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PubMed1996

Extended glycoprotein structure of the seven domains in human carcinoembryonic antigen by X-ray and neutron solution scattering and an automated curve fitting procedure: implications for cellular adhesion.

Carcinoembryonic antigen (CEA) is one of the most widely used cell-surface tumour markers for tumour monitoring and for targeting by antibodies. It is heavily glycosylated (50% carbohydrate) and a monomer is constructed from one V-type and six C2-type fold domains of the immunoglobulin superfamily. The solution arrangement at low resolution of the seven domains in CEA cleaved from its membrane anchor was determined by X-ray and neutron scattering. Guinier analyses showed that the X-ray radius of gyration RG of CEA was 8.0 nm. The length of CEA was 27 to 33 nm, and is consistent with an extended arrangement of seven domains. The X-ray cross-sectional radius of gyration RXS was 2.1 nm, and is consistent with extended carbohydrate structures in CEA. The neutron data gave CEA a relative molecular mass of 150,000, in agreement with a value of 152,500 from composition data, and validated the X-ray analyses. The CEA scattering curves were analysed using an automated computer modelling procedure based on the crystal structure of CD2. The V-type and C2-type domains in CD2 were separated, and the C2-type domain was duplicated five times to create a linear seven-domain starting model for CEA. A total of 28 complex-type oligosaccharide chains in extended conformations were added to this model. By fixing the six interdomain orientations to be the same, three-parameter searches of the rotational orientations between the seven domains gave 4056 possible CEA models. The best curve fits from these corresponded to a family of zig-zag models. The long axis of each domain was set at 160(+/-25) degrees relative to its neighbour, and the two perpendicular axes were orientated at 10(+/-30) degrees and -5(+/-35) degrees. Interestingly, the curve fit from this model is within error of that calculated from a CEA model generated directly from the CD2 crystal structure by the superposition of adjacent domains. Zig-zag models of this type imply that the protein face of the GFCC' beta-sheet in neighbouring CEA domains lie on alternate sides of the CEA structure. Such a model has implications for the adhesion interactions between CEA molecules on adjacent cells or for the antibody targeting of CEA.

Amino Acid Sequence↗
PubMed1998

Identification of a model cardiac glycoside receptor: comparisons with Na+,K+-ATPase.

The availability of high-affinity anti-digoxin monoclonal antibodies (mAbs) offers the potential for their use as models for the characterization of the relationship between receptor structure and cardiac glycoside binding. We have characterized the binding of anthroylouabain (AO), a fluorescent derivative of the cardiac glycoside ouabain, to mAbs 26-10, 45-20, and 40-50 [Mudgett-Hunter, M., et al. (1995) Mol. Immunol. 22, 477] and lamb kidney Na+, K+-ATPase by monitoring the resultant AO fluorescence emission spectra, anisotropy, lifetime values, and Förster resonance energy transfer (FRET) from protein tryptophan(s) (Trp) to AO. These data suggest that the structural environment in the vicinity of the AO-binding site of Na+,K+-ATPase is similar to that of mAb 26-10 but not mAbs 45-20 and 40-50. A model of AO complexed to the antigen binding fragment (Fab) of mAb 26-10 which was generated using known X-ray crystal structural data [Jeffrey, P. D., et al. (1993) Proc. Natl. Acad. Sci. U.S.A. 90, 10310] shows a heavy chain Trp residue (Trp-H100) that is close ( approximately 3 A) to the anthroyl moiety. This is consistent with the energy transfer seen upon AO binding to mAb 26-10 and suggests that Trp-H100, which is part of the antibody's cardiac glycoside binding site, is a major determinant of the fluorescence properties of bound AO. In contrast, the generated model of AO complexed to Fab 40-50 [Jeffrey, P. D., et al. (1995) J. Mol. Biol. 248, 344] shows a heavy chain Tyr residue (Tyr-H100) which is part of the cardiac glycoside binding site, located approximately 10 A from the anthroyl moiety. The closest Trp residues (H52 and L35) are located approximately 17 A from the anthroyl moiety, and no FRET is observed despite the fact that these Trp residues are close enough for significant FRET to occur. The energy transfer seen upon AO binding to Na+,K+-ATPase suggests the presence of one completely quenched or two highly quenched enzyme Trp residues approximately 10 and approximately 17 A, respectively, from the anthroyl moiety. These data suggest that the Na+,K+-ATPase Trp residue(s) involved in fluorescence energy transfer to AO is likely to be part of the cardiac glycoside binding site.

