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Accuracy and precision of computer models to predict passage of crude protein and amino acids to the duodenum of lactating cows.

To evaluate the ability of several models to accurately and precisely predict the passage of crude protein (CP) and amino acids to the duodenum of lactating cows, we simulated data from six published studies using the 1989 National Research Council equations, the Mepron Dairy Ration Evaluator (version 1.1), the University of Pennsylvania release of the Net Carbohydrate and Protein System (version 2.12p), the Cornell Net Carbohydrate and Protein System (version 3), and CPM Dairy (version 1.0). Models overestimated the passage of CP from microbes by an average of 323 g/d, and underestimated the passage of CP from feed by an average of 874 g/d. These two errors were partially canceled when CP from microbes and feed were summed to estimate passage of total CP to the duodenum. Many dietary composition variables appeared to bias the predictions; however, the influence of any one variable was small. The efficiency of modeling was high for most predictions but was variable for predicting passage of specific individual amino acids to the small intestine depending on the model selected. These simulations indicated no obvious advantage for any model over the others tested. The models responded to changes in diets by altering the amount of protein from microbes and feed that reached the duodenum, resulting in improved accuracy of predictions of duodenal CP passage compared with simply assuming a constant value for passage of CP to the duodenum.

Amino Acids↗

Computer model for mechanisms underlying ultradian oscillations of insulin and glucose.

Oscillations in human insulin secretion have been observed in two distinct period ranges, 10-15 min (i.e. rapid) and 100-150 min (i.e., ultradian). The cause of the ultradian oscillations remains to be elucidated. To determine whether the oscillations could result from the feedback loops between insulin and glucose, a parsimonious mathematical model including the major mechanisms involved in glucose regulation was developed. This model comprises two major negative feedback loops describing the effects of insulin on glucose utilization and glucose production, respectively, and both loops include the stimulatory effect of glucose on insulin secretion. Model formulations and parameters are representative of results from published clinical investigations. The occurrence of sustained insulin and glucose oscillations was found to be dependent on two essential features: 1) a time delay of 30-45 min for the effect of insulin on glucose production and 2) a sluggish effect of insulin on glucose utilization, because insulin acts from a compartment remote from plasma. When these characteristics were incorporated in the model, numerical simulations mimicked all experimental findings so far observed for these ultradian oscillations, including 1) self-sustained oscillations during constant glucose infusion at various rates; 2) damped oscillations after meal or oral glucose ingestion; 3) increased amplitude of oscillation after increased stimulation of insulin secretion, without change in frequency; and 4) slight advance of the glucose oscillation compared with the insulin oscillation.(ABSTRACT TRUNCATED AT 250 WORDS)

Activity Cycles↗

Computer model of fetal-maternal heat exchange in sheep.

We constructed and used a mathematical model of maternal-fetal heat exchange in the sheep to explore the effects of changes in certain parameters on steady-state fetal temperatures and to determine whether the fetus in the model has any potential to control its own temperature. The model took into account both fetal and placental heat production and exchange of heat in the placenta, across the fetal skin, via amniotic fluid, and through the uterine wall. The maternal ewe was assumed to be a constant temperature heat sink. Changes in placental or fetal heat production were calculated to change the ratio of heat exiting across the placenta or fetal skin significantly but to have little effect on fetal core temperature, e.g., a rise of only 0.8 degrees C was predicted after a twofold increase in fetal heat production. Fetal placental blood flow was calculated to affect fetal temperature the most of any flow, a reduction to zero causing fetal temperature to rise 5.0 degrees C. Changes in heat conductances between fetal skin and amniotic fluid, or between amniotic fluid and uterine wall, had minimal effect on fetal temperature. From the model calculations here and because heat exchange within the sheep placenta has previously been calculated to be extremely efficient, we conclude that the fetal sheep has little ability to control its temperature by changes in heat dissipated through extraplacental pathways. Thus the model predicts an effective heat clamp that closely links fetal to maternal temperature.

Animals↗

The role of intramyocardial pressure during coronary sinus interventions: a computer model study.

A model consisting of an arterial, a capillary, and a venous compartment was developed to reproduce experimentally determined hemodynamic results of the arterial and venous sides of the coronary circulation. From the model, intramyocardial flow between capillaries and veins, which is inaccessable to measurement, was then estimated. Results are given for normal perfusion and coronary sinus occlusion conditions. For both conditions, intramyocardial pressure was varied within the model in order to study its impact on intramyocardial flow. For low and moderate intramyocardial pressures under coronary sinus occlusion, retrograde flow from veins to capillaries was seen to increase with increasing intramyocardial pressure. However, for very high values of intramyocardial pressure, which are close to left ventricular pressure, retrograde flow declined.

