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At least 307 records · Page 17Linked to original sources
PubMed1982

Concanavalin-A-mediated thymocyte agglutination: a model for a quantitative study of cell adhesion.

This report describes a quantitative study of the agglutination of rat thymocytes with concanavalin A (ConA). The probability that two ConA-coated cells remain bound after centrifugation was determined over a wide range of lectin concentrations. The minimal force required to separate agglutinated cells and the number of ConA molecules bound per cell were measured in similar experimental conditions. Agglutinated cells were examined by electron microscopy to estimate the area of membrane involved in adhesion. The dependence of agglutination on cell metabolism was studied: cold (4 degrees C), sodium azide (15 mM) and cytochalasin B (10 micrograms/ml) inhibited thymocyte adhesion. The importance of lateral movements of ConA molecules was assayed by measuring the adhesion of ConA-coated glutaraldehyde-fixed thymocytes to untreated cells: substantial binding occurred, but at a reduced level relative to untreated cells. A mathematical analysis of experimental data allowed the following conclusions. (1) At least 10(3) ConA bonds were involved in cross-linking two bound cells, which required the lectin molecules to be concentrated in the binding area, at least when low ConA concentrations (0.5 microgram/ml or less) were used. (2) The dependence of the binding probability on lectin concentration was fairly linear when the latter was small, which implied that the limiting step in cell-cell adhesion was the formation of a bond between a single ConA molecule and a ligand on the other cell. (3) The mean intercellular-contact time for the formation of this first bond was about 10 S for high concentrations of ligand (8 micrograms/ml). It was possible to fit the above data into a physically consistent quantitative model of cell adhesion.

Animals↗
PubMed2006

Implementation of a combined association-linkage model for quantitative traits in linear mixed model procedures of statistical packages.

A transmission disequilibrium test for quantitative traits which combines association and linkage analyses is currently available in several dedicated software packages. We describe how to implement such models in linear mixed model procedures that are available in widely used statistical packages such as SPSS. We also briefly mention a few extensions of the model that become naturally available once the model is implemented in such procedures.

Diseases in Twins↗
PubMed1985

Quantitative genetic models of sexual selection.

Quantitative genetic models of sexual selection have disproven some of the central tenets of both the handicap mechanism and the 'sexy son' hypothesis. These results suggest that the 'good genes' approach to sexual selection may generally lead to erroneous results. Runaway sexual selection seems possible under a wide variety of circumstances. Quantitative genetic models have revealed runaway processes for sexually selected attributes expressed in both sexes and for attributes of parental care. Furthermore, the runaway could occur simultaneously in a series of populations that straddle an environmental gradient. While the models support the feasibility of runaway processes, empirical studies are needed to evaluate whether runaways actually happen. Estimates of critical genetic parameters are particularly needed, as well as measures of natural and sexual selection acting on the same population. The models also show that sexual selection has tremendous potential to produce population differentiation, particularly in epigamic traits. Differentiation is promoted by indeterminancy of evolutionary outcome, transient differences among populations during the final slow approach to equilibrium, sampling drift among equilibrium populations, and the tendency of sexual selection to amplify geographic variation arising from spatial differences in natural selection. Recent work with two- and three-locus models of sexual selection has produced results that parallel the results of the polygenic models. Thus the feature of indeterminate equilibria (outcome dependent on initial conditions) is common to both types of model.

Animals↗
PubMed2005

simBio: a Java package for the development of detailed cell models.

