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Modeling of the pyruvate production with Escherichia coli: comparison of mechanistic and neural networks-based models.

Three different models: the unstructured mechanistic black-box model, the input-output neural network-based model and the externally recurrent neural network model were used to describe the pyruvate production process from glucose and acetate using the genetically modified Escherichia coli YYC202 ldhA::Kan strain. The experimental data were used from the recently described batch and fed-batch experiments [ Zelić B, Study of the process development for Escherichia coli-based pyruvate production. PhD Thesis, University of Zagreb, Faculty of Chemical Engineering and Technology, Zagreb, Croatia, July 2003. (In English); Zelić et al. Bioproc Biosyst Eng 26:249-258 (2004); Zelić et al. Eng Life Sci 3:299-305 (2003); Zelić et al Biotechnol Bioeng 85:638-646 (2004)]. The neural networks were built out of the experimental data obtained in the fed-batch pyruvate production experiments with the constant glucose feed rate. The model validation was performed using the experimental results obtained from the batch and fed-batch pyruvate production experiments with the constant acetate feed rate. Dynamics of the substrate and product concentration changes was estimated using two neural network-based models for biomass and pyruvate. It was shown that neural networks could be used for the modeling of complex microbial fermentation processes, even in conditions in which mechanistic unstructured models cannot be applied.

Acetates↗

Coupling of a 3D finite element model of cardiac ventricular mechanics to lumped systems models of the systemic and pulmonic circulation.

In this study we present a novel, robust method to couple finite element (FE) models of cardiac mechanics to systems models of the circulation (CIRC), independent of cardiac phase. For each time step through a cardiac cycle, left and right ventricular pressures were calculated using ventricular compliances from the FE and CIRC models. These pressures served as boundary conditions in the FE and CIRC models. In succeeding steps, pressures were updated to minimize cavity volume error (FE minus CIRC volume) using Newton iterations. Coupling was achieved when a predefined criterion for the volume error was satisfied. Initial conditions for the multi-scale model were obtained by replacing the FE model with a varying elastance model, which takes into account direct ventricular interactions. Applying the coupling, a novel multi-scale model of the canine cardiovascular system was developed. Global hemodynamics and regional mechanics were calculated for multiple beats in two separate simulations with a left ventricular ischemic region and pulmonary artery constriction, respectively. After the interventions, global hemodynamics changed due to direct and indirect ventricular interactions, in agreement with previously published experimental results. The coupling method allows for simulations of multiple cardiac cycles for normal and pathophysiology, encompassing levels from cell to system.

Animals↗

Parametric modeling of DSC-MRI data with stochastic filtration and optimal input design versus non-parametric modeling.

In the paper MRI measurements are used for assessment of brain tissue perfusion and other features and functions of the brain (cerebral blood flow - CBF, cerebral blood volume - CBV, mean transit time - MTT). Perfusion is an important indicator of tissue viability and functioning as in pathological tissue blood flow, vascular and tissue structure are altered with respect to normal tissue. MRI enables diagnosing diseases at an early stage of their course. The parametric and non-parametric approaches to the identification of MRI models are presented and compared. The non-parametric modeling adopts gamma variate functions. The parametric three-compartmental catenary model, based on the general kinetic model, is also proposed. The parameters of the models are estimated on the basis of experimental data. The goodness of fit of the gamma variate and the three-compartmental models to the data and the accuracy of the parameter estimates are compared. Kalman filtering, smoothing the measurements, was adopted to improve the estimate accuracy of the parametric model. Parametric modeling gives a better fit and better parameter estimates than non-parametric and allows an insight into the functioning of the system. To improve the accuracy optimal experiment design related to the input signal was performed.

Animals↗

Applied muscle modelling: implementation of muscle-specific models.

Recent work in musculoskeletal modelling has seen the use of models which represent individual muscles in the human system. This paper presents a model of forearm supination in which models generate specific muscular forces to produce external supinator torque. The model output is compared to measured external torque for isometric and dynamic loading conditions. These data are used to construct isometric torque-angle and torque-angular velocity graphs for both model and experimental output. The discussion focuses on specific topics regarding implementation of muscle models in applied situations. These topics are demonstrated by observing the effect of parameter alteration on model output.

Computer Simulation↗

X-ray diffraction studies of 14-filament models of deoxygenated sickle cell hemoglobin fibers. II. Models based on the deoxygenated sickle hemoglobin crystal structure.