Animals↗
PubMed1997

A dynamic model of ventricular interaction and pericardial influence.

A mathematical model describing the dynamic interaction between the left and the right ventricle over the complete cardiac cycle is presented. The pericardium-bound left and right ventricles are represented as two coupled chambers consisting of the left and right free walls and the interventricular septum. Time-varying pressure-volume relationships characterize the component compliances, and the interaction of these components produces the globally observed ventricular pump properties (total chamber pressure and volume). The model 1) permits the simulation of passive (diastolic) and active (systolic) ventricular interaction, 2) provides temporal profiles of hemodynamic variables (e.g., ventricular pressures, volumes, and flow) that agree well with reported observations, and 3) can be used to examine the effect of the pericardium on ventricular interaction and ventricular mechanics. It can be reduced to equivalency with models previously reported by invoking simplifying assumptions. Furthermore, model-generated "dynamic interaction gains" are employed to quantify the mode and degree of ventricular interaction. The model also yields qualitative predictions of septal and free wall displacements similar to those detected experimentally via M-mode echocardiography. Such analogies may be extended easily to the study of pathophysiological states via appropriate modifications to 1) the pressure-volume characteristics of the component walls (and/or pericardium) and/or 2) the specific time course of activation of the ventricular free wall or the septum. A limited number of examples are included to demonstrate the utility of the model, which may be used as an adjunct to new experimental investigations into ventricular interaction.

Blood Volume↗
PubMed1978

Experience with a Fourier method for determining the extracellular potential fields of excitable cells with cylindrical geometry.

In this chapter, well-known solutions that utilize a Fourier transform method for determining the extracellular, volume-conductor potential distribution surrounding elongated excitable cells of cylindrical geometry are reformulated as a discrete Fourier transform (DFT) problem, which subsequently permits the volume-conductor problem to be viewed as an equivalent linear-filtering problem. This DFT formulation is fast and computationally efficient. In addition, it lends itself to the application of some rather well-known techniques in linear systems theory (e.g., the DFT for convolution and least mean-square (Wiener) filtering for optimal prediction of a signal in random noise). Two specific examples are employed to demonstrate the utility of this discrete Fourier method: (1) the single, isolated, active nerve fiber in an essentially infinite volume conductor and (2) the isolated, active nerve trunk in a similar type of extracellular medium. In each of these, our DFT method is employed to obtain both the classical "forward" and "inverse" potential solutions for each volume conductor problem. In the case where the single, active nerve fiber is the bioelectric source in the volume conductor, simulated action-potential data from an invertebrate giant axon is utilized, and potentials at various points in the extracellular medium are calculated. The calculated potential distributions in axial distance z, at various radial distances r, are consistent with well-known experimental fact. When the active nerve trunk acts as the bioelectric source, the DFT method provides calculated potential distributions that are fairly consistent with experimental data under a variety of experimental conditions. For example, in these experiments, a special, isolated frog spinal cord preparation is used that permits separate or combined stimulation of the motor and sensory nerve fiber components of the attached sciatic nerve trunk. By manipulating the stimulus intensity applied to the motor (ventral) or appropriate sensory (dorsal) roots of the spinal cord, a variety of multiphasic extracellular volume-conductor potentials can be recorded from the sciatic nerve. The excellent agreement of model-generated and experimental data, regardless of the complexity of surface potential waveform, tends to validate the modeling assumptions and offer encouragement that this computationally efficient DFT method may be usefully employed in volume-conductor problems where both the bioelectric source, and the surrounding volume conductor, are of a much more complicated nature.

