A dynamic model of the hypoxia-inducible factor 1α (HIF-1α) network

Activation of the hypoxia-inducible factor (HIF) pathway is a critical step in the transcriptional response to hypoxia. Although many of the key proteins involved have been characterised, the dynamics of their interactions in generating this response remain unclear. In the present study, we have generated a comprehensive mathematical model of the HIF-1a pathway based on core validated components and dynamic experimental data, and confirm the previously described connections within the predicted network topology. Our model confirms previous work demonstrating that the steps leading to optimal HIF-1a transcriptional activity require sequential inhibition of both prolyl- and asparaginyl-hydroxylases. We predict from our model (and confirm experimentally) that there is residual activity of the asparaginyl-hydroxylase FIH (factor inhibiting HIF) at low oxygen tension. Furthermore, silencing FIH under conditions where prolyl-hydroxylases are inhibited results in increased HIF-1a transcriptional activity, but paradoxically decreases HIF-1a stability. Using a core module of the HIF network and mathematical proof supported by experimental data, we propose that asparaginyl hydroxylation confers a degree of resistance upon HIF-1a to proteosomal degradation. Thus, through in vitro experimental data and in silico predictions, we provide a comprehensive model of the dynamic regulation of HIF-1a transcriptional activity by hydroxylases and use its predictive and adaptive properties to explain counter-intuitive biological observations.

Dynamic simulation of chemical plant

A CSSL- type modular FORTRAN package, called ACES, has been developed to assist in the simulation of the dynamic behaviour of chemical plant. ACES can be harnessed, for instance, to simulate the transients in startups or after a throughput change. ACES has benefited from two existing simulators. The structure was adapted from ICL SLAM and most plant models originate in DYFLO. The latter employs sequential modularisation which is not always applicable to chemical engineering problems. A novel device of twice- round execution enables ACES to achieve general simultaneous modularisation. During the FIRST ROUND, STATE-VARIABLES are retrieved from the integrator and local calculations performed. During the SECOND ROUND, fresh derivatives are estimated and stored for simultaneous integration. ACES further includes a version of DIFSUB, a variable-step integrator capable of handling stiff differential systems. ACES is highly formalised . It does not use pseudo steady- state approximations and excludes inconsistent and arbitrary features of DYFLO. Built- in debug traps make ACES robust. ACES shows generality, flexibility, versatility and portability, and is very convenient to use. It undertakes substantial housekeeping behind the scenes and thus minimises the detailed involvement of the user. ACES provides a working set of defaults for simulation to proceed as far as possible. Built- in interfaces allow for reactions and user supplied algorithms to be incorporated . New plant models can be easily appended. Boundary- value problems and optimisation may be tackled using the RERUN feature. ACES is file oriented; a STATE can be saved in a readable form and reactivated later. Thus piecewise simulation is possible. ACES has been illustrated and verified to a large extent using some literature-based examples. Actual plant tests are desirable however to complete the verification of the library. Interaction and graphics are recommended for future work.

Dynamic measurement of accommodative responses while viewing stereoscopic images

Using video refraction accommodative and convergence dynamic responses were measured to stepped changes in convergence stimuli with unchanged accommodative stimuli (conflicting stereoscopic image) and compared with responses to non-conflicting target stimuli. Three targets were used that varied in their spatial frequency components. An accommodative transient overshoot was evident in four out of seven subjects for only conflicting stimuli. One showed accommodative and convergence oscillation probably due to difficulty in fusing the stereoscopic target when it had a higher spatial component, however, this oscillation diminished when the target was spatial low-pass filtered. We hypothesise that transient responses to step stimuli is initiated by convergence-driven accommodation and subsequently followed by slower fine-control of accommodation modulated by the amount of blur. Inter-subject differences in convergence-driven accommodation may also be a factor to consider. For stereoscopic stimuli, it is proposed that the increase in blur immediately after the onset of the accommodative response inhibits cessation of the response.