Quantitative dynamic computer models, which integrate a variety of molecular functions into a cell model, provide a powerful tool to create and test working hypotheses. We have developed a new modeling tool, the simBio package (freely available from ), which can be used for constructing cell models, such as cardiac cells (the Kyoto model from Matsuoka et al., 2003, 2004 a, b, the LRd model from Faber and Rudy, 2000, and the Noble 98 model from Noble et al., 1998), epithelial cells (Strieter et al., 1990) and pancreatic beta cells (Magnus and Keizer, 1998). The simBio package is written in Java, uses XML and can solve ordinary differential equations. In an attempt to mimic biological functional structures, a cell model is, in simBio, composed of independent functional modules called Reactors, such as ion channels and the sarcoplasmic reticulum, and dynamic variables called Nodes, such as ion concentrations. The interactions between Reactors and Nodes are described by the graph theory and the resulting graph represents a blueprint of an intricate cellular system. Reactors are prepared in a hierarchical order, in analogy to the biological classification. Each Reactor can be composed or improved independently, and can easily be reused for different models. This way of building models, through the combination of various modules, is enabled through the use of object-oriented programming concepts. Thus, simBio is a straightforward system for the creation of a variety of cell models on a common database of functional modules.

Algorithms↗
PubMed1990

Global parameter optimization for cardiac potassium channel gating models.

Quantitative ion channel model evaluation requires the estimation of voltage dependent rate constants. We have tested whether a unique set of rate constants can be reliably extracted from nonstationary macroscopic voltage clamp potassium current data. For many models, the rate constants derived independently at different membrane potentials are not unique. Therefore, our approach has been to use the exponential voltage dependence predicted from reaction rate theory (Stevens, C. F. 1978. Biophys. J. 22:295-306; Eyring, H., S. H. Lin, and S. M. Lin. 1980. Basic Chemical Kinetics. Wiley and Sons, New York) to couple the rate constants derived at different membrane potentials. This constrained the solution set of rate constants to only those that also obeyed this additional set of equations, which was sufficient to obtain a unique solution. We have tested this approach with data obtained from macroscopic delayed rectifier potassium channel currents in voltage-clamped guinea pig ventricular myocyte membranes. This potassium channel has relatively simple kinetics without an inactivation process and provided a convenient system to determine a globally optimized set of voltage-dependent rate constants for a Markov kinetic model. The ability of the fitting algorithm to extract rate constants from the macroscopic current data was tested using "data" synthesized from known rate constants. The simulated data sets were analyzed with the global fitting procedure and the fitted rate constants were compared with the rate constants used to generate the data. Monte Carlo methods were used to examine the accuracy of the estimated kinetic parameters. This global fitting approach provided a useful and convenient method for reliably extracting Markov rate constants from macroscopic voltage clamp data over a broad range of membrane potentials. The limitations of the method and the dependence on initial guesses are described.

Analysis of Variance↗
PubMed1999

Ecological character displacement in quantitative genetic models.

We study, both analytically and numerically, models of ecological character displacement for two species that compete for the same set of food sources. These models include quantitative genetics and Lotka-Volterra type competition and are symmetric with respect to the two species. We allow for various shapes of the carrying capacity and the competition function, and we discuss under what general conditions large character displacement can occur. While some of these conditions, like genetic rigidity, or flat and truncated carrying capacity curves, were known before, we also find that slow dynamics of the genetic variance, steep slopes in the interaction function and carrying capacities that are not truncated can lead to large displacements. We interpret these conditions biologically and also give new insights into models which have been previously investigated.

Animals↗
PubMed1989

A building block model for quantitative genetics.

We introduce a quantitative genetic model for multiple alleles which permits the parameterization of the degree, D, of dominance of favorable or unfavorable alleles. We assume gene effects to be random from some distribution and independent of the D's. We then fit the usual least-squares population genetic model of additive and dominance effects in an infinite equilibrium population to determine the five genetic components--additive variance sigma 2 a, dominance variance sigma 2 d, variance of homozygous dominance effects d2, covariance of additive and homozygous dominance effects d1, and the square of the inbreeding depression h--required to treat finite populations and large populations that have been through a bottleneck or in which there is inbreeding. The effects of dominance can be summarized as functions of the average, D, and the variance, sigma 2 D. An important distinction arises between symmetrical and nonsymmetrical distributions of gene effects. With symmetrical distributions d1 = -d2/2 which is always negative, and the contribution of dominance to sigma 2 a is equal to d2/2. With nonsymmetrical distributions there is an additional contribution H to sigma 2 a and -H/2 to d1, the sign of H being determined by D and the skew of the distribution. Some numerical evaluations are presented for the normal and exponential distributions of gene effects, illustrating the effects of the number of alleles and of the variation in allelic frequencies. Random additive by additive (a*a) epistatic effects contribute to sigma 2 a and to the a*a variance, sigma 2/aa, the relative contributions depending on the number of alleles and the variation in allelic frequencies.(ABSTRACT TRUNCATED AT 250 WORDS)

