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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↗
PubMed1990

The impact of taxation on the distribution of wealth in an economy with changing population.

The authors examine the determinants of the personal distribution of income and wealth using an overlapping generations model in which all individuals are assumed to be identical except for their inherited wealth. "It is shown that, in general, higher tax rates reduce distributive inequality as long as the rate of interest is exogenously given. In steady state, however, where the rate of interest is determined endogenously, increasing taxation and higher social security payments both diminish the capital labor ratio so that the rate of interest rises. If this interest effect is strong enough then it may outbalance the tendency toward more equality because higher interest rates enhance initial differences in the distribution of both income and wealth and, eventually, the inequality in the distribution of income and wealth in the society." The geographical focus is on developed countries.

Developed Countries↗
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↗
PubMed2000

A mechanistic, predictive model of dose-response curves for cell cycle phase-specific and -nonspecific drugs.

In vitro dose-response curves for anticancer agents are useful for predicting the clinical response to chemotherapy, and models to capture the time-dependency of dose-response curves are necessary for potential clinical extrapolation. Usually, the modified Hill model is used (see Levasseur et al., Cancer Res., 58: 5749-5761, 1998), although this model is neither mechanistic nor predictive for understanding how drug and tumor cell characteristics affect the shape of the dose-response curve. A new exponential kill (EK) model is proposed to predict the shape of dose-response curves based on the cell cycle phase specificity of a drug, the cell cycle time, the duration and concentration of drug exposure at the site of action, and a scaling factor for the level of drug resistance. Explicit analytical equations are presented for predicting the ICx (the concentration required to reduce cell growth by x%), the maximum cell kill achievable at high doses after a given duration of drug exposure, and the slope of the survival fraction versus log (concentration) plot at the ICx. Numerical solutions illustrate that there may be an optimal, finite duration of drug exposure that maximizes cell kill for a given area under the concentration versus time curve, and an analytical equation is given to calculate when such an optimal, finite duration exists. The EK model generates sigmoidal dose-response curves, like those seen empirically and previously described by the Hill model, which eventually plateau with increasing drug concentration at levels that depend on the cell cycle specificity of the drug, the cell cycle time, and the duration of exposure to the drug. This study includes no original data. Instead, empirical results in the literature are used to test the model. Because data by Levasseur et al. (1998) was fit to the Hill model assuming the plateau in the effect versus concentration curve to be independent of exposure duration, a full test of the model is not possible using their published data. Some tests of the EK model were possible, however, showing that EK model predictions yield good fits to in vitro data published in that and in another study. In addition, combining the EK model with a pharmacokinetic model resulted in predictions that were consistent with results of clinical studies comparing etoposide given in different schedules. Further tests of the model are necessary.

Antineoplastic Agents↗
PubMed1996

The new organization of the health care delivery system.

The U.S. health care system is restructuring at a dizzying pace. In many parts of the country, managed care has moved into third-generation models emphasizing capitated payment for enrolled lives and, in the process, turning most providers and institutions into cost centers to be managed rather than generators of revenue. While the full impact of the new managed care models remains to be seen, most evidence to date suggests that it tends to reduce inpatient use, may be associated with greater use of physician services and preventive care, and appears to result in no net differences either positive or negative with regard to quality or outcomes of care in comparison with fee-for-service plans. Some patients, however, tend to be somewhat less satisfied with scheduling of appointments and the amount of time spent with providers. There is no persuasive evidence that managed care lowers the rate of growth in overall health care costs within a given market. Further, managed care performance varies considerably across the country, and the factors influencing managed care performance are not well understood. Organized delivery systems are a somewhat more recent phenomenon representing various forms of ownership and strategic alliances among hospitals, physicians, and insurers designed to provide more cost-effective care to defined populations by achieving desired levels of functional, physician-system, and clinical integration. Early evidence suggests that organized delivery systems that are more integrated have the potential to provide more accessible coordinated care across the continuum, and appear to be associated with higher levels of inpatient productivity, greater total system revenue, greater total system cash flow, and greater total system operating margin than less integrated delivery forms. Some key success factors for developing organized delivery systems have been identified. Important roles are played by organizational culture, information systems, internal incentives, total quality management, physician leadership, and the growth of group practices. This chapter describes the growth and evolution of managed care and organized delivery systems, the research evidence regarding managed care and organized delivery systems, and the likely future organization of the health system in light of recent trends and evidence. It also highlights some of the more important public policy implications of the new health care infrastructure.

Cost Control↗
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↗
PubMed1980

Population and agricultural development models: the promise of the third generation.

The author briefly describes the work of Malthus and the development of first- and second-generation economic-demographic models. He then discusses a proposed third-generation model which "examines conjointly both consequences and determinants of population growth, and analyzes them at the level of the agricultural household." A project being conducted by the Food and Agricultural Organization to construct a third-generation model using data from the Philippines and two other countries is described

Agriculture↗
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↗
PubMed2000

The Mt. Hood challenge: cross-testing two diabetes simulation models.

Starting from identical patients with type 2 diabetes, we compared the 20-year predictions of two computer simulation models, a 1998 version of the IMIB model and version 2.17 of the Global Diabetes Model (GDM). Primary measures of outcome were 20-year cumulative rates of: survival, first (incident) acute myocardial infarction (AMI), first stroke, proliferative diabetic retinopathy (PDR), macro-albuminuria (gross proteinuria, or GPR), and amputation. Standardized test patients were newly diagnosed males aged 45 or 75, with high and low levels of glycated hemoglobin (HbA(1c)), systolic blood pressure (SBP), and serum lipids. Both models generated realistic results and appropriate responses to changes in risk factors. Compared with the GDM, the IMIB model predicted much higher rates of mortality and AMI, and fewer strokes. These differences can be explained by differences in model architecture (Markov vs. microsimulation), different evidence bases for cardiovascular prediction (Framingham Heart Study cohort vs. Kaiser Permanente patients), and isolated versus interdependent prediction of cardiovascular events. Compared with IMIB, GDM predicted much higher lifetime costs, because of lower mortality and the use of a different costing method. It is feasible to cross-validate and explicate dissimilar diabetes simulation models using standardized patients. The wide differences in the model results that we observed demonstrate the need for cross-validation. We propose to hold a second 'Mt Hood Challenge' in 2001 and invite all diabetes modelers to attend.

Albuminuria↗
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↗
PubMed2002

Regulatory modules shared within gene classes as well as across gene classes can be detected by the same in silico approach.

Transcriptional regulation depends on the binding of transcription factors to their corresponding binding sites. The response to cellular signals is often mediated by the cooperative binding of transcription factors to well defined regulatory modules consisting of at least two transcription factor binding sites. Such regulatory modules can be responsible for the common regulation of genes within a gene class or confer a common function to promoters belonging to different gene classes. We developed in silico models representing a common framework of potential regulatory sites specific for one promoter class (actins). We also generated models for two different functional promoter modules both of which confer responsiveness to tumor necrosis factor (TNF) and interferon (IFN) to a variety of promoters. All models exhibited high selectivity, e.g. the mammalian muscle actin promoter model produced no false negatives in a database search.

Actins↗
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↗