Managing the dynamic configuration of enterprises

Due to environmental changes and business trends such as globalisation, outsourcing and virtualisation, more and more companies get involved in business activities that are outside their direct control. This typically occurs by entering into collaborative relationships and joint ventures with specialised companies in order to fulfil the demands of customers quickly (DiMaggio, 2001). Organisational structures that results from such collaborative relationships and joint ventures are referred to in this paper as enterprises and the management of them known as enterprise management. The authors use the definition of the European Commission (2003) that defines an enterprise as “… an entity, regardless of its legal form … including partnerships or associations regularly engaged in economic activities.” Therefore in its most simple form an enterprise could be a single integrated company. However, findings from this research show that enterprises can also be made up of parts of different companies and the structure of the enterprise is contingent upon a variety of different factors. The success of the enterprise as a collaborative venture depends on the ability of companies to intermediate their internal core competencies into other participating companies’ value streams and simultaneously outsource their own peripheral activities to companies that can perform them quicker, cheaper, and more effectively (Lal et al., 1995). In other words, the peripheral activities of one member-company must be complemented by a core competence of another member-company within an overall enterprise.

Dynamic simulation of chemical processes

This thesis describes the design and implementation of an interactive dynamic simulator called DASPRII. The starting point of this research has been an existing dynamic simulation package, DASP. DASPII is written in standard FORTRAN 77 and is implemented on universally available IBM-PC or compatible machines. It provides a means for the analysis and design of chemical processes. Industrial interest in dynamic simulation has increased due to the recent increase in concern over plant operability, resiliency and safety. DASPII is an equation oriented simulation package which allows solution of dynamic and steady state equations. The steady state can be used to initialise the dynamic simulation. A robust non linear algebraic equation solver has been implemented for steady state solution. This has increased the general robustness of DASPII, compared to DASP. A graphical front end is used to generate the process flowsheet topology from a user constructed diagram of the process. A conversational interface is used to interrogate the user with the aid of a database, to complete the topological information. An original modelling strategy implemented in DASPII provides a simple mechanism for parameter switching which creates a more flexible simulation environment. The problem description generated is by a further conversational procedure using a data-base. The model format used allows the same model equations to be used for dynamic and steady state solution. All the useful features of DASPI are retained in DASPII. The program has been demonstrated and verified using a number of example problems, Significant improvements using the new NLAE solver have been shown. Topics requiring further research are described. The benefits of variable switching in models has been demonstrated with a literature problem.

A study of the dynamic behaviour of a pulsed column solvent extraction plant

A study has been made of the dynamic behaviour of a nuclear fuel reprocessing plant utilising pulsed solvent extraction columns. A flowsheet is presented and the choice of an extraction device is discussed. The plant is described by a series of modules each module representing an item of equipment. Each module consists of a series of differential equations describing the dynamic behaviour of the equipment. The model is written in PMSP, a language developed for dynamic simulation models. The differential equations are solved to predict plant behaviour with time. The dynamic response of the plant to a range of disturbances has been assessed. The interactions between pulsed columns have been demonstrated and illustrated. The importance of auxillary items of equipment to plant performance is demonstrated. Control of the reprocessing plant is considered and the effect of control parameters on performance assessed.

Dynamic simulation of chemical plant

This thesis describes the design and implementation of a new dynamic simulator called DASP. It is a computer program package written in standard Fortran 77 for the dynamic analysis and simulation of chemical plants. Its main uses include the investigation of a plant's response to disturbances, the determination of the optimal ranges and sensitivities of controller settings and the simulation of the startup and shutdown of chemical plants. The design and structure of the program and a number of features incorporated into it combine to make DASP an effective tool for dynamic simulation. It is an equation-oriented dynamic simulator but the model equations describing the user's problem are generated from in-built model equation library. A combination of the structuring of the model subroutines, the concept of a unit module, and the use of the connection matrix of the problem given by the user have been exploited to achieve this objective. The Executive program has a structure similar to that of a CSSL-type simulator. DASP solves a system of differential equations coupled to nonlinear algebraic equations using an advanced mixed equation solver. The strategy used in formulating the model equations makes it possible to obtain the steady state solution of the problem using the same model equations. DASP can handle state and time events in an efficient way and this includes the modification of the flowsheet. DASP is highly portable and this has been demonstrated by running it on a number of computers with only trivial modifications. The program runs on a microcomputer with 640 kByte of memory. It is a semi-interactive program, with the bulk of all input data given in pre-prepared data files with communication with the user is via an interactive terminal. Using the features in-built in the package, the user can view or modify the values of any input data, variables and parameters in the model, and modify the structure of the flowsheet of the problem during a simulation session. The program has been demonstrated and verified using a number of example problems.