Computer Simulation↗

Downstream determinants of pulsatility of the mean velocity waveform in the umbilical artery as predicted by a computer model.

An electrical analog model of the umbilicoplacental circulation that was based on hemodynamic measurements in fetal sheep was used to predict the mean blood velocity waveform in the umbilical artery. A 300% increase in placental resistance reduced the normally forward diastolic blood velocity in the umbilical artery nearly to zero. When resistance was normal, variations in umbilical arterial wall thickness (h) and elastic modulus (E) had little effect on the velocity waveform, whereas a 20% increase in radius (a) halved the ratio of the diastolic-to-systolic blood velocity (D/S). When placental resistance was high, abnormal umbilical arterial wall properties (a large, or h or E small) further reduced D/S. We conclude that high placental resistance, low umbilical arterial resistance, or a combination of high placental resistance with abnormal umbilical arterial wall properties are the primary downstream determinants of elevated pulsatility in umbilical arterial blood velocity.

Animals↗

Computer modelling of the 3-dimensional structures of the cyanobacterial hepatotoxins microcystin-LR and nodularin.

The 3-dimensional structures of two cyanobacterial hepatotoxins microcystin-LR, a cyclic heptapeptide and nodularin, a cyclic pentapeptide, and the novel amino acid ADDA (3-amino-9-methoxy-2,6,8-trimethyl-10-phenyl-4,6-decadienoic acid) were constructed, and optimized using the CHEM-X molecular mechanics program. The peptide rings were planar and of rectangular shape. Optimized ADDA formed a U-shape and a difference in the orientation of ADDA with respect to the peptide ring of the two hepatotoxins was observed.

Computer Simulation↗

Computational modeling of healing: an application of the material force method.

The basic aim of the present contribution is the qualitative simulation of healing phenomena typically encountered in hard and soft tissue mechanics. The mechanical framework is provided by the theory of open system thermodynamics, which will be formulated in the spatial as well as in the material motion context. While the former typically aims at deriving the density and the spatial motion deformation field in response to given spatial forces, the latter will be applied to determine the material forces in response to a given density and material deformation field. We derive a general computational framework within the finite element context that will serve to evaluate both the spatial and the material motion problem. However, once the spatial motion problem has been solved, the solution of the material motion problem represents a mere post-processing step and is thus extremely cheap from a computational point of view. The underlying algorithm will be elaborated systematically by means of two prototype geometries subjected to three different representative loading scenarios, tension, torsion, and bending. Particular focus will be dedicated to the discussion of the additional information provided by the material force method. Since the discrete material node point forces typically point in the direction of potential material deposition, they can be interpreted as a driving force for the healing mechanism.

Animals↗

Computer model of endochondral growth and ossification in long bones: biological and mechanobiological influences.

Endochondral growth and ossification, the processes by which cartilage increases in size and is replaced by bone, are affected by biological factors such as intrinsic genetic makeup and systemic chemical agents. In addition, these processes are affected by epigenetic mechanical factors: they may be accelerated in regions of intermittent high shear stress and decelerated in regions of intermittent high hydrostatic pressure. Previous models of bone development have not incorporated both biological and mechanobiological influences on endochondral growth and ossification. We have implemented a finite element analysis to model a developing bone rudiment from 8 weeks of gestational development to approximately 2 years after birth. As a function of time, we calculated a maturity index that reflects the progression of a region of cartilage through the endochondral ossification sequence of proliferation, hypertrophy, mineralization, and replacement by bone. We calculated a specific growth rate for each region of cartilage and estimated overall longitudinal growth of the rudiment. Regions of cartilage replaced by bone were remodeled. The results from the maturity index can be compared with distributions of proliferative, hypertrophic, and mineralized cartilage seen on histology at various stages in development. The results of the simulation predicted prenatal and postnatal developmental events, including formation of a secondary ossific nucleus, a layer of articular cartilage, and a growth plate. Our results demonstrate the necessity to include biological and mechanobiological influences when endochondral growth and ossification are considered.

Animals↗

Effect of airway inertance on linear regression estimates of resistance and compliance in mechanically ventilated infants: a computer model study.