Action Potentials↗
PubMed1990

Novel method for the rapid evaluation of packing in protein structures.

There has been considerable effort to predict the structure of proteins from their amino acid sequences. A major problem in all prediction efforts has been that, short of a direct comparison with crystallographic co-ordinates, it is often difficult to evaluate the merit of a model, or "proposed" protein structure. Here, we present a method for evaluating proposed protein structures that does not require a structural model of complete atomic detail. Our method evaluates residue-residue packing density using a simplified model of the polypeptide chain where amino acids are represented as one, two (histidine, tyrosine and phenylalanine), or three (tryptophan) spheres. This method also gives a measure of the appropriateness of residue-residue contacts, thus giving a measure of the amino acid distribution throughout the protein. Amino acid packing and amino acid distribution, as evaluated by this technique, are consistent with the accuracy of model-built structures. We have been able to select the best structures from a set of combinatorially generated models using this method, and we anticipate that it will be useful as a general tool for model-building.

Amino Acid Sequence↗
PubMed1996

Ability of mathematical models to predict faecal output with a pulse dose of indigestible marker.

The aim of the work was to compare the faecal output and digestibility estimated by two mathematical approaches with the actual amount of faeces excreted or feed digested by Simmental cows. Experimental data (intakes and digestibility measured over 5 d) and faecal Cr concentrations (measured at 0, 4, 8, 12, 16, 24, 32, 48, 56, 72, 96, 120 and 144 h after a pulse dose of Cr-mordanted forage) were collected from published experiments and fitted to a multicompartmental (MC) model and a gamma age-dependent (AD) model. From a statistical point of view, the MC model was very satisfactory while the AD model produced lower r2 and higher SE values and reached satisfactory statistical values only for higher DM intakes (lactating animals). The MC model produced higher correlations with the digestibility values while the AD model generated better correlations with the intake data; DM intake and digestibilities were more highly correlated with the model's parameters than neutral-detergent fibre terms. The regression between the estimated faecal outputs obtained with the two models showed an intercept close to 0 (P > 0.05) and angular coefficients near 1; there was a good correspondence of the estimates especially for the lowest values of output. The r2 values of the regressions were 0.800 and 0.829 for the MC and AD models respectively and their SE were 2.93 and 2.63. The ability of the two models to predict faecal output and digestibility was very similar, independent of the statistical accuracy of fitting the Cr-concentration data. The results indicate that variation of Cr concentration is the result of the entire digestive process, i.e. dilution and passage, which interact in a competitive or associative way.

Animal Feed↗
PubMed1988

Indirect vertical cultural transmission: a model for nongenetic parental influences on the liability to psychiatric illness.

A long tradition in psychiatry has focused on parental traits that directly influence the liability to psychiatric disorders in offspring. Because these traits rarely resemble the disorders they cause, traditional models of cultural transmission (which assume that "like perpetuates like") may not be appropriate. The author develops and illustrates several models for indirect vertical cultural transmission of psychiatric illness. These models generate falsifiable predictions about the pattern of risk in relatives of affected individuals. For example, all such models predict a substantially higher risk of illness in siblings than in offspring of affected individuals. It is now possible to develop and test rigorous models for the cultural transmission of psychiatric illness.

Culture↗
PubMed1994

Three-dimensional pharmacophores from binding data.

The application of HASL (hypothetical active site lattice) methodology has been successfully extended to generate putative pharmacophoric patterns in three dimensions capable of quantitatively predicting binding activity. The transformation of a HASL model to a pharmacophore is illustrated using pKi values published for 84 HIV-1 protease inhibitors. Starting with a HASL model generated at 2.00 A and containing 899 lattice points, a selective trimming process was used to identify significant lattice points. In this manner, a set of 11 points was found which represents a potential pharmacophoric pattern and predicts the pKi activity of the 84-inhibitor set with a correlation (r2) of 0.827. Furthermore, the locations of these points were found to coincide with a number of strategic binding areas within the known active site structure HIV-1 protease, thus providing a physical confirmation of their relevancy.

