Hardware reduction in digital delta-sigma modulators via error masking - part I: MASH DDSM

Two classes of techniques have been developed to whiten the quantization noise in digital delta-sigma modulators (DDSMs): deterministic and stochastic. In this two-part paper, a design methodology for reduced-complexity DDSMs is presented. The design methodology is based on error masking. Rules for selecting the word lengths of the stages in multistage architectures are presented. We show that the hardware requirement can be reduced by up to 20% compared with a conventional design, without sacrificing performance. Simulation and experimental results confirm theoretical predictions. Part I addresses MultistAge noise SHaping (MASH) DDSMs; Part II focuses on single-quantizer DDSMs..

The analysis of Bcr-Abl—Nox signalling in chronic myeloid leukaemia

Chronic Myeloid Leukaemia (CML) is a myeloproliferative disorder characterised by increased proliferation of haematopoietic stem cells. CML results following generation of the chimeric protein Bcr-Abl, a constitutively active tyrosine kinase which induces oncogenesis in part by promoting increased cell survival and proliferation. Since the development of Bcr-Abl-specific tyrosine kinase inhibitors (TKIs) there has been a substantial improvement in the clinical treatment of CML. Unfortunately, residual disease and the development of TKI resistance has become an ever growing concern, resulting in the need for a greater understanding of the disease in order to develop new treatment strategies. Interestingly, constitutive expression of the Bcr-Abl in CML is known to produce elevated levels of Reactive Oxygen Species (ROS) which are known to influence a variety of cellular processes. Previous studies have demonstrated that NADPH oxidase (Nox) activity contributes to intracellular-ROS levels in Bcr-Abl-positive cells, enhancing survival signalling. The objective of this study was to elucidate how Nox protein activity was influenced downstream of Bcr-Abl while examining how Nox-derived ROS influenced CML disease phenotype to identify the potential in targeting these proteins to improve CML treatment. These studies demonstrated that inhibition of Bcr-Abl signalling, led to a significant reduction in ROS levels which was concurrent with the GSK-3dependent, post-translational down-regulation of the small membrane-bound protein p22phox, an essential component of the Nox complex. siRNA knockdown of p22phox identified it to have a significant role in cellular proliferation and cell viability, demonstrating the importance of Nox protein activity in CML disease phenotype. Furthermore, removal of p22phox was demonstrated to make cells significantly more susceptible to Bcr-Abl-specific TKI treatment, while pharmacological silencing of Nox activity in combination with TKIs was demonstrated to produce substantial, synergistic increases in cell death through augmentation of apoptosis, demonstrating the therapeutic potential of targeting Nox proteins in combination with Bcr-Abl inhibition.

Anticipatory vigilance: A classic grounded theory of risk reduction and management in the perioperative setting

This research aimed to investigate the main concern facing nurses in minimising risk within the perioperative setting and to generate an explanatory substantive theory of how they resolve this through anticipatory vigilance. In the context of the perioperative setting, nurses encounter challenges in minimising risks for their patients on a continuous basis. Current explanations of minimising risk in the perioperative setting offers insights into how perioperative nurses undertake their work. Currently research in minimising risk is broadly related to dealing with errors as opposed to preventing them. To date, little is known about how perioperative nurses practice and maintain safety. This study was guided by the principles of classic grounded theory as described by Glaser (1978, 1998, 2001). Data was collected through individual unstructured interviews with thirty seven perioperative nurses (with varying lengths of experiences of working in the area) and thirty three hours of non-participant observation within eight different perioperative settings in the Republic of Ireland. Data was simultaneously collected and analysed. The theory of anticipatory vigilance emerged as the pattern of behaviour through which nurse’s deal with their main concern of minimising risk in a high risk setting. Anticipatory vigilance is enacted through orchestrating, routinising and momentary adapting within a spirit of trusting relations within the substantive area of the perioperative setting. This theory of offers an explanation on how nurses resolve their main concern of minimising risk within the perioperative setting. The theory of anticipatory vigilance will be useful to nurses in providing a comprehensive framework of explanation and understanding on how nurses deal with minimising risk in the perioperative setting. The theory links perioperative nursing, risk and vigilance together. Clinical improvements through understanding and awareness of the theory of anticipatory vigilance will result in an improved quality environment, leading to safe patient outcomes.

