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PubMed1995

A random-walk/giant-loop model for interphase chromosomes.

Fluorescence in situ hybridization data on distances between defined genomic sequences are used to construct a quantitative model for the overall geometric structure of a human chromosome. We suggest that the large-scale geometry during the G0/G1 part of the cell cycle may consist of flexible chromatin loops, averaging approximately 3 million bp, with a random-walk backbone. A fully explicit, three-parametric polymer model of this random-walk/giant-loop structure can account well for the data. More general models consistent with the data are briefly discussed.

Base Composition↗
PubMed2000

A signal detection model predicts the effects of set size on visual search accuracy for feature, conjunction, triple conjunction, and disjunction displays.

Recently, quantitative models based on signal detection theory have been successfully applied to the prediction of human accuracy in visual search for a target that differs from distractors along a single attribute (feature search). The present paper extends these models for visual search accuracy to multidimensional search displays in which the target differs from the distractors along more than one feature dimension (conjunction, disjunction, and triple conjunction displays). The model assumes that each element in the display elicits a noisy representation for each of the relevant feature dimensions. The observer combines the representations across feature dimensions to obtain a single decision variable, and the stimulus with the maximum value determines the response. The model accurately predicts human experimental data on visual search accuracy in conjunctions and disjunctions of contrast and orientation. The model accounts for performance degradation without resorting to a limited-capacity spatially localized and temporally serial mechanism by which to bind information across feature dimensions.

Adult↗
PubMed1988

A novel general biophysical model for simulating episodic endocrine gland signaling.

A multiple-parameter convolution integral is used to define and generate waveforms that quantitatively and qualitatively resemble the experimentally observed behavior of episodic endocrine signals. Our formulation of the convolution integral in terms of multiple distinct parameters with statistically bounded values allows investigators to quantitatively model variations in the duration, amplitude, frequency, and/or contour of the hormone secretory pulse, as well as alterations in rates of endogenous hormone clearance. Here we demonstrate the applicability of this new concept of endocrine gland signaling to experimentally observed (physiological) endocrine data, parameter sensitivity analysis, the evaluation of statistical errors in hormone peak detection, and the estimation of random-pulse coincidence rates between two independent endocrine series.

Animals↗
PubMed2002

A duplication growth model of gene expression networks.

MOTIVATION: There has been considerable interest in developing computational techniques for inferring genetic regulatory networks from whole-genome expression profiles. When expression time series data sets are available, dynamic models can, in principle, be used to infer correlative relationships between gene expression levels, which may be causal. However, because of the range of detectable expression levels and the current quality of the data, the predictive nature of such inferred, quantitative models is questionable. Network models derived from simple rate laws offer an intermediate level analysis, going beyond simple statistical analysis, but falling short of a fully quantitative description. This work shows how such network models can be constructed and describes the global properties of the networks derived from such a model. These global properties are statistically robust and provide insights into the design of the underlying network. RESULTS: Several whole-genome expression time series data sets from yeast microarray experiments were analyzed using a Markov-modeling method (Dewey and Galas, FUNC: Integr. Genomics, 1, 269-278, 2001) to infer an approximation to the underlying genetic network. We found that the global statistical properties of all the resulting networks are similar. The overall structure of these biological networks is distinctly different from that of other recently studied networks such as the Internet or social networks. These biological networks show hierarchical, hub-like structures that have some properties similar to a class of graphs known as small world graphs. Small world networks exhibit local cliquishness while exhibiting strong global connectivity. In addition to the small world properties, the biological networks show a power law or scale free distribution of connectivities. An inverse power law, N(k) approximately k(-3/2), for the number of vertices (genes) with k connections was observed for three different data sets from yeast. We propose network growth models based on gene duplication events. Simulations of these models yield networks with the same combination of global graphical properties that we inferred from the expression data.

Algorithms↗
PubMed2002

Model-based interpretation of cardiac beats by evolutionary algorithms: signal and model interaction.

This paper presents a new approach for cardiac beat interpretation, based on a direct integration between a model and observed ECG signals. Physiological knowledge is represented by means of a semi-quantitative model of the cardiac electrical activity. The interpretation of cardiac beats is formalized as an optimization problem, by minimizing an error function defined between the model's output and the observations. Evolutionary algorithms (EAs) are used as the search technique in order to obtain the set of model parameters reproducing at best the observed phenomena. Examples of model adaptation to three different kinds of cardiac beats are presented. Preliminary results show the potentiality of this approach to reproduce and explain complex pathological disorders and to better localize their origin.