Binding Sites↗
PubMed1987

ISMOD: an all-subsets regression program for generalized linear models. I. Statistical and computational background.

This paper describes a system written to carry out regression analyses under certain generalized linear models that are widely used in biomedical research. These include continuous response models such as the Weibull, log-logistic, log-normal and Cox proportional hazards models used in survival analysis, and also discrete Poisson, binomial and multinomial response regression models. The system fits models, generates residuals and other diagnostic output, and has an all-subsets regression feature. This paper describes the models implemented and gives statistical background; Part II describes the ISMOD system and presents examples of its application.

Biometry↗
PubMed1991

A distributed-parameter model of the myelinated nerve fiber.

This paper presents a new model for the characterization of electrical activity in the nodal, paranodal and internodal regions of isolated amphibian and mammalian myelinated nerve fibers. It differs from previous models in the following ways: (1) in its ability to incorporate detailed anatomical and electrophysiological data; (2) in its approach to the myelinated nerve fiber as a multi-axial cable; and (3) in the numerical algorithm used to obtain distributed model equation solutions for potential and current. The morphometric properties are taken from detailed electron microscopic anatomical studies (Berthold & Rydmark, 1983a, Experientia 39, 964-976). The internodal axolemma is characterized as an excitable membrane and model-generated nodal and internodal membrane action potentials are presented. A system of describing equations for the equivalent network model is derived, based on the application of Kirchoff's Current Law, which take the form of multiple cross-coupled parabolic partial differential equations. An implicit numerical integration method is developed and the numerical solution implemented on a parallel processor. Non-uniform spatial step sizes are used, enabling detailed representation of the nodal region while minimizing the number of total segments necessary to represent the overall fiber. Conduction velocities of 20.2 m sec-1 at 20 degrees C for a 15 microns diameter amphibian fiber and 57.6 m sec-1 at 37 degrees C for a 17.5 microns diameter mammalian fiber are achieved, which agrees qualitatively with published experimental data at similar temperatures (Huxley & Stämpfli, 1949, J. Physiol., Lond. 108, 315-339; Rasminsky, 1973, Arch, Neurol. 28, 287-292). The simulation results demonstrate the ability of this model to produce detailed representations of the transaxonal, transmyelin and transfiber potentials and currents, as well as the longitudinal extra-axonal, periaxonal and intra-axonal currents. Also indicated is the potential contribution of the paranodal axolemma to nodal activity as well as the presence of significant longitudinal currents in the periaxonal space adjacent to the node of Ranvier.

Action Potentials↗
PubMedDate not supplied

A peripartum neurologic event: shooting from the hip.

We have shown that a simplified model, generated quickly in response to an emergency consultation, may provide useful insights in certain situations. A more developed model was useful in verifying these insights. Because the more complex model considered a longer time horizon than the simple model, it allows us to consider questions regarding long-term benefits of aneurysm repair. When modeling any problem, the most important reason for performing decision analysis is to gain insight from analyzing the clinical setting and from constructing the model. The quantitative results are usually of only minor importance. However, our most important insights are sometimes gained by looking beyond the quantitative level to understand the interactions of various effects within the model. In this case, it was those insights that were of the greatest benefit to the patient in arriving at a decision to have cerebral arteriography.