Alleles↗
PubMed2004

Recognition and management of hereditary breast cancer syndromes.

Clinicians should recognize the genetic syndromes that predispose to the development of breast cancer so that patients may be afforded the opportunity to have genetic testing to assist them and their family members in making medical management decisions. Approximately 80%-90% of hereditary breast cancer cases are caused by mutations in the BRCA1 and BRCA2 genes. Other important clinical genetic predispositions include Cowden syndrome, Li-Fraumeni syndrome, Peutz-Jeghers syndrome, and ataxia-telangiectasia. The key to identifying women who are at risk for a hereditary breast cancer lies in obtaining an adequate, three-generation family history, including ethnic background. For unaffected women, breast cancer risks can be estimated using the quantitative models of Gail and Claus, but there are limitations to these models. Other quantitative models predict the likelihood that a patient is carrying a mutated gene. Genetic testing is available at selected laboratories for each of the hereditary syndromes described, and there are three possible outcomes to testing. These outcomes and their management implications are described in detail. Clinical management options for women at high risk for breast cancer include surveillance, chemoprevention, and prophylactic surgery. Application of these principles can reduce morbidity in women with genetic predispositions to breast cancer.

Anticarcinogenic Agents↗
PubMed1993

Quantitative discomanometry and acute disk injuries: an experimental model.

Quantitative discomanometry is a study of intradiscal pressure changes during quantitative injection. The purpose of this study was to determine if correlations exist between discomanometric parameters and disk injuries. Sixteen three-vertebrae porcine spine segments, with two intervening disks, were subjected to standardized high-speed trauma. The injuries were documented by a radiographic injury score (RIS), using pre- and posttrauma lateral radiographs. An anatomic injury score (AIS) also was obtained, based on an anatomic dissection and mid-sagittal plane cuts of the frozen specimen. Before the cutting, each of the disks was subjected to quantitative discomanometry, providing pressure/volume curves. Significant negative correlations were found between the RIS and the maximum pressure sustained (R = -0.60, p < 0.001), and pressure/volume slope (R = -0.60, p < 0.001). Similar relationships were found between the AIS and the maximum pressure (R = -0.71, p < 0.001), and pressure/volume slope (R = -0.63, p < 0.001). This study suggests that quantitative discomanometry can be used to quantify disk injuries. Because the intradiscal pressurization mimics the physiology with weight bearing, its use as a measure of integrity of the end-plate-annulus-end-plate enclosure might be justified.

Acute Disease↗
PubMed1989

Transient response of retinal rod outer segment phosphodiesterase to actinic light pulses. I. Simple quantitative kinetic model.