The calculated transforms of a number of crystal-based models of the deoxygenated sickle cell hemoglobin fiber have been compared with X-ray diffraction data of 15 A (1 A = 0.1 nm) resolution. The fiber models consist of 14 single strands of sickle cell hemoglobin (HbS) molecules, which associate into seven protofilaments arranged similarly to those present in the crystal structure. Six of the protofilaments are arranged in three crystallographic until cells extending in the c-axis direction with the seventh protofilament positioned so as to provide an elliptical cross-section when the assemblage is viewed down the fiber axis. Models were generated by systematically and independently translating each of the model's three subcells in steps of 3.5 A along the fiber axis. The seventh protofilament was kept fixed as a point of reference. Each translation of a subcell corresponded to a different fiber model whose transform was then compared with observed data. In all, over 46,000 transforms were computed; of these, three models with minimal residuals were identified. The free energy of packing for all crystal-based models was evaluated to find configurations of protofilaments possessing minimal free energies. The results of the calculations support the subcell configurations of two of the three models with minimal residuals.

Hemoglobin, Sickle↗

Models of the biological age of the rat. II. Multiple regression models in the study on influencing aging.

The study of influences on multicellular aging requires mathematical models of biological age (BA) as a standard against which deviations from "normal aging" can be measured. A long-term cohort study with initially 1100 male Sprague-Dawley rats served to establish multiple regression models of BA and to test the effects of fast days, physical training, a combination of fast days plus physical training, and the long-term action of subcutaneously applied lyophilized heterologous fetal testis material. All influences started after the attainment of maturity. The models were calculated on the basis of an exponential decrease in vitality during senescence. Twenty-three parameters from a total number of 42 were selected for a general model. By means of a factor analysis, the general model was subdivided into five factor models of BA to distinguish between primary and various types of secondary aging changes. All experimental conditions showed clearly detectable but not dramatic effects on the general model of BA in the sense of a revitalizaion. The most pronounced effect was found in the group pretreated with testis lyophilisate. The results obtained with the factor models suggest that this effect might be due to influences on primary aging as well as on some secondary changes.

Aging↗

Modelling of parasite populations: gastrointestinal nematode models.

This paper surveys models of nematode parasites of veterinary importance. A distinction is drawn between generic models which are usually simple formulations applicable to whole classes of parasite and specific models which are often more complex and designed to address questions concerning a particular species. Most of the models considered employ a deterministic framework. Four main groups are considered: generic models of trichostrongylid infection of domestic ruminants, specific models of trichostrongylid infection of domestic ruminants, specific models of experimental laboratory infections of rodents, and a specific model of nematode infections in wildlife.

Animals↗

Sartwell's incubation period model revisited in the light of dynamic modeling.

The objective is to look into the well-known robustness of Sartwell's disease incubation period (IP) lognormal model. A new approach is proposed that embeds the pathogenesis of infection into the framework of percolation theory derived from the physical sciences. A two-step model of the individual disease process is proposed. The first step has a stochastic basis: it is aimed at establishing the threshold position of subjects bound to be diseased. Agent and host factors entertain and help the process reach the threshold. They include all the biologic risk factors (age, exposure dose and intensity, route of inoculation, etc.) to which Sartwell's model is usually found robust. The threshold is the point of no return of the disease process. The threshold provides the initial conditions of the second step. The second step traces the evolution of the pathologic process until disease onset: it is based on a nonlinear deterministic model that progressively unfolds the individual fates. As a chaotic regime is embedded into the model and as chaos unavoidably develops at some time entailing disease onset, the IP distribution becomes independent of the initial conditions laid out at the threshold. Unpredictable disease time courses and onsets are obtained. Biological examples supporting the model are provided. A simulation of 1000 pathologic processes is undertaken according to a simple birth-and-death process of microorganisms or cancer cells. As expected, a lognormal fits the IP distribution over a wide range. A lack of lengthy IPs is, however, observed. A simple multiplicative process coincides exactly with a lognormal model, but a multiplicative-competitive process such as that which is embedded in the nonlinear deterministic model has a narrower distribution. Large sample sizes are, however, needed to uncover this departure from the lognormal. Biologically, at least two phases of the empiric IP should be told apart: lengthy IPs should be distinguished from short and median IPs. Lengthy IPs emphasize interaction (complexity) between the disease progression and the immunological defenses of the host. Simulated distributions involving process complexity closely fit selected cancer data sets. Process complexity of the host pathologic unfolding can actually be recognized and quantified.