Respiratory inertance (I) is usually ignored when resistance (R) and compliance (C) of mechanically ventilated infants are estimated by least squares linear regression. Values of I that have been reported for these patients can cause impedances whose magnitudes approximate respiratory resistance. We show theoretically that if inertance is neglected no error is expected in resistance estimates, but a positive bias in compliance can be, proportional to the inertance, the compliance, and the sinusoidal frequency at which the measurements are made. To determine the errors in parameter estimates when the pressure waveform is non-sinusoidal, we simulated linear regression based on non-inertive and inertive models. R, C, and I of the simulated lung were varied over the range expected in an infant intensive care unit. The ventilator was simulated as a critically damped second order system with a square pulse input. The rise time (TR) of the pressure pulse was varied over the range reported in infant ICUs. Simulated measurements confirmed that resistance is correctly estimated if inertance is neglected. Maximum error in compliance estimates (13%) occurred when TR and R were low, and C and I were high. The variation in the error in estimated compliance was consistent with the theory. Coefficients of variation of the parameters, the standard errors, and R2 of the regressions tended to deteriorate with increasing compliance error, but the relationships were not single valued. These statistics may alert investigators to possible bias in compliance caused by neglected inertance, but cannot be used to correct any bias.

Airway Resistance↗

The role of the hyperpolarization-activated inward current If in arrhythmogenesis: a computer model study.

Atrial fibrillation is the most common cardiac arrhythmia. Structural cardiac defects such as fibrosis and gap junction remodeling lead to a reduced cellular electrical coupling and are known to promote atrial fibrillation. It has been observed that the expression of the hyperpolarization-activated current If is increased under pathological conditions. Recent experimental data indicate a possible contribution of If to arrhythmogenesis. In this paper, the role of If in action potential propagation in normal and in pathological tissue is investigated by means of computer simulations. The effect of diffuse fibrosis and gap junction remodeling is simulated by reducing cellular coupling nonuniformly. As expected, the conduction velocity decreases when cellular coupling is reduced. In the presence of If the conduction velocity increases both in normal and in pathological tissue. In our simulations, ectopic activity is present in regions with high expression of If and is facilitated by cellular uncoupling. We conclude that an increased If may facilitate propagation of the action potential. Hence, If may prevent conduction slowing and block. Overexpression of If may lead to ectopic activity, especially when cellular coupling is reduced under pathological conditions.

Action Potentials↗

Computer modeling of human fertility: the impact of reproductive heterogeneity on measures of fertility.

As a result of the paucity of biological markers for both reproductive events and exposure to reproductive toxicants, it is likely that individual members of populations will be misclassified with respect to reproductive performance and xenobiotic exposure. A four-parameter computerized model of fertility (frequency of intercourse, male fecundity, female fecundity, and spontaneous abortion) was developed to explore the effect of misclassification of populations on several measures of fertility. The measures of fertility explored include cumulative percent pregnant, time to pregnancy, cycle specific fertility, and fecundability ratio. The cumulative percent pregnant and time to pregnancy appeared to be insensitive to small changes in reproductive competence. The fecundability ratio decreased in proportion to the size of population exposed to a reproductive toxicant. The three reproductive parameters, time to pregnancy, cumulative percent pregnant, and fecundability, do not appear useful as measures of reproductive heterogeneity in populations. The reproductive heterogeneity of a population was best defined by the change in cycle-specific fertility rate over the period of observation. These simulations suggest that the change in the cycle-specific fertility rate should be evaluated and comparable in all population groups over the period of observation to assure reproductive homogeneity.

Abortion, Spontaneous↗

Computational modeling of a new fluorescent biosensor for caspase proteolytic activity improves dynamic range.

The class of fluorescence resonance energy transfer (FRET) protein biosensors that are useful for measuring protease activity is composed of a tandem fusion of yellow fluorescent protein (YFP), a cleavage recognition sequence, and cyan fluorescent protein (CFP). The dynamic range of these FRET-based protein biosensors is often weak, but applications such as high throughput drug screening require stronger dynamic ranges. Using the biosensor for the caspase-3 protease as an example, here we showed a computational approach to improve the FRET dynamic range based on the atomic structure of caspase-3 bound to its inhibitor. This result was verified from our experiments where the FRET dynamic range improved by at least 60% on average in both in vitro and in vivo contexts. In concept, the same strategy can be applied to improve dynamic range of other FRET-based protein biosensors for protease activity where there exist solved atomic structures for protein complexes.

Caspase 3↗

Quantifying the role of inhibition in associative long-term potentiation in dentate granule cells with computational models.

