An identifiability analysis of a parent-metabolite pharmacokinetic model for ivabradine.

The paper considers the structural identifiability of a parent–metabolite pharmacokinetic model for ivabradine and one of its metabolites. The model, which is linear, is considered initially for intravenous administration of ivabradine, and then for a combined intravenous and oral administration. In both cases, the model is shown to be unidentifiable. Simplification of the model (for both forms of administration) to that proposed by Duffull et al. (1) results in a globally structurally identifiable model. The analysis could be applied to the modeling of any drug undergoing first-pass metabolism, with plasma concentrations available from drug and metabolite.

Environmental regulation of land use and public compensation: principles, and Swiss and Australian examples

The authors discuss the regulation of rural land use and compensation for property-rights restrictions, both of which appear to have become more commonplace in recent years but also more contested. The implications of contemporary theories in relation to this matter are examined, including: the applicability of new welfare economics; the relevance of the neoclassical theory of politics; and the implications of contemporary theories of social conflict resolution and communication. Examination of examples of Swiss and Australian regulation of the use of rural properties, and the ensuing conflicts, reveals that many decisions reflect a mixture of these elements. Rarely, if ever, are social decisions in this area made solely on the basis of welfare economics, for instance social cost-benefit analysis. Only some aspects of such decisions can be explained by the neoclassical theory of politics. Theories of social conflict resolution suggest why, and in what way, approaches of discourse and participation may resolve conflicts regarding regulation and compensation. These theories and their practical application seem to gain in importance as opposition to government decisions increases. The high degree of complexity of most conflicts concerning regulation and compensation cannot be tackled with narrow economic theories. Moreover, the Swiss and Australian examples show that approaches involving conflict resolution may favour environmental standards.

Assessment of the ability to model proteins with leucine-rich repeats in light of the latest structural information

The three-dimensional structures of leucine-rich repeat (LRR) -containing proteins from five different families were previously predicted based on the crystal structure of the ribonuclease inhibitor. using an approach that combined homology-based modeling, structure-based sequence alignment of LRRs, and several rational assumptions. The structural models have been produced based on very limited sequence similarity, which, in general. cannot yield trustworthy predictions. Recently, the protein structures from three of these five families have been determined. In this report we estimate the quality of the modeling approach by comparing the models with the experimentally determined structures. The comparison suggests that the general architecture, curvature, interior/exterior orientations of side chains. and backbone conformation of the LRR structures can be predicted correctly. On the other hand. the analysis revealed that, in some cases. it is difficult to predict correctly the twist of the overall super-helical structure. Taking into consideration the conclusions from these comparisons, we identified a new family of bacterial LRR proteins and present its structural model. The reliability of the LRR protein modeling suggests that it would be informative to apply similar modeling approaches to other classes of solenoid proteins.

Monitoring the composition and form of urban environments based on the vegetation-impervious surface-soil (VIS) model by sub-pixel analysis techniques

The majority of the world's population now resides in urban environments and information on the internal composition and dynamics of these environments is essential to enable preservation of certain standards of living. Remotely sensed data, especially the global coverage of moderate spatial resolution satellites such as Landsat, Indian Resource Satellite and Systeme Pour I'Observation de la Terre (SPOT), offer a highly useful data source for mapping the composition of these cities and examining their changes over time. The utility and range of applications for remotely sensed data in urban environments could be improved with a more appropriate conceptual model relating urban environments to the sampling resolutions of imaging sensors and processing routines. Hence, the aim of this work was to take the Vegetation-Impervious surface-Soil (VIS) model of urban composition and match it with the most appropriate image processing methodology to deliver information on VIS composition for urban environments. Several approaches were evaluated for mapping the urban composition of Brisbane city (south-cast Queensland, Australia) using Landsat 5 Thematic Mapper data and 1:5000 aerial photographs. The methods evaluated were: image classification; interpretation of aerial photographs; and constrained linear mixture analysis. Over 900 reference sample points on four transects were extracted from the aerial photographs and used as a basis to check output of the classification and mixture analysis. Distinctive zonations of VIS related to urban composition were found in the per-pixel classification and aggregated air-photo interpretation; however, significant spectral confusion also resulted between classes. In contrast, the VIS fraction images produced from the mixture analysis enabled distinctive densities of commercial, industrial and residential zones within the city to be clearly defined, based on their relative amount of vegetation cover. The soil fraction image served as an index for areas being (re)developed. The logical match of a low (L)-resolution, spectral mixture analysis approach with the moderate spatial resolution image data, ensured the processing model matched the spectrally heterogeneous nature of the urban environments at the scale of Landsat Thematic Mapper data.