Adult↗
PubMed1995

Mechanical control of swimming speed: stiffness and axial wave form in undulating fish models

The purpose of this study was to investigate the mechanical control of speed in steady undulatory swimming. The roles of body flexural stiffness, driving frequency and driving amplitude were examined; these variables were chosen because of their importance in vibration theory and their hypothesized functions in undulatory swimming. Using a mold of a pumpkinseed sunfish Lepomis gibbosus, we cast three-dimensional vinyl models of four different flexural stiffnesses. We swam the models in a flow tank and powered them via the input of an oscillating sinusoidal bending couple in the horizontal plane at the posterior margin of the neurocranium. To simulate the hydrodynamic conditions of steady swimming, drag and thrust acting on the model were balanced by adjusting flow speed. Under these conditions, the actuated models generated traveling waves of bending. At steady speeds, the motions of the ventral and lateral surfaces of the model were video-taped and analyzed to yield the following response variables: tail-beat amplitude, propulsive wavelength, wave speed and depth of the trailing edge of the caudal fin. Experimental results showed that changes in body flexural stiffness can control propulsive wavelength, wave speed, Froude efficiency and, in consequence, swimming speed. Driving frequency can control tail-beat amplitude, propulsive wavelength, Froude efficiency, relative rate of working and, in consequence, swimming speed. Although there is no significant correlation between rostral amplitude and swimming speed, rostral amplitude can control swimming speed indirectly by controlling tail-beat amplitude and relative power. Compared with live sunfish using undulatory waves at the same speed, models have a lower Froude efficiency. On the basis of the mechanical control of swimming speed in model sunfish, we predict that, in order to swim at fast speeds, live sunfish increase the flexural stiffness of their bodies by a factor of two relative to their passive body stiffness.

Journal Article↗
PubMed1994

Modeling Alzheimer's disease in transgenic mice.

Alzheimer's disease is a common neurodegenerative disorder of unknown etiology characterized by the accumulation of beta amyloid plaques and neurofibrillary tangles in the brain. Attempts have been made to engineer an animal model of the disease using a variety of transgenic approaches. So far the models have only been partially successful. The methods used and the models generated are discussed.

Alzheimer Disease↗
PubMed1995

Detection of vulnerability loci by association and sib-pair methods.

A haplotype-based haplotype relative risk (HHRR) analysis of simulated data for 200 affected offspring and their parents (Genetic Analysis Workshop 9, Problem 1) detected linkage disequilibrium at 2 of 360 marker loci. An additive model was suggested but not proven by haplotypes of affected vs. unaffected offspring. These findings were consistent with the generating model. Affected sib pair analysis failed to detect additional loci. Discussion among workshop participants suggested that the chi-square test used here (2 [transmitted vs. nontransmitted] x n [alleles] for each locus) was invalid because of the nonindependence of proportions of transmitted alleles. In post-workshop analyses, transmission disequilibrium tests (TDTs) for each allele at each locus detected only the true associations if p values were corrected by one of two methods: Bonferroni correction for 2,035 TDTs, or correcting each test for n (number of tests at the locus) minus 1 and then for the number of loci tested. Screening loci for linkage disequilibrium requires careful attention to correction for multiple comparisons.

Alleles↗
PubMed1998

Assessment of regional left ventricular wall stress after myocardial infarction by echocardiography-based structural analysis.

OBJECTIVES: The objective of this study was to determine the distribution of regional left ventricular (LV) wall stress after myocardial infarction (MI). BACKGROUND: After a large MI, structural changes occur in the heart that ultimately may lead to alterations in LV size and shape, a process generally referred to as ventricular remodeling. Regional variation in myocardial wall stress may be responsible for initiation of physiologic and cellular changes that result in myocardial hypertrophy, dilatation, and remodeling after MI. Simplified geometric analytic methods of estimating global LV wall stress cannot determine regional variation such as that occurring after MI. METHODS AND RESULTS: To assess regional LV wall stress after MI, we applied the finite element method to patient-specific end-systolic LV models generated from echocardiographic imaging. After validation by comparison with analytic solutions of LV wall stress in idealized ventricles, LV models were constructed from rotated orthogonal apical images from 13 normal volunteers, 16 patients with recent (<4 days) anterior MI, and 7 patients with recent infero-posterior MI. The mean Von Mises stress was calculated for the entire LV and for 5 separate regions of the LV. Von Mises LV wall stress was increased globally in patients with anterior MI (211 +/- 46 kdyne/cm2; P < .002) or infero-posterior MI (175 +/- 23 kdyne/cm2; P = .04) compared with normal patients (144 +/- 57 kdyne/cm2). Global wall stress correlated directly with ejection fraction (P < .0001) and inversely with wall motion index (P < .004) in patients with anterior MI. Wall stress in the apical regions was increased by a factor of 2.3 in patients with anterior MI (P < .0001), whereas other regions did not differ from normal patients. There were no individual regions that were significantly different from normal in patients with infero-posterior MI. CONCLUSIONS: Anterior MI is associated with an increase in apical end-systolic wall stress compared with normal and infero-posterior MI. This may be an important stimulus for LV remodeling after anterior MI.

