Efficient and cost-effective experimental determination of kinetic constants and data: the success of a Bayesian systematic approach to drug transport, receptor binding, continuous culture and cell transport kinetics

Details about the parameters of kinetic systems are crucial for progress in both medical and industrial research, including drug development, clinical diagnosis and biotechnology applications. Such details must be collected by a series of kinetic experiments and investigations. The correct design of the experiment is essential to collecting data suitable for analysis, modelling and deriving the correct information. We have developed a systematic and iterative Bayesian method and sets of rules for the design of enzyme kinetic experiments. Our method selects the optimum design to collect data suitable for accurate modelling and analysis and minimises the error in the parameters estimated. The rules select features of the design such as the substrate range and the number of measurements. We show here that this method can be directly applied to the study of other important kinetic systems, including drug transport, receptor binding, microbial culture and cell transport kinetics. It is possible to reduce the errors in the estimated parameters and, most importantly, increase the efficiency and cost-effectiveness by reducing the necessary amount of experiments and data points measured. (C) 2003 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Aldose reductase and the importance of experimental design

Kinetic studies on the AR (aldose reductase) protein have shown that it does not behave as a classical enzyme in relation to ring aldose sugars. As with non-enzymatic glycation reactions, there is probably a free radical element involved derived from monosaccharide autoxidation. in the case of AR, there is free radical oxidation of NADPH by autoxidizing monosaccharides, which is enhanced in the presence of the NADPH-binding protein. Thus any assay for AR based on the oxidation of NADPH in the presence of autoxidizing monosaccharides is invalid, and tissue AR measurements based on this method are also invalid, and should be reassessed. AR exhibits broad specificity for both hydrophilic and hydrophobic aldehydes that suggests that the protein may be involved in detoxification. The last thing we would want to do is to inhibit it. ARIs (AR inhibitors) have a number of actions in the cell which are not specific, and which do not involve them binding to AR. These include peroxy-radical scavenging and effects of metal ion chelation. The AR/ARI story emphasizes the importance of correct experimental design in all biocatalytic experiments. Developing the use of Bayesian utility functions, we have used a systematic method to identify the optimum experimental designs for a number of kinetic model data sets. This has led to the identification of trends between kinetic model types, sets of design rules and the key conclusion that such designs should be based on some prior knowledge of K-m and/or the kinetic model. We suggest an optimal and iterative method for selecting features of the design such as the substrate range, number of measurements and choice of intermediate points. The final design collects data suitable for accurate modelling and analysis and minimizes the error in the parameters estimated, and is suitable for simple or complex steady-state models.

Design, synthesis and computational modelling of aromatic tweezer-molecules as models for chain-folding polymer blends

Novel 'tweezer-type' complexes that exploit the interactions between pi-electron-rich pyrenyl groups and pi-electron deficient diimide units have been designed and synthesised. The component molecules leading to complex formation were accessed readily from commercially available starting materials through short and efficient syntheses. Analysis of the resulting complexes, using the visible charge-transfer band, revealed association constants that increased sequentially from 130 to 11,000 M-1 as increasing numbers of pi-pi-stacking interactions were introduced into the systems. Computational modelling was used to analyse the structures of these complexes, revealing low-energy chain-folded conformations for both components, which readily allow close, multiple pi-pi-stacking and hydrogen bonding to be achieved. In this paper, we give details of our initial studies of these complexes and outline how their behaviour could provide a basis for designing self-healing polymer blends for use in adaptive coating systems. (C) 2008 Elsevier Ltd. All rights reserved.

Designs for an adaptive tuned vibration absorber with variable shape stiffness element

An adaptive tuned vibration absorber (ATVA) with a smart variable stiffness element is capable of retuning itself in response to a time-varying excitation frequency., enabling effective vibration control over a range of frequencies. This paper discusses novel methods of achieving variable stiffness in an ATVA by changing shape, as inspired by biological paradigms. It is shown that considerable variation in the tuned frequency can be achieved by actuating a shape change, provided that this is within the limits of the actuator. A feasible design for such an ATVA is one in which the device offers low resistance to the required shape change actuation while not being restricted to low values of the effective stiffness of the vibration absorber. Three such original designs are identified: (i) A pinned-pinned arch beam with fixed profile of slight curvature and variable preload through an adjustable natural curvature; (ii) a vibration absorber with a stiffness element formed from parallel curved beams of adjustable curvature vibrating longitudinally; (iii) a vibration absorber with a variable geometry linkage as stiffness element. The experimental results from demonstrators based on two of these designs show good correlation with the theory.