Redox biology of myeloid leukaemias

Internal tandem duplication of FMS-like receptor tyrosine kinase (FLT3-ITD) has been associated with an aggressive AML phenotype. FLT3-ITD expressing cell lines have been shown to generate increased levels of reactive oxygen species (ROS) and DNA double strand breaks (dsbs). However, the molecular basis of how FLT3-ITD-driven ROS leads to the aggressive form of AML is not clearly understood. Herein, we observe that the majority of H2O2 in FLT3-ITD-expressing MV4-11 cells colocalises to the endoplasmic reticulum (ER). Furthermore, ER localisation of ROS in MV4-11 cells corresponds to the localisation of p22phox, a small membrane-bound subunit of NOX complex. Furthermore, we show that 32D cells, a myeloblast-like cell line transfected with FLT3-ITD, possess higher steady protein levels of p22phox than their wild type FLT3 (FLT3-WT)-expressing counterparts. Moreover, the inhibition of FLT3-ITD, using various FLT3 tyrosine kinase inhibitors, uniformly results in a posttranslational downregulation of p22phox. We also show that depletion of NOX2 and NOX4 and p22phox, but not NOX1 proteins causes a reduction in endogenous H2O2 levels. We show that genomic instability induced by FLT3-ITD leads to an increase in nuclear levels of H2O2. The presence of H2O2 in the nucleus is largely reduced by inhibition of FLT3-ITD or NOX. Furthermore, similar results are also observed following siRNA knockdowns of p22phox or NOX4. We demonstrate that 32D cells transfected with FLT3-ITD have a higher level of DNA damage than 32D cells transfected with FLT3-WT. Additionally, inhibition of FLT3-ITD, p22phox and NOX knockdowns decrease the number of DNA dsbs. In summary, this study presents a novel mechanism of genomic instability generation in FLT3-ITD-expressing AML cells, whereby FLT3-ITD activates NOX complexes by stabilising p22phox. This in turn leads to elevated generation of ROS and DNA damage in these cells.

Oxidation-reduction potential and its influence on Cheddar cheese quality

Oxidation-reduction (redox) potential is a fundamental physicochemical parameter that affects the growth of microorganisms in dairy products and contributes to a balanced flavour development in cheese. Even though redox potential has an important impact on the quality of dairy products, it is not usually monitored in dairy industry. The aims of this thesis were to develop practical methods for measuring redox potential in cheese, to provide detailed information on changes in redox potential during the cheesemaking and cheese ripening and how this parameter is influenced by starter systems and to understand the relationship between redox potential and cheese quality. Methods were developed for monitoring redox potential during cheesemaking and early in ripening. Changes in redox potential during laboratory scale manufacture of Cheddar, Gouda, Emmental, and Camembert cheeses were determined. Distinctive kinetics of reduction in redox potential during cheesemakings were observed, and depended on the cheese technology and starter culture utilised. Redox potential was also measured early in ripening by embedding electrodes into Cheddar cheese at moulding together with the salted curd pieces. Using this approach it was possible to monitor redox potential during the pressing stage. The redox potential of Emmental cheese was also monitored during ripening. Moreover, since bacterial growth drives the reduction in redox potential during cheese manufacture and ripening, the ability of Lactococcus lactis strains to affect redox potential was studied. Redox potential of a Cheddar cheese extract was altered by bacterial growth and there were strain-specific differences in the nature of the redox potential/time curves obtained. Besides, strategies to control redox potential during cheesemaking and ripening were developed. Oxidizing or reducing agents were added to the salted curd before pressing and results confirmed that a negative redox potential is essential for the development of sulfur compounds in Cheddar cheese. Overall, the studies described in this thesis gave an evidence of the importance of the redox potential on the quality of dairy products. Redox potential could become an additional parameter used to select microorganisms candidate as starters in fermented dairy products. Moreover, it has been demonstrated that the redox potential influences the development of flavour component. Thus, measuring continuously changes in redox potential of a product and controlling, and adjusting if necessary, the redox potential values during manufacture and ripening could be important in the future of the dairy industry.