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PubMed1999

Mathematical modelling of morphogenesis in fungi: a key role for curvature compensation ('autotropism') in the local curvature distribution model.

The assumption that the mushroom stem has the ability to undergo autonomic straightening enables a mathematical model to be written that accurately mimics the gravitropic reaction of the stems of Coprinus cinereus. The straightening mechanism is called curvature compensation here, but is equivalent to the 'autotropism' that often accompanies the gravitropic reactions of axial organs in plants. In the consequently revised local curvature distribution model, local bending rate is determined by the difference between the 'bending signal' (generated by gravitropic signal perception systems) and the 'straightening signal' (proportional to the local curvature at the given point). The model describes gravitropic stem bending in the standard assay with great accuracy but has the virtue of operating well outside the experimental data set used in its derivation. It is shown, for example, that the mathematical model can be fitted to the gravitropic reactions of stems treated with metabolic inhibitors by a change of parameters that parallel the independently derived physiological interpretation of inhibitor action. The revised local curvature distribution model promises to be a predictive tool in the further analysis of gravitropism in mushrooms.

Calcimycin↗

PubMed2002

The genetic absence epilepsy rat from Strasbourg (GAERS), a rat model of absence epilepsy: computer modeling and differential gene expression.

PURPOSE: We present results obtained by computer modeling of the thalamic network and differential gene expression analysis in a rat strain with absence epilepsy, the genetic absence epilepsy rat from Strasbourg (GAERS). METHODS: (a) Computer modeling used equations from the Hodgking-Huxley model with a circuit of 13 reticular thalamic (nRt) and 39 thalamocortical (TC) neurons; (b) gene-expression analysis using differential mRNA display (DD), in situ hybridization, Northern blotting, and competitive reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS: (a) Computer modeling showed an increased network synchrony in the thalamic circuit as the value of conductance of low-voltage activated calcium channel (LVACC) is increased. (b) Using differential mRNA display, a 40% upregulation of the H-ferritin mRNA in the hippocampus was demonstrated. Looking for some candidate genes of the VACC family, no difference was found in the alpha1G mRNA expression between GAERS and control animals, whereas a decreased expression of the alpha1E subunit was observed in the cerebellum and the brainstem of the GAERS. This phenomenon was not observed in young animals when the epileptic phenotype is not expressed. CONCLUSIONS: The use of computer modeling appeared to be an efficient way to evaluate the impacts of electrophysiologic findings in vivo from single cells on an entire circuit. No clear single gene defect was revealed so far in GAERS. More information could arise from linkage analysis. However, some brain structures like hippocampus or cerebellum classically not known to be involved in the production of absence spike-and-wave discharges could in fact participate in the development of this phenotype.

Animals↗

PubMed2000

Pharmacokinetic and pharmacodynamic modeling of mizolastine in healthy volunteers with an indirect response model.

OBJECTIVE: The aim of this work was to model the pharmacokinetic and pharmacodynamic relationship of mizolastine, a new H1-receptor antagonist obtained from histamine-induced wheal and flare inhibition test. METHODS: Fifteen healthy volunteers participated in this double-blind crossover study and randomly received single doses of 5, 10, 15, and 20 mg of mizolastine and placebo at 1 week intervals. Simultaneous histamine tests and blood samples were performed before and at 9 different times up to 24 hours after each dosing. Pharmacokinetic and pharmacodynamic modeling were performed subject by subject for the 4 doses altogether by nonlinear regression. First, plasma concentrations were fit according to a two-compartment open model with zero order absorption and first order elimination. Then an indirect response model with inhibition of the formation rate was developed to describe the pharmacodynamic relationships between flare or wheal raw areas and plasma concentrations with the use of the pharmacokinetic parameters that were previously estimated. RESULTS: Mizolastine dose dependently inhibited the histamine-induced wheal and flare formation with a submaximum effect attained after 10 mg. The mean values of the pharmacodynamic parameters of apparent zero-order rate constant for the flare or wheal spontaneous appearance (k(in)), the first-order rate constant for the flare or wheal disappearance, the mizolastine concentration that produced 50% suppression of the maximum attainable inhibition of k(in), and the maximum attainable inhibition of the effect production were 14.1 cm2/h (coefficient of variation [CV], 32%), 0.68 h(-1) (CV, 24%), 21.1 ng/mL (CV, 77%), and 0.92 (CV, 8%), respectively, for the flare and 1.9 cm2/h (CV, 64%), 0.63 h-1 (CV, 39%), 43.9 ng/mL (CV, 68%), and 0.87 (CV, 12%), respectively, for the wheal inhibition. CONCLUSION: Pharmacokinetic and pharmacodynamic relationships of mizolastine were reliably described with the use of an indirect pharmacodynamic model; this led to an accurate prediction of the pharmacodynamic activity of mizolastine.