We present a quantitative kinetic model for the transient velocity (microM of cGMP hydrolyzed/s) response of retinal rod outer segment (ROS) cGMP phosphodiesterase (v(t) versus t) to a stimulating light pulse in the linear response range. The model gives an excellent fit to experimental v(t) versus t data for ROS suspensions at different concentrations of GTP and GDP and clarifies experimental results which are difficult to understand in the absence of such a model. It contains the minimum number of steps required to fit our experimental data and consists of one rate-limiting step with specific rate kL for the production of active phosphodiesterase (PDE), PDE*, by photoactivated rhodopsin, R*, and deactivation processes for R* and PDE* with lifetimes tau R and tau P, respectively. The experimental graphs of v(t) versus t at each concentration of GTP and GDP are characterized by a fast rise to a peak value, vpeak, followed by a slow decay to zero level. The minimal kinetic model allows us to characterized completely the effects of GTP and GDP, and any other pertinent species, in terms of their effects on the parameters kL, tau R, and tau P. Our kinetic model indicates that for "washed" ROS preparations (a) the risetime of v(t) is determined by tau P which has a value of about 2 s and is insensitive to [GTP]. (b) The decay of v(t) is determined by tau R which decreases with [GTP] and has a value greater than 300 s at low [GTP] and a limiting value of 50 s at high [GTP]. We attribute the greater than 300 s lifetime to the complex R*G (where G is ROS G protein) and the 50-s lifetime to free R*. (c) The rate kL increases hyperbolically with [GTP] with a half-maximal value of 56 microM and kL.max = 22-45 s-1. (d) Peak velocity is given by the expression vpeak alpha kL tau P which is consistent with the dependence of kL on [GTP] and the experimental finding that vpeak varies hyperbolically with [GTP]. The minimal model has also allowed us to (a) develop clear definitions of amplification for the light-triggered enzymatic cascade and (b) clarify experimental methods for measuring gain.(ABSTRACT TRUNCATED AT 400 WORDS)

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1994

Dose-response assessment for developmental toxicity. III. Statistical models.

Although quantitative modeling has been central to cancer risk assessment for years, the concept of dose-response modeling for developmental effects is relatively new. The benchmark dose (BMD) approach has been proposed for use with developmental (as well as other noncancer) endpoints for determining reference doses and reference concentrations. Statistical models appropriate for representing the unique features of developmental toxicity testing have been developed and applied (K. Rai and J. Van Ryzin, 1985, Biometrics 41, 1-9; L. Kupper, C. Portier, M. Hogan, and E. Yamamoto, 1986, Biometrics 42, 85-98; R. Kodell, R. Howe, J. Chen, and D. Gaylor, 1991, Risk Anal. 11, 583-590). Generalizations of those models (designated the RVR, LOG, and NCTR models, respectively) account for the correlations among observations in individual fetuses or implant within litters; the potential for variables other than dose, such as litter size, to affect the probability of adverse outcome; and the possibility of a threshold dose below which background response rates are unaltered. The generalized models were applied to a database of 607 endpoints with significant dose-related increases in response rate. It was determined that the models were generally capable of fitting the observed dose-response patterns, with the LOG model appearing to be superior with respect to fit. A significant contributor to the ability of the LOG model to fit the data was its flexibility with respect to the representation of the dependence of response probability on litter size, a trait not shared by the other two models. Litter size appeared to be a significant covariable for predicting response rates, even when intralitter correlation was accounted for by assuming a beta-binomial distribution for the observations among individual fetuses. In contrast, a threshold dose parameter did not appear to be necessary to adequately describe the observed dose-response patterns. BMD estimates (corresponding to 5% additional risk) from all three models were similar to one another and to BMDs estimated from other, generic dose-response models (not specifically designed for developmental toxicity testing) that modeled average proportion of fetuses affected. The BMDs at the 5% level of risk were similar to no observed adverse effect levels determined by statistical tests of trend. Greater emphasis on and further examination of dose-response modeling for developmental toxicity testing are needed; biologically based approaches that consider the continuum of developmental effects induced in such tests should be encouraged.

Animals↗
PubMed2003

On the nature of the multivalency effect: a thermodynamic model.