Disease↗

Modelling and multivariable control in anaesthesia using neural-fuzzy paradigms. Part I. Classification of depth of anaesthesia and development of a patient model.

OBJECTIVE: The first part of this research relates to two strands: classification of depth of anaesthesia (DOA) and the modelling of patient's vital signs. METHODS AND MATERIAL: First, a fuzzy relational classifier was developed to classify a set of wavelet-extracted features from the auditory evoked potential (AEP) into different levels of DOA. Second, a hybrid patient model using Takagi-Sugeno Kang fuzzy models was developed. This model relates the heart rate, the systolic arterial pressure and the AEP features with the effect concentrations of the anaesthetic drug propofol and the analgesic drug remifentanil. The surgical stimulus effect was incorporated into the patient model using Mamdani fuzzy models. RESULTS: The result of this study is a comprehensive patient model which predicts the effects of the above two drugs on DOA while monitoring several vital patient's signs. CONCLUSION: This model will form the basis for the development of a multivariable closed-loop control algorithm which administers "optimally" the above two drugs simultaneously in the operating theatre during surgery.

Algorithms↗

In silico ADME modelling: prediction models for blood-brain barrier permeation using a systematic variable selection method.

Quantitative Structure-Property Relationship models (QSPR) based on in vivo blood-brain permeation data (logBB) of 88 diverse compounds, 324 descriptors and a systematic variable selection method, namely 'Variable Selection and Modeling method based on the prediction (VSMP)', are reported. Of all the models developed using VSMP, the best three-descriptors model is based on Atomic type E-state index (SsssN), AlogP98 and Van der Waal's surface area (r=0.8425, q=0.8239, F=68.49 and SE=0.4165); the best four-descriptors model is based on Kappa shape index of order 1, Atomic type E-state index (SsssN), Atomic level based AI topological descriptor (AIssssC) and AlogP98 (r=0.8638, q=0.8472, F=60.982 and SE=0.3919). The performance of the models on three test sets taken from the literature is illustrated and compared with the results from other reported computational approaches. Test set III constitutes 91 compounds from the literature with known qualitative BBB indication and is used for virtual screening studies. The success rate of the reported models is 82% in the case of BBB+ compounds and a similar success rate is observed with BBB- compounds. Finally, as the models reported herein are based on computed properties, they appear as a valuable tool in virtual screening, where selection and prioritization of candidates is required.

Blood-Brain Barrier↗

Marmoset monkey models of Parkinson's disease: which model, when and why?

Parkinson's disease (PD) is a debilitating neurodegenerative disease, with clinical features of tremor, muscular rigidity and akinesia, occurring as a result of midbrain dopamine loss. The search for treatments has relied heavily on animal models of the disorder. The use of monkey models of PD plays a distinct role in the development and assessment of novel treatments. The common marmoset (Callithrix jacchus) is a popular New World monkey used in the search for new treatments. These monkeys are easy to handle and survive well in captivity. This review examines the advantages of using marmoset monkeys in PD research and examines the different models available with reference to their use in pre-clinical assessment for novel therapeutic treatments. The most common models involve the administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 6-hydroxydopamine (6-OHDA). Recently, selective cerebral transgenic over-expression of alpha-synuclein has also been attempted in marmosets as a potential model for PD. Each model has its advantages. The MPTP-based model in marmosets resembles the disease with regards to the neuroanatomy of neurotransmitter loss; the unilateral application of 6-OHDA allows for the assessment of more complex sensorimotor deficits due to the presence of an intact 'control' side; the over-expression of alpha-synuclein in the midbrain results in the slow onset of behavioural symptoms allowing for a pre-symptomatic time window. The appropriateness of each of these marmoset models for the assessment of treatments depends on several factors including the experimental aim of the study and whether emphasis is placed on the analysis of behavioural deficits.

Animals↗

On the use of a patient-specific rapid-prototyped model to simulate the response of the human head to impact and comparison with analytical and finite element models.