Cisplatin-induced ototoxicity and pharmacokinetics: Preliminary findings in a dog model

The early effects of clinical dose of cisplatin (100 mg/m(2)) on distort ion-product otoacoustic emissions (DPOAE) thresholds and the relationship between DPOAE threshold shifts and changes in plasma concentrations of filterable and total platinum (Pt) following infusion of cisplatin in a dog model were investigated. The DPOAE thresholds (based on input-output function) were measured 2 days before a single high dose of cisplatin administration, and compared with measurements recorded 2 and 4 days after infusion. The results revealed DPOAE thresholds to be elevated by 4 days after the administration of cisplatin. However, this elevation could not be correlated with plasma concentrations of filterable and total Pt, which showed little variation over the 48-hour postinfusion period between animals. The present study demonstrated that DPOAE thresholds have the potential to be used as an indicator of cisplatin-induced ototoxicity, and cisplatin-induced ototoxicity could not be explained by plasma Pt kinetics in individual animals.

Robust model-order reduction of complex biological processes

This paper addresses robust model-order reduction of a high dimensional nonlinear partial differential equation (PDE) model of a complex biological process. Based on a nonlinear, distributed parameter model of the same process which was validated against experimental data of an existing, pilot-scale BNR activated sludge plant, we developed a state-space model with 154 state variables in this work. A general algorithm for robustly reducing the nonlinear PDE model is presented and based on an investigation of five state-of-the-art model-order reduction techniques, we are able to reduce the original model to a model with only 30 states without incurring pronounced modelling errors. The Singular perturbation approximation balanced truncating technique is found to give the lowest modelling errors in low frequency ranges and hence is deemed most suitable for controller design and other real-time applications. (C) 2002 Elsevier Science Ltd. All rights reserved.

Finite difference time domain (FDTD) method for modeling the effect of switched gradients on the human body in MRI

Numerical modeling of the eddy currents induced in the human body by the pulsed field gradients in MRI presents a difficult computational problem. It requires an efficient and accurate computational method for high spatial resolution analyses with a relatively low input frequency. In this article, a new technique is described which allows the finite difference time domain (FDTD) method to be efficiently applied over a very large frequency range, including low frequencies. This is not the case in conventional FDTD-based methods. A method of implementing streamline gradients in FDTD is presented, as well as comparative analyses which show that the correct source injection in the FDTD simulation plays a crucial rule in obtaining accurate solutions. In particular, making use of the derivative of the input source waveform is shown to provide distinct benefits in accuracy over direct source injection. In the method, no alterations to the properties of either the source or the transmission media are required. The method is essentially frequency independent and the source injection method has been verified against examples with analytical solutions. Results are presented showing the spatial distribution of gradient-induced electric fields and eddy currents in a complete body model.

A quantitative state and transition model for the Mitchell grasslands of central western Queensland

Concerns of reduced productivity and land degradation in the Mitchell grasslands of central western Queensland were addressed through a range monitoring program to interpret condition and trend. Botanical and eclaphic parameters were recorded along piosphere and grazing gradients, and across fenceline impact areas, to maximise changes resulting from grazing. The Degradation Gradient Method was used in conjunction with State and Transition Models to develop models of rangeland dynamics and condition. States were found to be ordered along a degradation gradient, indicator species developed according to rainfall trends and transitions determined from field data and available literature. Astrebla spp. abundance declined with declining range condition and increasing grazing pressure, while annual grasses and forbs increased in dominance under poor range condition. Soil erosion increased and litter decreased with decreasing range condition. An approach to quantitatively define states within a variable rainfall environment based upon a time-series ordination analysis is described. The derived model could provide the interpretive framework necessary to integrate on-ground monitoring, remote sensing and geographic information systems to trace states and transitions at the paddock scale. However, further work is needed to determine the full catalogue of states and transitions and to refine the model for application at the paddock scale.

A high definition, finite difference time domain method

A high definition, finite difference time domain (HD-FDTD) method is presented in this paper. This new method allows the FDTD method to be efficiently applied over a very large frequency range including low frequencies, which are problematic for conventional FDTD methods. In the method, no alterations to the properties of either the source or the transmission media are required. The method is essentially frequency independent and has been verified against analytical solutions within the frequency range 50 Hz-1 GHz. As an example of the lower frequency range, the method has been applied to the problem of induced eddy currents in the human body resulting from the pulsed magnetic field gradients of an MRI system. The new method only requires approximately 0.3% of the source period to obtain an accurate solution. (C) 2003 Elsevier Science Inc. All rights reserved.