A quantitative model is proposed for the analysis of the thermodynamic parameters of multivalent interactions in dilute solutions or with immobilized multimeric receptor. The model takes into account all bound species and describes multivalent binding via two microscopic binding energies corresponding to inter- and intramolecular interactions (Delta G(o)inter and Delta G(o)intra), the relative contributions of which depend on the distribution of complexes with different numbers of occupied binding sites. The third component of the overall free energy, which we call the "avidity entropy" term, is a function of the degeneracy of bound states, Omega(i), which is calculated on the basis of the topology of interaction and the distribution of all bound species. This term grows rapidly with the number of receptor sites and ligand multivalency, it always favors binding, and explains why multivalency can overcome the loss of conformational entropy when ligands displayed at the ends of long tethers are bound. The microscopic parameters and may be determined from the observed binding energies for a set of oligovalent ligands by nonlinear fitting with the theoretical model. Here binding data obtained from two series of oligovalent carbohydrate inhibitors for Shiga-like toxins were used to verify the theory. The decavalent and octavalent inhibitors exhibit subnanomolar activity and are the most active soluble inhibitors yet seen that block Shiga-like toxin binding to its native receptor. The theory developed here in conjunction with our protocol for the optimization of tether length provides a predictive approach to design and maximize the avidity of multivalent ligands.

Kinetics↗
PubMed2001

Middle-ear function with tympanic-membrane perforations. II. A simple model.

A quantitative model of the human middle ear with a tympanic-membrane (TM) perforation is developed. The model is constrained by several types of acoustic measurements made on human cadaver ears, which indicate that perforation-induced changes in transmission result primarily from changes in driving pressure across the TM and that perforation-induced change in the structure of the TM and its coupling to the ossicles contributes a substantially smaller component. The model represents the effect of a perforation on the pressure difference across the TM by inclusion of a path for sound coupling through the perforation from the ear canal to the middle-ear cavity. The model implies that hearing loss with perforations depends primarily on three quantities: the perforation diameter, sound frequency, and the volume of air in the middle-ear cavity. For the conditions that produce the largest hearing loss (low frequency and large perforation), the model yields a simple dependence of loss on frequency, perforation diameter, and middle-ear cavity volume. Predictions from this model may be useful to clinicians in determining whether, in particular cases, hearing losses are explainable by the observed perforations or if additional pathology must be involved.

Deafness↗
PubMed1979

Zinc metabolism in humans: a kinetic model.

A quantitative model is developed that describes the kinetics of the early phases of zinc metabolism in humans. The model is based on averaged data obtained over 5 days from 17 atients with smell and/or taste dysfunction who were given 69mZn in trace amounts orally and intravenously. A function describing the rate of entry of 69mZn into systemic plasma following ingestion of the isotope is derived showing that about 37% of the ingested zinc enters plasma. Gastrointestinal absorption is essentially completed by 4 h. Sixty-seven percent of the absorbed zinc in the portal circulation is extracted by the liver before being released into the systemic circulation and agrees with the calculated extraction efficiency from the systemic circulation. There are both rapid and slow exchnage phases between plasma and liver and between plasma and red cells. The calculated steady-state zinc values for plasma, red cells, and liver agree with previously reported measured values implying there are no additional zinc pools in these tissues. The tracer data, however, account for only 10% of total body zinc, the remaining 90% in tissues whose kinetics are too slow to be resolved from a 5-day study.

Adult↗
PubMed1981

Hydrolysis of rat chylomicron acylglycerols: a kinetic model.

A quantitative model describing the kinetics of hydrolysis of rat chylomicron acylglycerols by bovine milk lipoprotein lipase has been developed using data from studies on rat lymph chylomicrons containing doubly labeled acylglycerols. The detailed analysis indicates that, in addition to hydrolysis from tri- to di-, di- to mono-, and monoacylglycerol to glycerol, and apparently direct hydrolysis pathway of tri- to monoacylglycerol is also present. This accounts for the transient accumulation of monoacylglycerol seen in some of the experiments. For most hydrolysis steps, a Michaelis-Menten mechanism adequately describes the rate of hydrolysis as a function of lipoprotein lipase concentration. A higher order, more complex mechanism, however, is necessary for the apparent tri- to monoacylglycerol hydrolysis pathway. A mathematical function that describes the way free fatty acid released can control the rates of hydrolysis, and how the presence of the binding sites for free fatty acid on albumin in the incubation medium can modulate this, in included. The model simultaneously satisfies the kinetics of hydrolysis for tri-, di-, and monoacylglycerol together with the kinetics of the glycerol and fatty acid moieties for a wide range of albumin and lipoprotein lipase concentrations.