Global non-dynamic refinement of radial orbit error for altimetric earth satellites

The accuracy of altimetrically derived oceanographic and geophysical information is limited by the precision of the radial component of the satellite ephemeris. A non-dynamic technique is proposed as a method of reducing the global radial orbit error of altimetric satellites. This involves the recovery of each coefficient of an analytically derived radial error correction through a refinement of crossover difference residuals. The crossover data is supplemented by absolute height measurements to permit the retrieval of otherwise unobservable geographically correlated and linearly combined parameters. The feasibility of the radial reduction procedure is established upon application to the three day repeat orbit of SEASAT. The concept of arc aggregates is devised as a means of extending the method to incorporate longer durations, such as the 35 day repeat period of ERS-1. A continuous orbit is effectively created by including the radial misclosure between consecutive long arcs as an infallible observation. The arc aggregate procedure is validated using a combination of three successive SEASAT ephemerides. A complete simulation of the 501 revolution per 35 day repeat orbit of ERS-1 is derived and the recovery of the global radial orbit error over the full repeat period is successfully accomplished. The radial reduction is dependent upon the geographical locations of the supplementary direct height data. Investigations into the respective influences of various sites proposed for the tracking of ERS-1 by ground-based transponders are carried out. The potential effectiveness on the radial orbital accuracy of locating future tracking sites in regions of high latitudinal magnitude is demonstrated.

An investigation of the dynamic characteristics of a bolted-rotor system

A Jeffcott rotor consists of a disc at the centre of an axle supported at its end by bearings. A bolted Jeffcott rotor is formed by two discs, each with a shaft on one side. The discs are held together by spring loaded bolts near the outer edge. When the rotor turns there is tendency for the discs to separate on one side. This effect is more marked if the rotor is unbalanced, especially at resonance speeds. The equations of motion of the system have been developed with four degrees of freedom to include the rotor and bearing movements in the respective axes. These equations which include non-linear terms caused by the rotor opening, are subjected to external force such from rotor imbalance. A simulation model based on these equations was created using SIMULINK. An experimental test rig was used to characterise the dynamic features. Rotor discs open at a lateral displacement of the rotor of 0.8 mm. This is the threshold value used to show the change of stiffness from high stiffness to low stiffness. The experimental results, which measure the vibration amplitude of the rotor, show the dynamic behaviour of the bolted rotor due to imbalance. Close agreement of the experimental and theoretical results from time histories, waterfall plots, pseudo-phase plots and rotor orbit plot, indicated the validity of the model and existence of the non-linear jump phenomenon.

Some aspects of the dynamic performance of machine tool structural joints

The work presented in this thesis is concerned with the dynamic behaviour of structural joints which are both loaded, and excited, normal to the joint interface. Since the forces on joints are transmitted through their interface, the surface texture of joints was carefully examined. A computerised surface measuring system was developed and computer programs were written. Surface flatness was functionally defined, measured and quantised into a form suitable for the theoretical calculation of the joint stiffness. Dynamic stiffness and damping were measured at various preloads for a range of joints with different surface textures. Dry clean and lubricated joints were tested and the results indicated an increase in damping for the lubricated joints of between 30 to 100 times. A theoretical model for the computation of the stiffness of dry clean joints was built. The model is based on the theory that the elastic recovery of joints is due to the recovery of the material behind the loaded asperities. It takes into account, in a quantitative manner, the flatness deviations present on the surfaces of the joint. The theoretical results were found to be in good agreement with those measured experimentally. It was also found that theoretical assessment of the joint stiffness could be carried out using a different model based on the recovery of loaded asperities into a spherical form. Stepwise procedures are given in order to design a joint having a particular stiffness. A theoretical model for the loss factor of dry clean joints was built. The theoretical results are in reasonable agreement with those experimentally measured. The theoretical models for the stiffness and loss factor were employed to evaluate the second natural frequency of the test rig. The results are in good agreement with the experimentally measured natural frequencies.