Administration, Oral↗

PubMed1992

Modeling household fertility decisions: a nonlinear simultaneous probit model.

"This article proposes new methods for modeling household fertility decisions....Specifically, we model the trivariate distribution of wife's stated desire for additional children, husband's stated desire for additional children, and subsequent fertility. In the model, the stated desire of the husband (wife) is viewed as an indicator of the husband's (wife's) latent disposition toward subsequent fertility. The husband's (wife's) disposition is allowed to depend on the wife's (husband's) disposition. The two dispositions are then combined to generate the couple's propensity for subsequent fertility. We show how such models can be estimated and tested and how the parameters can be used to assess the relative influence of each partner on the propensity." The model is tested using U.S. data from the Princeton Fertility Study for the 1950s and 1960s. The results indicate that "both husband's disposition score and wife's disposition score affect the propensity score, and, under some additional assumptions, that husbands and wives have equal relative influence on the propensity."

Americas↗

PubMed2001

Alternative models for carcinogenicity testing: weight of evidence evaluations across models.

Twenty-one chemicals were evaluated by standardized protocols in 6 mouse models that have been sugggested as alternatives to the 2-year mouse bioassay. Included were genotoxic and nongenotoxic chemicals, carcinogens and noncarcinogens, immunosuppressive and estrogenic agents, peroxisome proliferators, and chemicals producing cancer in rodents by other mechanisms. Mice were sacrificed at the end of 6 to 12 months, depending on the model. Standardized histopathology, biostatistical analyses, and criteria for overall evaluation of the results were employed. The TgAC transgenic (dermal and oral administration), the Tg-rasH2 transgenic, the heterozygous p53 gene knockout, the homozygous XPA and homozygous XPA-heterozygous p53 gene knockout, and the neonatal mouse models were evaluated. The chemicals were also evaluated in the in vitro SHE assay. Comparison of the results between the various in vivo models suggest that they might have usefulness as screening bioassays for hazard identification for potential human carcinogens. They have the benefits of being quicker, less expensive, and involve fewer animals than the traditional 2-year mouse bioassay. They do not appear to be overly sensitive. However, they do not definitively distinguish between genotoxic and nongenotoxic carcinogens, and they do not have 100% specificity for identifying human carcinogens. Like the 2-year bioassay, the results from these models need to be evaluated in conjunction with other information on a chemical in an overall weight-of-evidence, integrated analytical approach to assess risk for human exposures.

Animal Testing Alternatives↗

PubMed2006

Replicated positive results for the VCC model of vocational intervention after ABI within the social model of disability.

PRIMARY OBJECTIVE: Replicated evaluation of the Vocational Case Co-ordinator (VCC) Model for vocational rehabilitation after acquired brain injury (ABI). RESEARCH DESIGN: Referral cohort studied within the social model of disability. METHODS AND PROCEDURES: One hundred and thirty-eight participants with ABI were assisted by a VCC to develop self-directed vocational plans and networks of medical centre and community services. Early intervention, work trials, temporary or long-term supported employment and employer education are fundamental features of the VCC Model. MAIN OUTCOMES AND RESULTS: One year after initial placement 80% of participants remained in community-based employment, 56% of the total sample with no support. Better outcomes were associated with earlier intervention but not with initial injury severity. CONCLUSIONS: Results replicate original findings of the effectiveness of the VCC Model of vocational rehabilitation after ABI with a different VCC. Implications for social change within the social model of disability are discussed.

Adolescent↗

PubMed2004

Stage model of recovery for chemically dependent adolescents: part 1--methods and model.

This qualitative study, presented in two parts, refines the model of how chemically dependent adolescents initiate and engage in the recovery process. Part 1 describes the research process and results used to derive the model. The model was derived from theory grounded in verbatim reports of 30 chemically dependent participants who first attempted recovery from chemical dependence during adolescence. The constant comparative method of grounded theory was used to analyze the data. This stage model of adolescent recovery includes the using/precontemplation, transition, early recovery, and ongoing recovery stages; the transition stage is divided into contemplation and action phases. The stages, phases, and significant events are similar, but not identical to, those presented in adult-based models of recovery from chemical dependence. In Part 2, the resulting theory is compared with extant theories on stages of recovery in chemically dependent adults, treatment implications for the adolescent population are reviewed, and topics for further research are suggested.