Adaptive designs for Phase I dose-finding studies

Improving methodology for Phase I dose-finding studies is currently of great interest in pharmaceutical and medical research. This article discusses the current atmosphere and attitude towards adaptive designs and focuses on the influence of Bayesian approaches.

Simplified parameter adaptive control

A simple parameter adaptive controller design methodology is introduced in which steady-state servo tracking properties provide the major control objective. This is achieved without cancellation of process zeros and hence the underlying design can be applied to non-minimum phase systems. As with other self-tuning algorithms, the design (user specified) polynomials of the proposed algorithm define the performance capabilities of the resulting controller. However, with the appropriate definition of these polynomials, the synthesis technique can be shown to admit different adaptive control strategies, e.g. self-tuning PID and self-tuning pole-placement controllers. The algorithm can therefore be thought of as an embodiment of other self-tuning design techniques. The performances of some of the resulting controllers are illustrated using simulation examples and the on-line application to an experimental apparatus.

Adaptive deadbeat control of stochastic systems

This paper considers the use of a discrete-time deadbeat control action on systems affected by noise. Variations on the standard controller form are discussed and comparisons are made with controllers in which noise rejection is a higher priority objective. Both load and random disturbances are considered in the system description, although the aim of the deadbeat design remains as a tailoring of reference input variations. Finally, the use of such a deadbeat action within a self-tuning control framework is shown to satisfy, under certain conditions, the self-tuning property, generally though only when an extended form of least-squares estimation is incorporated.

Enhancement of a telemanipulator design with a human arm model

In this chapter we described how the inclusion of a model of a human arm, combined with the measurement of its neural input and a predictor, can provide to a previously proposed teleoperator design robustness under time delay. Our trials gave clear indications of the superiority of the NPT scheme over traditional as well as the modified Yokokohji and Yoshikawa architectures. Its fundamental advantages are: the time-lead of the slave, the more efficient, and providing a more natural feeling manipulation, and the fact that incorporating an operator arm model leads to more credible stability results. Finally, its simplicity allows less likely to fail local control techniques to be employed. However, a significant advantage for the enhanced Yokokohji and Yoshikawa architecture results from the very fact that it’s a conservative modification of current designs. Under large prediction errors, it can provide robustness through directing the master and slave states to their means and, since it relies on the passivity of the mechanical part of the system, it would not confuse the operator. An experimental implementation of the techniques will provide further evidence for the performance of the proposed architectures. The employment of neural networks and fuzzy logic, which will provide an adaptive model of the human arm and robustifying control terms, is scheduled for the near future.

Modeling requirement driven architecture of adaptive healthcare system based on semiotics

In order to improve the quality of healthcare services, the integrated large-scale medical information system is needed to adapt to the changing medical environment. In this paper, we propose a requirement driven architecture of healthcare information system with hierarchical architecture. The system operates through the mapping mechanism between these layers and thus can organize functions dynamically adapting to user’s requirement. Furthermore, we introduce the organizational semiotics methods to capture and analyze user’s requirement through ontology chart and norms. Based on these results, the structure of user’s requirement pattern (URP) is established as the driven factor of our system. Our research makes a contribution to design architecture of healthcare system which can adapt to the changing medical environment.

Cross-layer design for multiuser MIMO MRC systems with feedback constraints

Cross-layer techniques represent efficient means to enhance throughput and increase the transmission reliability of wireless communication systems. In this paper, a cross-layer design of aggressive adaptive modulation and coding (A-AMC), truncated automatic repeat request (T-ARQ), and user scheduling is proposed for multiuser multiple-input-multiple-output (MIMO) maximal ratio combining (MRC) systems, where the impacts of feedback delay (FD) and limited feedback (LF) on channel state information (CSI) are also considered. The A-AMC and T-ARQ mechanism selects the appropriate modulation and coding schemes (MCSs) to achieve higher spectral efficiency while satisfying the service requirement on the packet loss rate (PLR), profiting from the feasibility of using different MCSs to retransmit a packet, which is destined to a scheduled user selected to exploit multiuser diversity and enhance the system's performance in terms of both transmission efficiency and fairness. The system's performance is evaluated in terms of the average PLR, average spectral efficiency (ASE), outage probability, and average packet delay, which are derived in closed form, considering transmissions over Rayleigh-fading channels. Numerical results and comparisons are provided and show that A-AMC combined with T-ARQ yields higher spectral efficiency than the conventional scheme based on adaptive modulation and coding (AMC), while keeping the achieved PLR closer to the system's requirement and reducing delay. Furthermore, the effects of the number of ARQ retransmissions, numbers of transmit and receive antennas, normalized FD, and cardinality of the beamforming weight vector codebook are studied and discussed.