In the dentate gyrus, coactivation of a mildly strong ipsilateral perforant path (pp) input with a weak contralateral pp input will not induce associative long-term potentiation in the weak input path unless both inputs project to the same part of the molecular layer. This "spatial convergence requirement" is thought to arise from either voltage attenuation between input locations or inhibition. Simulations with a detailed model of a dentate granule cell were performed to rule out voltage attenuation and to quantify the inhibition necessary to obtain the spatial convergence requirement. Strong lateral and weak medial or strong medial and weak lateral pp input were activated eight times at 400 Hz. Calcium current through N-methyl-D-aspartate receptor channels and subsequent changes in calcium concentration and the concentration of calmodulin bound with four calcium ions ([Cal-Ca4]) in the spine head were computed for a medial and a lateral pp synapse. To satisfy the spatial convergence requirement, peak [Cal-Ca4] had to be much larger in the strongly activated path synapse than in the weakly activated path synapse. With no inhibition in the model, differences in peak [Cal-Cal4] at the two synapses were small, ruling out voltage attenuation as the explanation of the spatial convergence requirement. However, with shunting inhibition, modeled by reducing membrane resistivity to 1,600 omega cm2 in the distal two-thirds of the dendritic tree, peak [Cal-Ca4] was 3-5 times larger in the strongly activated path synapse than in the weakly activated path synapse. The magnitude of shunting inhibition was varied to determine the level that maximized this difference in peak [Cal-Ca4]. For strong lateral and weak medial pp input, the optimal level was one that prevented the cell from firing an action potential. For strong medial and weak lateral pp input, the optimal level was one at which the cell fired two action potentials. The distribution of shunting inhibition that best satisfied the spatial convergence requirement was inhibition on the distal two-thirds of the dendritic tree with or without inhibition at the soma, with inhibition stronger in the distal third than in the middle third. It was estimated that the number of inhibitory synapses involved in the shunting inhibition should be 25-50% of the number of excitatory synapses activated by the eight-pulse, 400-Hz tetanus. This number could be 20-50% of the total number of inhibitory synapses in the distal two-thirds of the dendritic tree. The addition of a single inhibitory synapse on a dendrite had a significant effect on peak spine head [Cal-Ca4] in nearby spines. Inhibitory synapses had to be activated four or more times at 100 Hz for effective shunting to take place, and the inhibition had to begin no later than 2-5 ms after the first excitatory input. The results suggest that inhibition can isolate potentiated synapses to particular dendritic domains and that the location of activated inhibitory synapses may affect potentiation of individual synapses on individual dendrites.

Association Learning↗

An improved computer model for 60cobalt dose distributions.

A previously developed model for the calculation of 60Co isodose contours exhibits poor fit to experimental data at certain points. Methods for improving the fit at these points are described. The model contains few parameters, and may be useful for treatment planning in cases for which data are not available.

Cobalt Radioisotopes↗

Biologically motivated computational modeling of formaldehyde carcinogenicity in the F344 rat.

Formaldehyde inhalation at 6 ppm and above causes nasal squamous cell carcinoma (SCC) in F344 rats. The human health implications of this effect are of significant interest since human exposure to environmental formaldehyde is widespread, though at lower concentrations than those that cause cancer in rats. In this article, which is part of a larger effort to predict the human cancer risks of inhaled formaldehyde, we describe biologically motivated quantitative modeling of the exposure-tumor response continuum in the rat. An anatomically realistic, three-dimensional fluid dynamics model of the F344 rat nasal airways was used to predict site-specific flux of formaldehyde from inhaled air into tissue, since both SCC and preneoplastic lesions develop in a characteristic site-specific pattern. Flux into tissue was used as a dose metric for two modes of action, direct mutagenicity and cytolethality-regenerative cellular proliferation (CRCP), which in turn were linked to key parameters of a two-stage clonal growth model. The direct mutagenicity mode of action was represented by a low dose linear dose-response model of DNA-protein cross-link (DPX) formation. An empirical J-shaped dose-response model and a threshold model fit to the empirical data were used for CRCP. In the clonal growth model, the probability of mutation per cell generation was a function of the tissue concentration of DPX while the rate of cell division was calculated from the CRCP data. Maximum likelihood methods were used to estimate parameter values. Survivor (a nontumor outcome) and tumor data for controls from the National Toxicology Program database and from two formaldehyde inhalation bioassays were used for likelihood calculations. The J-shaped dose-response for CRCP provided a better description of the SCC data than did the threshold model. Sensitivity analyses indicated that the rodent tumor response is due to the CRCP mode of action, with the directly mutagenic pathway having little, if any, influence. When evaluated in light of modeling and database uncertainties, particularly the specification of the clonal growth model and the dose-response data for CRCP, this work provides suggestive though not definitive evidence for a J-shaped dose-response for formaldehyde-mediated nasal SCC in the F344 rat.