Every year, thousands of fatalities result from head injuries, the majority of which are sustained in automotive accidents. In this paper, an experimental study of the response of the human head to impact is presented. A rapid prototyped model of a human head was generated based on high-resolution magnetic resonance imaging (MRI) scan data. The physical model was subjected to low velocity impacts using a metallic pendulum and a sensitivity study was performed to explore the influence of various parameters, including mass and velocity of the impactor, on the response. The experimental response characteristics are compared with predictions from an analytical model as well as with numerical predictions from finite element (FE) models generated from the same MRI data set. The results from the experimental tests closely match those predicted by both the analytical and the FE models and thus provide us with substantive corroboration of all three approaches. The remarkable agreement obtained between the measured response characteristics of rapid-prototyped skulls and numerical (FE) models obtained from in vivo MRI data clearly demonstrates the potential use of rapid-prototyping to generate experimental models for head impact studies, and, more generally, for the study of the response of complex bio-structures to loading. In addition, the quantitative and qualitative accuracy of the predictions from the analytical model is clearly demonstrated by the FE and experimental corroboration. In particular, the analytical prediction that, as impact mass drops the impact duration becomes increasingly short, appears to be substantiated, which has important implications for the onset of high pressure and shear strain gradients in the brain with potentially deleterious effects.

Adult↗

What should animal models of depression model?

In this article, we discuss what animal models of depression should be attempting to 'model'. One must first determine if the goal is to model the regulatory mechanisms by which antidepressant treatments alleviate the various symptoms of depression, or to model the dysregulatory mechanisms underlying the etiology of those symptoms. When modeling the mechanisms of antidepressant effects, a key feature that is often overlooked is the time course required for behavioral efficacy. Even in the clinical literature, there is considerable confusion and inconsistency in defining and identifying 'time of onset' of clinical effect. Although the 'therapeutic lag' may not be as long as has been commonly believed, it does occur. Observable improvement in either global symptomatology or specific symptoms becomes evident after 7-14 days of treatment, and more complete recovery takes considerably longer. Thus, any model addressing potential mechanisms of antidepressant action should exhibit a similar time-dependency. Second, whether attempting to address mechanisms underlying behavioral effects of antidepressants, or the neurobiological substrates underlying the development and manifestation of depression, it is essential to recognize that the syndrome of depression is a diagnostic construct that includes a variety of disparate symptoms, some of which may be related mechanistically, and others that may not be specific to depression, but may cut across categorical diagnostic schemes. Further, it is critical to recognize the close relationship of depression and anxiety. Psychological studies have suggested that the myriad symptoms of depression and anxiety may be subsumed within a more limited number of distinct behavioral dimensions, such as negative affect (neuroticism), positive affect, or physiologic hyperarousal. These dimensions may be related to the functioning of specific neurobiological systems. Thus, rather than trying to recreate or mimic the entire spectrum of symptoms comprising the syndrome of depression, it may be more informative to develop animal models for these behavioral dimensions. Such models may then provide access not only to the neural regulatory mechanisms underlying effective antidepressant treatment, but may also provide clues to the processes underlying the development and manifestation of depression.

Animals↗

Measuring and modelling the airborne particulate matter mass concentration field in the street environment: model overview and evaluation.

This paper discusses the outline structure and preliminary evaluation of an emission-dispersion model for predicting the temporal and spatial distribution of vehicle-derived airborne particulate matter mass concentration in street canyons. The model is called Street Level Air Quality (SLAQ). SLAQ is semi-empirical, in that it uses not only results from field and wind tunnel experiments but also theory and models derived from multiple runs of numerical routines in order to simulate the basic physical processes within the street canyon. A combination of a plume model, for the direct contribution of vehicle exhaust, and a box model for the recirculating part of the pollutants in the street, is used to predict concentration for receptors within the canyon. Emission rates of vehicle-derived particulate matter are calculated within SLAQ, which serve as input to the dispersion module. Exhaust emission rates are scaled element by element along the street for each of the lanes according to the direction of traffic flow to account for modal operation of vehicles near signalised intersections. This refinement allows SLAQ to account for non-uniformity in along-canyon emission rates and to model a street that has several intersections along its length. Thermal turbulence due to environmental surface sensible heat and vehicle-generated heat is accounted for in the model. Other features of SLAQ include correction for the urban heat island effect, dry deposition, wet deposition, particle settling and estimation of wind direction standard deviation, when this latter data is not available. SLAQ has been evaluated in a street in Loughborough, Leicestershire, United Kingdom and correlation coefficient of 0.8 between the modelled and measured concentrations has been obtained.

Aerosols↗

Experimental models of subarachnoid hemorrhage in the rat: a refinement of the endovascular filament model.