Adolescent↗

PubMed1992

Comparison of protein models minimized by the all-atom and united-atom models in the AMBER force field: correlation of RMS deviation with the crystallographic R factor and size.

We performed energy minimization of 25 protein structures, which vary significantly in their size, secondary structural content and crystallographic R factor, in the AMBER force field. We used an unconstrained path and the conjugate gradients algorithm. To determine the reliability of the united-atom approximation, we minimized all the proteins using both the all-atom and united-atom models. The RMS deviations of the minimized structures were plotted as a function of the crystallographic R factors of the initial structures. For the all-atom models, we found a strong linear relationship between the RMS deviations and the R factors (correlation coefficient of 0.78). The RMS deviations of protein structures minimized using united-atom models showed a wider range of distribution and had a correlation coefficient with the R factors of only 0.52. The RMS deviations decrease with an increase in the size of the protein, probably due to the decreased ratio of surface area to volume with increasing size of the protein. The surface atoms and residues showed higher RMS deviations than those in the interior of the protein. Even in these plots the united-atom models show a wide range of distribution of data points. From these results, we recommend the use of all-atom models for energy minimization of proteins in the AMBER force field.

Computer Graphics↗

PubMed2004

The bereavement model, stroke and rehabilitation: a critical analysis of the use of a psychological model in professional practice.

PURPOSE: This pilot study aimed to explore with stroke survivors, carers and professionals, the impact of stroke and the process of recovery and rehabilitation. One theme that emerged in interviews with professionals was their use of the bereavement model in relation to recovery from stroke. The purpose of this paper is to explore the ways in which professionals use the bereavement model to explain and manage the rehabilitation of stroke survivors. METHOD: A person-centred study using qualitative research methods, semi structured interviews and self report diaries to explore with stroke survivors and carers the impact of stroke on their lives. Twenty-five interviews with stroke survivors, 23 individual or with carers and seven in two focus groups. Evidence from four self- report diaries provided more detailed examples of the everyday experiences of the survivors. A set of parallel interviews involving 17 professionals involved in the care and support of such individuals, nine individual and one group interview involving a community rehabilitation team. RESULTS: The bereavement model can be identified in the literature aimed at professionals, and was evident in some professional accounts of stroke but was absent from survivors' and carers' accounts of stroke. In over half the interviews, professionals made reference to the bereavement model to explain a process of loss and readjustment. While survivors in their accounts of life after a stroke did acknowledge the ways in which stroke disrupted every-day life and resulted in losses and disabilities, their perception of such losses and disruption was shaped by the context of their every-day life. Most survivors sought to actively manage their recovery by setting goals. They wanted professional support in achieving their goals. The bereavement model appeared to be used by professionals in situations where there was a conflict over goals and professionals felt that survivors had become 'stuck' and their goals unrealistic. CONCLUSIONS: Following stroke, people try to make sense of what has happened and normalize their lives by setting themselves goals to progress towards recovery. It is important that professionals communicate effectively so that their interventions are grounded in and support the survivors' goals and strategies.

Adult↗

PubMed1998

Regression spline models and model calibration in the identification of protein storage conditions.

The study of protein-construct activity provides valuable insight in the early stages of drug discovery. Identification of optimal storage conditions that maintain activity of the constructs is an important issue. In the study reported herein, a space-filling design was used to assess the effects of eight design variables--buffer, pH, NaCl, protein concentration, reducing agent, detergent, MgCl2, and temperature--on protein activity. A regression spline analysis is presented, and settings of the explanatory factors resulting in the best predicted protein activity over the explored space are identified. The models are selected initially based on the Akaike information criterion and later assessed via root mean square error and cross-validation root mean square error. Detergent, buffer, temperature, and smooth functions of pH and protein concentration were found to have large effects on protein activity. The models were calibrated via calculation of the empirical distribution of the cross-validation root mean square error. In this framework several models provide a similar fit, and further experimentation is required for more definitive conclusions regarding protein storage conditions to be made. The cross-validation root mean square error calibration of models is recommended for applications involving comparisons of models with respect to their predictive ability.

Buffers↗

PubMed2004

Model parameterization, prior distributions, and the general time-reversible model in Bayesian phylogenetics.