Cross-layer design for MIMO systems over spatially correlated and keyhole Nakagami-m fading channels

Cross-layer design is a generic designation for a set of efficient adaptive transmission schemes, across multiple layers of the protocol stack, that are aimed at enhancing the spectral efficiency and increasing the transmission reliability of wireless communication systems. In this paper, one such cross-layer design scheme that combines physical layer adaptive modulation and coding (AMC) with link layer truncated automatic repeat request (T-ARQ) is proposed for multiple-input multiple-output (MIMO) systems employing orthogonal space--time block coding (OSTBC). The performance of the proposed cross-layer design is evaluated in terms of achievable average spectral efficiency (ASE), average packet loss rate (PLR) and outage probability, for which analytical expressions are derived, considering transmission over two types of MIMO fading channels, namely, spatially correlated Nakagami-m fading channels and keyhole Nakagami-m fading channels. Furthermore, the effects of the maximum number of ARQ retransmissions, numbers of transmit and receive antennas, Nakagami fading parameter and spatial correlation parameters, are studied and discussed based on numerical results and comparisons. Copyright © 2009 John Wiley & Sons, Ltd.

Cross-layer design of enhanced AMC with truncated ARQ protocols

Using a cross-layer approach, two enhancement techniques applied for adaptive modulation and coding (AMC) with truncated automatic repeat request (T-ARQ) are investigated, namely, aggressive AMC (A-AMC) and constellation rearrangement (CoRe). Aggressive AMC selects the appropriate modulation and coding schemes (MCS) to achieve higher spectral efficiency, profiting from the feasibility of using different MCSs for retransmitting a packet, whereas in the CoRe-based AMC, retransmissions of the same data packet are performed using different mappings so as to provide different degrees of protection to the bits involved, thus achieving mapping diversity gain. The performance of both schemes is evaluated in terms of average spectral efficiency and average packet loss rate, which are derived in closed-form considering transmission over Nakagami-m fading channels. Numerical results and comparisons are provided. In particular, it is shown that A-AMC combined with T-ARQ yields higher spectral efficiency than the AMC-based conventional scheme while keeping the achieved packet loss rate closer to the system's requirement, and that it can achieve larger spectral efficiency objectives than that of the scheme using AMC along with CoRe.

Knowledge-based design cost estimation through extending industry foundation classes

In order to overcome divergence of estimation with the same data, the proposed digital costing process adopts an integrated design of information system to design the process knowledge and costing system together. By employing and extending a widely used international standard, industry foundation classes, the system can provide an integrated process which can harvest information and knowledge of current quantity surveying practice of costing method and data. Knowledge of quantification is encoded from literatures, motivation case and standards. It can reduce the time consumption of current manual practice. The further development will represent the pricing process in a Bayesian Network based knowledge representation approach. The hybrid types of knowledge representation can produce a reliable estimation for construction project. In a practical term, the knowledge management of quantity surveying can improve the system of construction estimation. The theoretical significance of this study lies in the fact that its content and conclusion make it possible to develop an automatic estimation system based on hybrid knowledge representation approach.

Change escalation processes and complex adaptive systems: from incremental reconfigurations to discontinuous restructuring

This study examines when “incremental” change is likely to trigger “discontinuous” change, using the lens of complex adaptive systems theory. Going beyond the simulations and case studies through which complex adaptive systems have been approached so far, we study the relationship between incremental organizational reconfigurations and discontinuous organizational restructurings using a large-scale database of U.S. Fortune 50 industrial corporations. We develop two types of escalation process in organizations: accumulation and perturbation. Under ordinary conditions, it is perturbation rather than the accumulation that is more likely to trigger subsequent discontinuous change. Consistent with complex adaptive systems theory, organizations are more sensitive to both accumulation and perturbation in conditions of heightened disequilibrium. Contrary to expectations, highly interconnected organizations are not more liable to discontinuous change. We conclude with implications for further research, especially the need to attend to the potential role of managerial design and coping when transferring complex adaptive systems theory from natural systems to organizational systems.