Administration, Inhalation↗

Multimodality diagnosis of liver tumors: feature analysis with CT, liver-specific and contrast-enhanced MR, and a computer model.

RATIONALE AND OBJECTIVES: The purpose of this study was to measure and to clarify the diagnostic contributions of image-based features in differentiating benign from malignant and hepatocyte-containing from non-hepatocyte-containing liver lesions. MATERIALS AND METHODS: Six experienced abdominal radiologists each read images from 146 cases (including a contrast material-enhanced computed tomographic [CT] scan and contrast-enhanced and unenhanced magnetic resonance [MR] images) following a checklist-questionnaire requiring them to rate quantitatively each of as many as 131 image features and then reported on each of the two differentiations. The diagnostic value of each feature was assessed, and linear discriminant analysis was used to develop statistical prediction rules (SPRs) for merging feature data into computerized "second opinions." For the two differentiations, accuracy (area under the receiver operating characteristic curve [Az]) was then determined for the radiologists' readings by themselves and for each of three SPRs. RESULTS: Thirty-seven candidate features had diagnostic value for each of the two differentiations (a slightly different feature set for each). Radiologists' performance at both differentiations was excellent (Az = 0.929 [benign vs malignant] and 0.926 [hepatocyte-containing vs non-hepatocyte-containing]). Performance of the SPR that operated on the features from all modalities together was better than that of radiologists (Az = 0.936 [benign vs malignant] and 0.951 [hepatocyte-containing vs non-hepatocyte-containing]), but this difference was of marginal statistical significance (P = .11). Contrast-enhanced MR imaging and contrast-enhanced CT each made significant adjunctive contributions to accuracy compared with unenhanced MR imaging alone. CONCLUSION: Many CT- and MR imaging-based features have diagnostic value in differentiating benign from malignant and hepatocyte-containing from non-hepatocyte-containing liver lesions. Radiologists could also benefit from the fully informed SPR's "second opinions."

Adult↗

Computer modelling of human behaviour in aircraft fire accidents.

The mathematical simulation of the evacuation process has a wide and largely untapped scope of application within the aircraft industry. The function of the mathematical model is to provide insight into complex behaviour by allowing designers, legislators, and investigators to ask 'what if' questions. Such a model, EXODUS, is currently under development, and this paper describes its evolution and potential applications. EXODUS is an egress model designed to simulate the evacuation of large numbers of individuals from an enclosure, such as an aircraft. The model tracks the trajectory of each individual as they make their way out of the enclosure or are overcome by fire hazards, such as heat and toxic gases. The software is expert system-based, the progressive motion and behaviour of each individual being determined by a set of heuristics or rules. EXODUS comprises five core interacting components: (i) the Movement Submodel -- controls the physical movement of individual passengers from their current position to the most suitable neighbouring location; (ii) the Behaviour Submodel -- determines an individual's response to the current prevailing situation; (iii) the Passenger Submodel -- describes an individual as a collection of 22 defining attributes and variables; (iv) the Hazard Submodel -- controls the atmospheric and physical environment; and (v) the Toxicity Submodel -- determines the effects on an individual exposed to the fire products, heat, and narcotic gases through the Fractional Effective Dose calculations. These components are briefly described and their capabilities and limitations are demonstrated through comparison with experimental data and several hypothetical evacuation scenarios.

Accidents, Aviation↗

Mechanisms of human motion perception: combining evidence from evoked potentials, behavioural performance and computational modelling.

Based on single cell recordings in monkey, it has been suggested that neural activity can be related directly to psychophysically measured threshold behaviour. Here, we investigated in humans whether evoked potentials correlate with behavioural measurements like discrimination thresholds and reaction time. Subjects were asked to report the perceived direction of object motion stimuli which contained variable amounts of coherent motion. Simultaneously, we recorded evoked potentials with a multielectrode array, or measured the reaction time. We show here that motion coherence had a strong influence on both amplitude and latency of the evoked potential. Stronger motion signals evoked stronger and faster cortical responses. The latency reduction of the motion onset response with increasing coherence correlated very well with the concurrent decrease in reaction time. Taken together, these results suggest that temporal integration is an important step in analysing motion signals to generate a reliable behavioural response. We stimulated a two-dimensional array of correlation-type motion detectors with the same motion sequences, and analysed the distribution of local motion signals according to signal detection theory. Performance resembled that of human subjects when the decision strategy was optimized so as to exclude small signals and, in particular, when the ideal observer had some knowledge about a region of interest in which the object was to be expected.

Cerebral Cortex↗