Physiologically based synthetic models of hepatic disposition

Current Physiologically based pharmacokinetic (PBPK) models are inductive. We present an additional, different approach that is based on the synthetic rather than the inductive approach to modeling and simulation. It relies on object-oriented programming A model of the referent system in its experimental context is synthesized by assembling objects that represent components such as molecules, cells, aspects of tissue architecture, catheters, etc. The single pass perfused rat liver has been well described in evaluating hepatic drug pharmacokinetics (PK) and is the system on which we focus. In silico experiments begin with administration of objects representing actual compounds. Data are collected in a manner analogous to that in the referent PK experiments. The synthetic modeling method allows for recognition and representation of discrete event and discrete time processes, as well as heterogeneity in organization, function, and spatial effects. An application is developed for sucrose and antipyrine, administered separately and together PBPK modeling has made extensive progress in characterizing abstracted PK properties but this has also been its limitation. Now, other important questions and possible extensions emerge. How are these PK properties and the observed behaviors generated? The inherent heuristic limitations of traditional models have hindered getting meaningful, detailed answers to such questions. Synthetic models of the type described here are specifically intended to help answer such questions. Analogous to wet-lab experimental models, they retain their applicability even when broken apart into sub-components. Having and applying this new class of models along with traditional PK modeling methods is expected to increase the productivity of pharmaceutical research at all levels that make use of modeling and simulation.

Continuous action system refinement

Action systems are a framework for reasoning about discrete reactive systems. Back, Petre and Porres have extended these action systems to continuous action systems, which can be. used to model hybrid systems. In this paper we define a refinement relation, and develop practical data refinement rules for continuous action systems. The meaning of continuous action systems is expressed in terms of a mapping from continuous action systems to action systems. First, we present a new mapping from continuous act ion systems to action systems, such that Back's definition of trace refinement is correct with respect to it. Second, we present a stream semantics that is compatible with the trace semantics, but is preferable to it because it is more general. Although action system trace refinement rules are applicable to continuous action systems with a stream semantics, they are not complete. Finally, we introduce a new data refinement rule that is valid with respect to the stream semantics and can be used to prove refinements that are not possible in the trace semantics, and we analyse the completeness of our new rule in conjunction with the existing trace refinement rules.

Anisotropy-based robust performance analysis of finite horizon linear discrete time varying systems

We consider a problem of robust performance analysis of linear discrete time varying systems on a bounded time interval. The system is represented in the state-space form. It is driven by a random input disturbance with imprecisely known probability distribution; this distributional uncertainty is described in terms of entropy. The worst-case performance of the system is quantified by its a-anisotropic norm. Computing the anisotropic norm is reduced to solving a set of difference Riccati and Lyapunov equations and a special form equation.

A rare earth element study of complex zircons from early Archaean Amitsoq gneisses, Godthåbsfjord, south-west Greenland

We present high spatial resolution ion-microprobe rare earth element (REE) data for discrete growth phases of complex polyphase zircons from early Archaean Amitsoq gneisses, outer Godthabsfjord, SW Greenland. In Matsuda diagrams, the two major growth phases, >3.8 Ga cores and ca. 3.65 Ga rims, have steep positive slopes from La to Lu, prominent positive Ce anomalies and negative Eu anomalies that are consistent with growth in a melt. Exceptions to this are non-cathodolurnmescent zircon developed between the cores and rims, sometimes truncating zoning in the cores, and late Archaean prismatic tip overgrowths, both of which exhibit flatter light REE (LREE) patterns and have small or no Eu anomaly, which we interpret as the result of metamorphism and/or small-degree, isolated partial melting. Our data support previous interpretations that the ca. 3.65 Ga zircon phase was generated in a melt, with the >3.8 Ga phase representing either original protolith zircons in a large degree partial melt or inherited zircons in an introduced magma. Regardless which of these two interpretations is correct for these, and similar, rocks in the outer GodthAbsfjord, the 3.65 Ga event will have profoundly affected isotopic systems and obscured beyond recognition any earlier igneous features such as cross-cutting relationships, which may only be assigned a minimum 3.65 Ga age. (C) 2003 Elsevier Science B.V. All rights reserved.

Warranty and discrete preventive maintenance

Preventive maintenance actions over the warranty period have an impact on the warranty servicing cost to the manufacturer and the cost to the buyer of fixing failures over the life of the product after the warranty expires. However, preventive maintenance costs money and is worthwhile only when these costs exceed the reduction in other costs. The paper deals with a model to determine when preventive maintenance actions (which rejuvenate the unit) carried out at discrete time instants over the warranty period are worthwhile. The cost of preventive maintenance is borne by the buyer. (C) 2003 Elsevier Ltd. All rights reserved.

