cell lines. Further studies into the sub-cellular transport machinery revealed the involvement of β-COPI coatomer protein in this mechanism of ATM trafficking, which was found to be autoregulated by ATM kinase, and required 387-388 ATM di-Lysine motif. The discovery of these functionally important autoregulatory mechanisms of ATM were further utilised to develop Luciferase reporter based biosensor of DNA damage and single cell fluorescence based ATM inhibition assay to screen for ATM inhibitors. Finally, following the discovery and characterisation of these functional spatio-temporal autoregulations of ATM, quantitative estimations of the kinetics of signalling cascades initiated by it during DDR and its overall outcome on cellular fate were determined to study ATM pathway systematically for employing a quantitative systems biology approach. These novel findings have immensely increased our understanding of ATM regulation and function. Elucidation of the mechanisms of novel autoregulations of ATM provide new dimensions through which DDR pathway could be manipulated, and as such could be utilised for achieving targeted cellular sensitivity in therapeutic intervention of cancer.

International Telemetering Conference Proceedings / October 20-23, 2003 / Riviera Hotel and Convention Center, Las Vegas, Nevada / Phase-locked loop (PLL) frequency synthesizers used for high-speed data transmission must rapidly hop and lock to new frequencies. The fundamental problem is that the settling time depends inversely on the loop bandwidth, and increasing the bandwidth causes unwanted noise interference and stability problems for the circuit. We demonstrate the feasibility of replacing the analog integrator in the PLL with a digital integrator. This circuit has advantages of increased hopping speed, ability to compensate for temperature drift and system stability. PLL lock-in was demonstrated in a prototype circuit designed and built with both discrete components and with a programmable logic device.

International Telemetering Conference Proceedings / October 25-28, 1999 / Riviera Hotel and Convention Center, Las Vegas, Nevada / The design, implementation, and performance of a digital modem employing Gaussian minimum shift keying (GMSK) is described. The GMSK modem is implemented in field programmable gate array (FPGA) chips, and a laboratory test setup was developed to validate its performance for a signal BT value of 1/5. The measured spectrum of the GMSK modem and its bit error rate (BER) performance, which are found in very close agreement with those of theory and simulation, are presented in this paper.

International Telemetering Conference Proceedings / October 26-29, 1998 / Town & Country Resort Hotel and Convention Center, San Diego, California / This paper analyzes the performance of a modified correlation, or delay-locked loop (DLL). These devices typically cross-correlate the received signal with a differentiated version of the originally transmitted signal. This paper describes some interesting properties the loop assumes when the differentiator is replaced by a Hilbert transform. The loop will still track the timing offset of the code, but it will also be able to acquire the signal when the initial offset is greater than one chip time. The new loop may also be superior to traditional DLL in low SNR environments, since it is much less likely to lose lock. Since the new loop is highly non-linear, it is studied through the use of computer simulations.

Data conversion is the crucial interface between the real world and digital processing systems. Analogue-to-digital converters and digital-to-analogue converters are two key conversion devices and used as the interface. Up to now, the conventional ADCs based on Nyquist sampling theorem are facing a critical challenge: the resolution and the sampling rate must be radically increased when some applications such as radar detection and ultra-wideband communication emerge. The offset of comparators and the setup time of sample-and-hold circuits, however, limit the resulution and clock rate of ADCs. Alternatively, in some applications such as speech, temperature sensor, etc. signals remain possibly unchanged for prolonged periods with brief bursts of significant activity. If trational ADCs are employed in such circumstances a higher bandwidth is required for transmitting the converted samples. On the other hand, sampling signals with an extremely high clock rate are also required for converting the signals with the feature of sparsity in time domain. The level-crossing sampling scheme (LCSS) is one of the data conversions suitable for converting signals with the sparsity feature and brief bursts of signigicant activity. due to the traditional LCSS with a fixed clock rate being limited in applications a novel irregular data conversion scheme called analogue-to-information system (AIS) is proposed in this thesis. The AIS is typically based upon LCSS, but an adjustable clock generator and a real time data compression scheme are applied to it. As the system-level simulations results of AIS show it can be seen that a data transmission saving rate nearly 30% is achieved for different signals. PLLs with fast pull-in and locking schemes are very important when they are applied in TDMA systems and fequency hopping wireless systems. So a novel triple path nonlinear phase frequency detector (TPNPFD) is also proposed in this thesis. Compared to otherPFDs, the pll-in and locking time in TPNPFD is much shorter. A proper transmission data format can make the recreation of the skipped samples and the reconstruction of the original signal more efficient, i.e. they can be achieved in a minimum number of the received data without increasing much more hardware complexity. So the preliminary data format used for transmitting the converted data from AIS is also given in the final chapter of this thesis for future works.