Animals↗
PubMed1993

Quantitative proton spectroscopy and histology of a canine brain tumor model.

Quantitative, single voxel proton nuclear magnetic resonance (NMR) spectroscopy and histological analysis was performed in eight dogs implanted with the transplantable canine glioma model of Wodinsky (Proc. Am. Assoc. Cancer Res. 10, 99 (1969)). Signals from choline, creatine, N-Acetyl Aspartate (NAA) and lactate were converted to molar concentration units and correlated with the quantitative analysis of histologically determined tissue types within the localized volume selected for NMR spectroscopy. In general, compared with normal brain, the lesions were associated with reductions in all metabolite concentrations, with the exception of lactate, which was increased. NAA and creatine decreases were most significantly correlated with the total lesion volume (P < 0.01), suggesting that these compounds are present in normal brain only. Changes in choline levels did not correlate strongly with any particular tissue type. Lactate was found to increase with increasing total lesion volume (P < 0.01), but not with increasing percent tumor, suggesting that it accumulates in abnormal tissue other than the tumor. The spectra reported were similar to those observed in human glioblastomas, with the exception that elevations of choline were not observed. The transplantable canine gliosarcoma system appears to be a suitable tumor model for evaluation by clinical radiological techniques such as magnetic resonance imaging (MRI) and proton NMR spectroscopy.

Animals↗
PubMed2006

A quantitative synchronization model for smooth pursuit target tracking.

We propose a quantitative model for human smooth pursuit tracking of a continuously moving visual target which is based on synchronization of an internal expectancy model of the target position coupled to the retinal target signal. The model predictions are tested in a smooth circular pursuit eye tracking experiment with transient target blanking of variable duration. In subjects with a high tracking accuracy, the model accounts for smooth pursuit and repeatedly reproduces quantitatively characteristic patterns of the eye dynamics during target blanking. In its simplest form, the model has only one free parameter, a coupling constant. An extended model with a second parameter, a time delay or memory term, accounts for predictive smooth pursuit eye movements which advance the target. The model constitutes an example of synchronization of a complex biological system with perceived sensory signals.

Attention↗
PubMed1978

The multicellular spheroid as a model tumor allograft. I. Quantitative assessment of spheroid destruction in alloimmune mice.

A quantitative model for the assessment of in situ immunity to solid tumor allografts has been developed. Multicellular spheroids of murine EMT6 mammary sarcoma cells were implanted in the peritoneal cavity of normal or specifically alloimmune mice. Damage to spheroids was quantitatively assessed at various times by trypsinizing the recovered spheroids and assaying for surviving EMT6 cells by a cloning technique. In alloimmune mice, significant destruction of spheroids was observed within 24 hr of implantation, and a 99% reduction in the number of clonogenic MT6 cells in spheroids was consistently found after 48 hr. In contrast, little or no cytotoxic effect was observed when spheroids were implanted for 48 hr in nonimmune mice or in mice immunized against unrelated alloantigens. Implantation of spheroids in alloimmune athymic (nu/nu) mice did not result in appreciable spheroid damage as compared with littermate controls. Histological analysis of spheroids taken from alloimmune mice at the time of maximum tumor cell destruction indicated that large numbers of mononuclear cells had infiltrated the spheroid. These results suggests that multicellular spheroids will be a useful model for quantitative studies of the cellular mechanisms responsible for tissue-damaging reactions in vivo.

Animals↗