Adverse feedback sequences in exploited marine systems: Are deliberate interruptive actions warranted?

Several mechanisms for self-enhancing feedback instabilities in marine ecosystems are identified and briefly elaborated. It appears that adverse phases of operation may be abruptly triggered by explosive breakouts in abundance of one or more previously suppressed populations. Moreover, an evident capacity of marine organisms to accomplish extensive geographic habitat expansions may expand and perpetuate a breakout event. This set of conceptual elements provides a framework for interpretation of a sequence of events that has occurred in the Northern Benguela Current Large Marine Ecosystem (off south-western Africa). This history can illustrate how multiple feedback loops might interact with one another in unanticipated and quite malignant ways, leading not only to collapse of customary resource stocks but also to degradation of the ecosystem to such an extent that disruption of customary goods and services may go beyond fisheries alone to adversely affect other major global ecosystem concerns (e.g. proliferations of jellyfish and other slimy, stingy, toxic and/or noxious organisms, perhaps even climate change itself, etc.). The wisdom of management interventions designed to interrupt an adverse mode of feedback operation is pondered. Research pathways are proposed that may lead to improved insights needed: (i) to avoid potential 'triggers' that might set adverse phases of feedback loop operation into motion; and (ii) to diagnose and properly evaluate plausible actions to reverse adverse phases of feedback operation that might already have been set in motion. These pathways include the drawing of inferences from available 'quasi-experiments' produced either by short-term climatic variation or inadvertently in the course of biased exploitation practices, and inter-regional applications of the comparative method of science.

Structural change in macroeconomic time series: A complex systems perspective

We demonstrate that the process of generating smooth transitions Call be viewed as a natural result of the filtering operations implied in the generation of discrete-time series observations from the sampling of data from an underlying continuous time process that has undergone a process of structural change. In order to focus discussion, we utilize the problem of estimating the location of abrupt shifts in some simple time series models. This approach will permit its to address salient issues relating to distortions induced by the inherent aggregation associated with discrete-time sampling of continuous time processes experiencing structural change, We also address the issue of how time irreversible structures may be generated within the smooth transition processes. (c) 2005 Elsevier Inc. All rights reserved.

Quantum optical systems for the implementation of quantum information processing

We review the field of quantum optical information from elementary considerations to quantum computation schemes. We illustrate our discussion with descriptions of experimental demonstrations of key communication and processing tasks from the last decade and also look forward to the key results likely in the next decade. We examine both discrete (single photon) type processing as well as those which employ continuous variable manipulations. The mathematical formalism is kept to the minimum needed to understand the key theoretical and experimental results.

Model-Driven safety evaluation with state-event-based component failure annotations

Over the past years, the paradigm of component-based software engineering has been established in the construction of complex mission-critical systems. Due to this trend, there is a practical need for techniques that evaluate critical properties (such as safety, reliability, availability or performance) of these systems. In this paper, we review several high-level techniques for the evaluation of safety properties for component-based systems and we propose a new evaluation model (State Event Fault Trees) that extends safety analysis towards a lower abstraction level. This model possesses a state-event semantics and strong encapsulation, which is especially useful for the evaluation of component-based software systems. Finally, we compare the techniques and give suggestions for their combined usage

Accelerated leap methods for simulating discrete stochastic chemical kinetics

Biologists are increasingly conscious of the critical role that noise plays in cellular functions such as genetic regulation, often in connection with fluctuations in small numbers of key regulatory molecules. This has inspired the development of models that capture this fundamentally discrete and stochastic nature of cellular biology - most notably the Gillespie stochastic simulation algorithm (SSA). The SSA simulates a temporally homogeneous, discrete-state, continuous-time Markov process, and of course the corresponding probabilities and numbers of each molecular species must all remain positive. While accurately serving this purpose, the SSA can be computationally inefficient due to very small time stepping so faster approximations such as the Poisson and Binomial τ-leap methods have been suggested. This work places these leap methods in the context of numerical methods for the solution of stochastic differential equations (SDEs) driven by Poisson noise. This allows analogues of Euler-Maruyuma, Milstein and even higher order methods to be developed through the Itô-Taylor expansions as well as similar derivative-free Runge-Kutta approaches. Numerical results demonstrate that these novel methods compare favourably with existing techniques for simulating biochemical reactions by more accurately capturing crucial properties such as the mean and variance than existing methods.

Linking contracts, processes and services: An event-driven approach

This paper addresses the problem of mapping business contract conditions onto the messages and rules that represent service interactions in a collaborative business process. We describe why this mapping is not straightforward by means of an example. We then consider a message-driven process language as a target for the mapping and use this mapping solution to discuss broad range of problems related to the mapping problem.