Mutation of herpesvirus thymidine kinase to generate ganciclovir-specific kinases for use in cancer gene therapies

Understanding the functional and mechanistic properties of themulti-substrate herpes simplex virus type-1 thymidine kinase(HSV-1 TK) remains critical to defining its role as a majorpharmacological target in herpesvirus and gene therapies forcancer. An inherent limitation of the activity of HSV-TK isthe >70-fold difference in the K_ms for phosphorylation ofthymidine over the pro-drug ganciclovir (GCV). To engineer anHSV-1 TK isoform that is specific for GCV as the preferred substrate,16 site-specific mutants were generated. The mutations wereconcentrated at conserved residues involved in nucleoside basebinding, Gln125 and near sites 3 and 4 involved in catalysisand substrate binding. The substrate preferences of each mutantenzyme were compared with wild-type HSV-1 TK. One mutant, termedQ7530 TK, had a lower K_m for GCV than thymidine. Expressionof the Q7530 TK in tumor cells indicated comparable metabolismto and improved sensitivity to GCV over wild-type HSV-1 TK,with minimal thymidine phosphorylation activity. A molecularmodeling simulation of the different HSV-1 TK active-sites wasdone for GCV and thymidine binding. It was concluded that mutationsat Gln125 and near site 4, especially at Ala168, were responsiblefor loss of deoxypyrimidine substrate binding.     

Size distribution functions of dispersions

The size distribution function of bubbles in thermodynamic equilibrium with the surrounding liquid has been derived in the absence of gravity. The derivation has been based on the assumption that the gas is dispersed into bubbles in a completely random way in respect of the energies of the bubbles. The size distribution function of bubbles obtained when surface tension effects are neglected is of the same form as the empirical Nukiyama-Tanasawa distribution, and gives also the size distribution function of droplets consisting of an incompressible liquid when the way the liquid is dispersed into droplets is assumed to be completely random with respect to the volumes of the droplets. The derived size distribution functions agree well with the experimental size distributions of bubbles in water having been generated by an air entrainment process at the surface of the water or behind a ventilated body.     

Water Governance in Canada: Innovation and Fragmentation

This paper explores Canada's approach to water governance. It argues that fragmented governance has had negative impacts on Canada's ability to manage water resources adequately (particularly in the context of urbanization, agriculture and resource extraction), and to deal with new issues (such as climate change). Further, it argues that Canada's highly decentralized approach to water governance creates challenges of integration, coordination and data availability. The paper explores possible future strategies for innovations in water governance that may have the potential to improve water management outcomes.     

Adaptive signal processing of asset price dynamics with predictability analysis

In this paper we illustrate the optimal filtering of log returns of commodity prices in which both the mean and volatility are modulated by a hidden Markov chain with finite state space. The optimal estimate of the Markov chain and the parameters of the price model are given in terms of discrete-time recursive filters. We provide an application on a set of high frequency gold price data for the period 1973-2006 and analyse the h-step ahead price predictions against the Diebold-Kilian metric. Within the modelling framework where the mean and volatility are switching regimes, our findings suggest that a two-state hidden Markov model is sufficient to describe the dynamics of the data and the gold price is predictable up to a certain extent in the short term but almost impossible to predict in the long term. The proposed model is also benchmarked with ARCH and GARCH models with respect to price predictability and forecasting errors.     

Application of virtual reality for peritoneal dialysis exchange learning in patients with end-stage renal disease and cognitive impairment

Virtual Reality - Cognitive impairment is not uncommon in patients with end-stage renal disease and can make it more difficult for these patients to carry out peritoneal dialysis (PD) on their own....     

Quality of life development during initial hemodialysis therapy and association with loss of residual renal function

Introduction: Health related quality of life (HRQOL) is markedly reduced in hemodialysis patients compared to the general population. We investigated the course of self‐reported HRQOL over time and the association with selected factors, focusing on changes in glomerular filtration rate (GFR). Methods: Eighty‐two newly started hemodialysis patients from the SAFIR cohort filled out the Kidney Disease Quality of Life Short Form Version 1.3 (KDQOL‐SF^TM) questionnaire at baseline, 6 and 12 months. The SAFIR study was a randomized, placebo‐controlled, double‐blind intervention study, examining the effects of the angiotensin II receptor blocker irbesartan. HRQOL was a secondary outcome measure. Main inclusion criteria: Dialysis vintage <1 year, left ventricular ejection fraction >30% and urinary output >300 mL/day. GFR was measured with mean creatinine and urea clearance from 24‐hour urine collections at baseline, 6 and 12 months. Findings: Irbesartan treatment did not affect HRQOL. Patients were pooled into one group for further analyses. Decline in GFR correlated significantly with decreasing HRQOL over time. HRQOL was stable over time, with a slight nonsignificant tendency toward improved HRQOL. The largest HRQOL‐differences (positive values equal improved HRQOL) observed during the 12 month study period were (mean[95% confidence interval]): Burden of kidney disease:6.4[?2.2;15.0], Role limitations‐physical:12.7[?2.1;27.5], and Role limitations‐emotional:9.7[?5.2;24.6]. Comorbidity, especially diabetes, hospital admissions, female gender, and age were strongly associated with lower HRQOL in cross sectional analysis. Discussion: Preservation of residual renal function seems to be important for HRQOL. In newly started HD patients, HRQOL showed little change after 12 months. HRQOL was negatively affected by comorbidity, especially diabetes, hospital admissions, female gender, and age.     

Socio-technical IS design science research: developing design theory for IS integration management

Design science research is an essential part of IS research since the field should not only try to understand how the world is, but also how to change it. We argue that the aim of IS design science research should be to develop practical knowledge not only for the design of novel information technology (IT), but also for IS governance and management. Whereas at least some methodological support exists for researchers engaged in IT-centric design science research, limited support is available for researchers who want to develop design knowledge and theory for IS governance and management. To overcome this shortcoming, we suggest a socio-technical IS design science research approach. The approach has four main activities: (1) identifying problem situations and desired outcomes, (2) reviewing extant theories, knowledge and data, (3) proposing/refining design theory and knowledge, and (4) testing design theory and knowledge. The applicability and usefulness of the proposed approach is shown by means of a design science research project concerning IS integration management in the context of mergers and acquisitions.     

Institutional pressures and mindful IT management: The case of a container terminal in China

Although it has been only ten years in operations, Yantian International Container Terminals Limited (YICT) has evolved as a world-class container terminal and become the first Chinese port to receive the Best Global Container Port of the Year award for 2005–2006, as well as being designated China's best container terminal in terms of operational efficiency for 2008. A success factor of YICT is its extensive use of IT in managing and enhancing the productivity and services of the port operations. Premised upon Institutional Theory and the organizational mindfulness perspectives (preoccupation with failure and success, reluctance to simplify interpretations, sensitivity to operations, commitment to resilience, and reliance on expertise over formal authority) and using case study methodology, we examined the institutional pressures faced by YICT in its IT management (ITM), and determined how YICT coped with its institutional pressures during its IT development.