Bayesian phylogenetic methods require the selection of prior probability distributions for all parameters of the model of evolution. These distributions allow one to incorporate prior information into a Bayesian analysis, but even in the absence of meaningful prior information, a prior distribution must be chosen. In such situations, researchers typically seek to choose a prior that will have little effect on the posterior estimates produced by an analysis, allowing the data to dominate. Sometimes a prior that is uniform (assigning equal prior probability density to all points within some range) is chosen for this purpose. In reality, the appropriate prior depends on the parameterization chosen for the model of evolution, a choice that is largely arbitrary. There is an extensive Bayesian literature on appropriate prior choice, and it has long been appreciated that there are parameterizations for which uniform priors can have a strong influence on posterior estimates. We here discuss the relationship between model parameterization and prior specification, using the general time-reversible model of nucleotide evolution as an example. We present Bayesian analyses of 10 simulated data sets obtained using a variety of prior distributions and parameterizations of the general time-reversible model. Uniform priors can produce biased parameter estimates under realistic conditions, and a variety of alternative priors avoid this bias.

Animals↗

PubMed2003

Uising WinBUGS to fit nonlinear mixed models with an application to pharmacokinetic modelling of insulin response to glucose challenge in sheep exposed antenatally to glucocorticoids.

Many chronic diseases of adulthood, such as hypertension and diabetes, are now believed to have at least some of their origins before birth. Extensive studies in animal models have identified antenatal exposure to excess glucocorticoids as a leading candidate for the physiological cause of fetal compromise. The resulting adverse intra-uterine environment appears to "program" the individual for higher risk of subsequent disease. We present an analysis of blood glucose and insulin concentrations collected during glucose tolerance tests at 6 and 12 months postnatal age in a cohort of sheep that were treated antenatally with injections of betamethasone (a synthetic glucocorticoid) which, when injected into the mother, cross the placenta to the fetus. A simple pharmacokinetic model, essentially a modification of the single compartment model with first-order absorption and elimination, is developed to describe the time course of glucose concentration and the associated insulin response. The resulting nonlinear mixed model is implemented in a Bayesian framework using the Markov chain Monte Carlo technique Gibbs Sampling via the software package BUGS. This sampling process allows inferences to be made directly about derived quantities with an immediate physical interpretation, such as the maximum insulin concentration in response to glucose challenge. At 6 months postnatal age, sheep treated with antenatal injections of synthetic glucocorticoids had raised insulin concentration in comparison to controls after bolus administration of glucose. This effect persisted to 12 months postnatal age only in the sheep that received multiple doses of glucocorticoids. Moreover, the raised insulin concentration in sheep that received direct injections of synthetic glucocorticoid as fetuses is accompanied by better glucose clearance than in those sheep that received only saline injections, a phenomenon that is not observed in the animals that received maternal injections. It is argued that the fitting of an appropriate statistical model to complex physiological data does not necessarily proclude a result that has a clear interpretation for clinical scientists.

Animals↗

PubMed1993

Development of simulation models for protein folding in a thermal annealing process--I: A simulation of BPTI folding by the pearl necklace model.

A model system is proposed to simulate the folding processes of proteins during thermal annealing. This system consists of four subsystems: (i) the pearl necklace model with isotropic inter-residue interactions; (ii) the extended pearl necklace model with anisotropic interaction potentials; (iii) molten globule phase dynamics; and (iv) final generation of the three-dimensional structure of a given protein. In this paper results obtained with the pearl necklace model are reported. This model consists of spherical elements and virtual bonds of 3.8 A in length and is intended to simulate dynamical processes at relatively high temperature where entropic terms play a dominant role. Inter-residue interactions are composed of spherical soft repulsive potentials and hydrophobic interactions inherent to respective residues. A simulation of folding processes of BPTI starting from the fully extended conformation indicated that intermediates, even at early stages of folding, are not randomly coiled but assume organized structures that resemble, to some extent, the native conformation.

Aprotinin↗

PubMed2001

Model-based administration of inhalation anaesthesia. 1. Developing a system model.

This paper is the first of a series of reports on a system model for the administration of inhalation anaesthesia. We present the development and basic testing of the model. It is a multiple-gas model; it covers fresh-gas flow rates from basal to more than total ventilation and includes an actual, not an idealized, circle-absorber breathing system featuring a standing bellows ventilator. Kinetics of nitrogen, oxygen, carbon dioxide, nitrous oxide, inhaled anaesthetic agents and helium are described. Their partial pressures sum to the total pressure. Ventilation and cardiac output are treated as continuous, not cyclical. The model of the breathing system was empirically matched to the chosen one (a GMS absorber and 7850 ventilator (Datex-Ohmeda)). Predictions for the wash-in of isoflurane and the uptake of desflurane and isoflurane agree well with observed data. The results obtained by continuously checking total gas pressures, calculating mass balances and simulating the measurement of alveolar space by the closed-circuit helium dilution method support the mathematical credibility of the model. It thus merits further exploration.