Female↗
PubMed1997

[A model for handling grievances in nursing services].

A model for management of grievances in a nursing service is described, in terms of the guidelines for model generation, based on a qualitative, exploratory, descriptive and theory generating research strategy and design. Potgieter's (1992) research served as the conceptual framework for the description of a model case. The statements derived from this description was used as basis for the description of the model. The central concepts were identified, defined and classified. The model was implemented in practice and was evaluated by means of a retrospective case study. Guidelines for the implementation of the model were consequently described and the model was positively evaluated by a panel of experts. The testing of hypothesis is recommended to validate the model.

Employee Grievances↗
PubMed1992

Alloplastic cranial implants made from computed tomographic scan-generated casts.

The complexity of cranioplasty increases with increased defect size. It is difficult to produce a symmetric, accurate implant presurgically or at the time of surgery when the defect is greater than 50 cm2. The procedure is also more difficult to perform when the defect is located in the temporal, infratemporal, or frontal areas. A new procedure generates a three-dimensional cast of the skull through computed tomography and computer-aided design reformation. This article describes the process of model generation and the production of a preprocessed cranial implant. To date, six cranial implants have been made with this technique. The whole head models are accurate and help the neurosurgeon-prosthodontist team in the creation of a symmetric, anatomically correct restoration. It is the technique of choice for large implants or where the cranial bones are thin. It is not necessary to augment or alter the implant during surgery. The technique reduces surgical time, and postsurgical complications have been minimal.

Artificial Intelligence↗
PubMed1993

Computer model of membrane current and intracellular Ca2+ flux in the isolated guinea pig ventricular myocyte.

This paper presents the equations and responses of a mathematical model that simulates the transmembrane current and intracellular concentrations of Ca2+ ([Ca2+]), Na+ ([Na+]), and K+ ([K+]) of an isolated guinea pig myocyte. The structure of the model is closely related to the formulation of DiFrancesco and Noble (9). Quantitative values are based on a large number of experimental constraints, taken from the literature on isolated myocytes as well as our own experimental studies, that describe the properties of individual channels and integrated responses of whole cells under a variety of conditions. The model was constructed as a homeostatic system. The equilibrium of the model corresponds to the resting potential and intracellular ionic concentrations of unstimulated myocytes. The model generates deviations from equilibrium corresponding to the behavior of cells after stimulation of action potentials at different rates, blockade of Na-K-adenosinetriphosphatase (ATPase), reduction in extracellular [K+], and injection of constant depolarizing current. Simulations from the model suggest that changes in myoplasmic [Ca2+] at different stimulation rates, the generation of restitution and postextrasystolic potentiation, and the development of intracellular [Ca2+] oscillations arise simply from different interactions between uptake of Ca2+ into the sarcoplasmic reticulum via the Ca(2+)-ATPase, Ca(2+)-induced Ca2+ release of Ca2+ into the myoplasm, flux between regions of uptake and release, and leakage between sarcoplasmic reticulum and myoplasm. The model also demonstrates that a wide variety of basic electrophysiological responses of the isolated guinea pig myocyte can be simulated with quantitative precision by a single set of equations based on experimentally measured transmembrane current and intracellular [Ca2+] and [Na+].

Action Potentials↗