The rat endovascular filament model has been utilized to study subarachnoid hemorrhage (SAH). Because the severity of the hemorrhage with this model has proven difficult to modulate, we attempted to vary the hemorrhage by modifying filament size, and compared this model to the blood injection method with regards to acute physiological responses and hemorrhage size. SAH was achieved using either a 3-0 or 4-0 filament, or by injecting 0.3 cc of autologous blood into the cisterna magna. Peak ICP elevations were lowest in the 4-0 filament group. CBF decreased acutely and rose from its nadir in all three models with the injection model demonstrating the earliest recovery. In the injection group, mean arterial blood pressure rose acutely and remained elevated, whereas in the 3-0 group, MABP rose transiently and in the 4-0 group it did not rise significantly. Histologically, there was less subarachnoid blood in the 4-0 group vs. the injection or 3-0 groups and a different distribution of blood in the two experimental models. Varying filament size provides a method to modulate the severity of SAH in the filament model. In addition, the rat endovascular filament and blood injection models produce different distribution of blood and physiological responses.

Animals↗

Model validation software for classification models using repeated partitioning: MVREP.

The process of assessing the prediction ability of a computational model is called model validation. For models predicting a categorical response, the prediction ability is usually quantified by prediction measures such as sensitivity, specificity, and accuracy. This paper presents a software Model Validation using Repeated Partitioning (MVREP) that implements a computer-intensive, nonparametric approach to model validation, which we call the re-partitioning method. MVREP, developed using the SAS Macro language, repeats the process of randomly partitioning a dataset and subsequently performing standard model validation procedures, such as cross-validation, a large number of times and generates the empirical sampling distributions of prediction measures. The means of the sampling distributions serve as the point estimates of prediction measures of the model. The variances of the sampling distributions provide a direct assessment of variability for the point estimates of prediction measures. An example is presented using a mouse developmental toxicity chemical dataset to illustrate how the software can be used for the assessment of structure-activity relationships models.

Animals↗

The community orientation of social model and medical model recovery programs.

This paper examines the extent to which two social model programs and one medical model program operating in the same county were able to establish links between their programs and the community at large. Emphasis on community and environment is a hallmark of social model programs, suggesting that more effective links will have been established at those programs than at the medical model program. Items from the community orientation subscale of the Social Model Philosophy Scale provide a guide for this qualitative analysis. Community resources considered include self-help 12-step programs, as well as community agencies chartered to address employment, education, family counseling, and housing. All three programs were found to have a strong emphasis on Alcoholics Anonymous (AA)/Narcotics Anonymous (NA). At the medical model program (MMP), patients were exposed to three to five AA or NA meetings per week during their 10-day stay, although for the most part, meetings in the MMP had few, if any, outsiders. The social model programs exposed residents to a number of different AA and NA meetings, both at the program and in the community over a period of months. The MMP program was found to have minimal links with the community for employment, education, or other services. The MMP program counselors did try to make referrals to other substance abuse programs upon release from the hospital, and to insure that patients had somewhere to go for shelter after being discharged. In contrast, social model programs encouraged residents to utilize community resources for health, education, and social service needs.

Community Health Services↗

A contaminated binormal model for ROC data: Part II. A formal model.

RATIONALE AND OBJECTIVES: A contaminated binormal receiver operating characteristic (ROC) model is proposed to account for ROC data that have very few false-positive reports even though many healthy subjects are sampled. The model assumes that no signal information is captured for a proportion of abnormalities, and that these abnormalities have the same distribution as noise along the latent decision axis. MATERIALS AND METHODS: The authors developed a formal psychophysical model, presented here in detail. They have specified the psychophysical assumptions of the theory, and have provided proofs that include all essential details, from assumptions to implications. With the technical details that are provided, this theory can be implemented with computer programs to fit data. RESULTS: The new model can fit ROC data in which some or all of the ROC points have false-positive fractions of 0 and true-positive fractions of less than 1, without implying that performance is perfect. The resulting ROC curves are always proper, never exhibiting inappropriate chance line crossings. The model predicts that, under certain conditions, a bimodal categorical rating histogram will be observed for the signal distribution. The model predicts a relationship between the mean and standard deviation of the signal distribution and holds that, for expert decision makers, there are situations in which the prevalence and utility matrix preclude operating points in some ROC regions. The model has a straightforward extension to the joint detection and localization ROC curve. CONCLUSION: The contaminated binormal model accounts for ROC data with few or no false-positive reports.

Decision Theory↗