Algorithms↗

PubMed1990

A dynamic growth model of vegetative soya bean plants: model structure and behaviour under varying root temperature and nitrogen concentration.

A differential equation model of vegetative growth of the soya bean plant (Glycine max (L.) Merrill cv. Ransom') was developed to account for plant growth in a phytotron system under variation of root temperature and nitrogen concentration in nutrient solution. The model was tested by comparing model outputs with data from four different experiments. Model predictions agreed fairly well with measured plant performance over a wide range of root temperatures and over a range of nitrogen concentrations in nutrient solution between 0.5 and 10.0 mmol NO3- in the phytotron environment. Sensitivity analyses revealed that the model was most sensitive to changes in parameters relating to carbohydrate concentration in the plant and nitrogen uptake rate.

Carbohydrate Metabolism↗

PubMed2006

Homology modeling using parametric alignment ensemble generation with consensus and energy-based model selection.

The accuracy of a homology model based on the structure of a distant relative or other topologically equivalent protein is primarily limited by the quality of the alignment. Here we describe a systematic approach for sequence-to-structure alignment, called 'K*Sync', in which alignments are generated by dynamic programming using a scoring function that combines information on many protein features, including a novel measure of how obligate a sequence region is to the protein fold. By systematically varying the weights on the different features that contribute to the alignment score, we generate very large ensembles of diverse alignments, each optimal under a particular constellation of weights. We investigate a variety of approaches to select the best models from the ensemble, including consensus of the alignments, a hydrophobic burial measure, low- and high-resolution energy functions, and combinations of these evaluation methods. The effect on model quality and selection resulting from loop modeling and backbone optimization is also studied. The performance of the method on a benchmark set is reported and shows the approach to be effective at both generating and selecting accurate alignments. The method serves as the foundation of the homology modeling module in the Robetta server.

Amino Acid Sequence↗

PubMed1998

Modeling the migration of fallout radionuclides in soil using a transfer function model.

A stochastic model for transport of radionuclides in soil is presented. It is based on probability density functions of solute displacements, which are interpreted as impulse response functions of a linear dynamic system. Two transport models are discussed: (1) a convective-stochastic approach which takes into account spatial variability of flow and sorption and leads to a lognormal probability distribution of displacements, and (2) the conventional convective-dispersive model with a constant retardation coefficient. To compare their applicability, both models were applied to depth distributions of 90Sr and 137Cs fallout measured in an Orthic Podsol. The convective-stochastic approach was found to provide a better representation of the observed depth distributions. Using this model, migration rates of the radionuclides were calculated.

Models, Theoretical↗

PubMed1997

CCK receptor antagonists in animal models of anxiety: comparison between exploration tests, conflict procedures and a model based on defensive behaviours.

The present experiments compared the behavioural effects of one cholecystokininA (CCKA; lorglumide) and two CCKB (PD 135,158 and LY 288513) receptor antagonists in classical animal models of anxiety, including conflict tests (punished lever pressing and Vogel drinking tests in rats) and exploratory models (elevated plus-maze test in rats and light/dark choice test in mice), and a recently developed mouse defence test battery (MDTB) which has been validated for the screening of both anti-panic and classical anxiolytic (i.e. benzodiazepines) drugs. Diazepam was used as a positive control. Results showed that all three CCK receptor antagonists were inactive in both conflict tests. Furthermore, despite the incorporation of more ethologically-derived measures (i.e. risk assessment activities or directed exploration, or both) no effects were observed in the elevated plus-maze and in the light/dark tests. These profiles contrast with that of diazepam which displayed clear anxiolytic-like effects in these models. In the MDTB, the CCK receptor antagonists failed to modify parameters (i.e. risk assessment, defensive threat/attack and escape attempts), which have been shown to be particularly sensitive to drugs effective in the treatment of generalized anxiety. By contrast, the CCKB receptor antagnoists PD 135,158 (0.001-0.01, 1 mg/kg, i.p.) and LY 288513 (1 and 3 mg/kg, i.p.) significantly decreased avoidance distance when the rat was first placed in the test apparatus, an effect which is consistent with an anti-panic-like action. Overall, these findings support the idea that classical animal models of anxiety may not be suitable for evaluation of the behavioural effects of CCK receptor antagonists, whereas tests which may model certain aspects of human panic such as the MDTB appear to be more reliable tools when screening such compounds.

Aggression↗