Investigation of candidate division TM7, a recently recognized major lineage of the domain bacteria with no known pure-culture representatives

A molecular approach was used to investigate a recently described candidate division of the domain Bacteria, TM7, currently known only from environmental 16S ribosomal DNA sequence data, A number of TM7-specific primers and probes were designed and evaluated. Fluorescence in situ hybridization (FISH) of a laboratory scale bioreactor using two independent TM7-specific probes revealed a conspicuous sheathed-filament morphotype, fortuitously enriched in the reactor. Morphologically, the filament matched the description of the Eikelboom morphotype 0041-0675 widely associated with bulking problems in activated-sludge wastewater treatment systems. Transmission electron microscopy of the bioreactor sludge demonstrated that the sheathed-filament morphotype had a typical gram-positive cell envelope ultrastructure. Therefore, TM7 is only the third bacterial lineage recognized to have gram-positive representatives. TM7-specific FISH analysis of two full-scale wastewater treatment plant sludges, including the one used to seed the laboratory scale reactor, indicated the presence of a number of morphotypes, including sheathed filaments. TM7-specific PCR clone libraries prepared from the two full-scale sludges yielded 23 novel TM7 sequences. Three subdivisions could be defined based on these data and publicly available sequences. Environmental sequence data and TM7-specific FISH analysis indicate that members of the TM7 division are present in a variety of terrestrial, aquatic, and clinical habitats. A highly atypical base substitution (Escherichia coli position 912; C to U) for bacterial 16S rRNAs was present in almost all TM7 sequences, suggesting that TM7 bacteria, like Archaea, may be streptomycin resistant at the ribosome level.

Model studies on the role of citrate, malate and pectin esterification on the enzymatic degradation of Al- and Ca-pectate gels: possible implications for Al-tolerance

Aluminium (At) tolerance in plants may be conferred by reduced binding of Al in the cell wall through low root cation exchange capacity (CEC) or by organic acid exudation. Root CEC is related to the degree of esterification (DE) of pectin in the cell wall, and pectin hydrolysis plays a role in cell expansion. Therefore, it was hypothesised that Al-tolerant plants with a low root CEC maintain pectin hydrolysis in the presence of Al, allowing cell expansion to continue. Irrespective of the DE, binding of Al to pectin reduced the enzymatic hydrolysis of Al-pectin gels by polygalacturonase (E.C. 3.2.1.15). Pectin gels with calcium (Ca) were slightly hydrolysed by polygalacturonase. It was concluded, therefore, that Al tolerance conferred by low root CEC is not mediated by the ability to maintain pectin hydrolysis. Citrate and malate, but not acetate, effectively dissolved Al-pectate gel and led to hydrolysis of the dissolved pectin by polygalacturonase. The organic acids did not dissolve Ca-pectate, nor did they increase pectin hydrolysis by polygalacturonase. It was concluded that exudation of some organic acids can remove Al bound to pectin and this could alleviate toxicity, constituting a tolerance mechanism. (C) 2003 Editions scientitiques et medicales Elsevier SAS. All rights reserved.

Methodologies for calibration and predictive analysis of a watershed model

The use of a fitted parameter watershed model to address water quantity and quality management issues requires that it be calibrated under a wide range of hydrologic conditions. However, rarely does model calibration result in a unique parameter set. Parameter nonuniqueness can lead to predictive nonuniqueness. The extent of model predictive uncertainty should be investigated if management decisions are to be based on model projections. Using models built for four neighboring watersheds in the Neuse River Basin of North Carolina, the application of the automated parameter optimization software PEST in conjunction with the Hydrologic Simulation Program Fortran (HSPF) is demonstrated. Parameter nonuniqueness is illustrated, and a method is presented for calculating many different sets of parameters, all of which acceptably calibrate a watershed model. A regularization methodology is discussed in which models for similar watersheds can be calibrated simultaneously. Using this method, parameter differences between watershed models can be minimized while maintaining fit between model outputs and field observations. In recognition of the fact that parameter nonuniqueness and predictive uncertainty are inherent to the modeling process, PEST's nonlinear predictive analysis functionality is then used to explore the extent of model predictive uncertainty.

The application of wave induced forces to a two-dimensional finite element long wave hydrodynamic model

This paper describes the modification of a two-dimensional finite element long wave hydrodynamic model in order to predict the net current and water levels attributable to the influences of waves. Tests examine the effects of the application of wave induced forces, including comparisons to a physical experiment. An example of a real river system is presented with comparisons to measured data, which demonstrate the importance of simulating the combined effects of tides and waves upon hydrodynamic behavior. (C) 2002 Elsevier Science Ltd. All rights reserved.