Algorithms↗
PubMed1996

T-cell-receptor affinity and thymocyte positive selection.

Development of thymocytes involves two distinct outcomes resulting from superficially similar events. Recognition by thymocytes of major histocompatibility complex (MHC) proteins plus peptides leads to their rescue from apoptosis (positive selection), and recognition of antigenic peptide induces cell death (negative selection). Antigen analogues, and sometimes low concentrations of antigenic peptide, induce positive selection; such analogues are often antagonists of mature T-cell clones. Various models seek to explain how recognition of different peptide/MHC complexes leads to such different outcomes: quantitative models relate response to the affinity, avidity or kinetics of T-cell-antigen receptor (TCR) binding, whereas qualitative models require conformational or spatial changes in the TCR or associated molecules to modulate signal transduction. We have used surface plasmon resonance to measure the kinetics of TCR interactions with positively and negatively selecting ligands to distinguish between these models, and find that affinity correlates to the outcome of selection. A 'window' of affinity resulting in positive selection extends over a 1-log range starting threefold below the affinity for negative selection.

Amino Acid Sequence↗
PubMed1997

Understanding the state variation in Medicare home health care. The impact of Medicaid program characteristics, state policy, and provider attributes.

OBJECTIVES: During the past 7 years there has been a significant increase in the use of the Medicare home health benefit. In this article, the authors document trends in the use of the benefit and develop multivariate models to identify the factors that explain state variation in its use. METHODS: To develop quantitative models, the authors collected state information on all variables for each of 3 years: 1991, 1992, and 1993. The authors chose to focus on those variables that had been found to be significant in other research as well as those that we posited would likely influence utilization. The authors tested similar sets of explanatory variables for each year of the analysis. The unit of analysis is the "state" and depending on data availability, the number of states included in the analyses range from between 46 to 49. (Arizona does not have a state Medicaid program.) RESULTS: The authors' analysis shows that interaction exists between state policies and use of the benefit. Utilization is higher in states that face greater fiscal pressure concerning their Medicaid budgets; the lack of state personal care programs increases Medicare use, and, when Medicaid home health expenditures decline, the number of Medicare home health care users increases. There is also an inverse relationship between the number of long-term care and skilled nursing facilities in a state and the use of the benefit. Thus, for some, the benefit serves as a substitute for long-term care needs and, for others, for postacute care needs. CONCLUSIONS: The overlap between the population served and the services provided by state programs and Medicare has given states and providers an opportunity to leverage Federal dollars in lieu of state program dollars. As the Federal government attempts to control expenditure growth, policy-makers must be mindful of how state actions can influence the level and type of Federal expenditure.

Aged↗
PubMed1997

Conductance-based integrate-and-fire models.

A conductance-based model of Na+ and K+ currents underlying action potential generation is introduced by simplifying the quantitative model of Hodgkin and Huxley (HH). If the time course of rate constants can be approximated by a pulse, HH equations can be solved analytically. Pulse-based (PB) models generate action potentials very similar to the HH model but are computationally faster. Unlike the classical integrate-and-fire (IAF) approach, they take into account the changes of conductances during and after the spike, which have a determinant influence in shaping neuronal responses. Similarities and differences among PB, IAF, and HH models are illustrated for three cases: high-frequency repetitive firing, spike timing following random synaptic inputs, and network behavior in the presence of intrinsic currents.

Action Potentials↗
PubMed2002

Pharmacokinetics of toxic chemicals in breast milk: use of PBPK models to predict infant exposure.

Factors controlling the transfer of potentially toxic chemicals in the breast milk of nursing mothers include both chemical characteristics, such as lipophilicity, and physiologic changes during lactation. Physiologically based pharmacokinetic (PBPK) models can aid in the prediction of infant exposure via breast milk. Benefits of these quantitative models include the ability to account for changing maternal physiology and transfer kinetics, as well as the chemical-specific characteristics, in order to produce more accurate estimates of neonatal risk. A recently developed PBPK model for perchlorate and iodide kinetics in the lactating and neonatal rat demonstrates the utility of PBPK modeling in predicting maternal and neonatal distribution of these two compounds. This model incorporates time-dependent changes in physiologic characteristics and includes interactions between iodide and perchlorate that alter the distribution and kinetics of iodide.

Adult↗
PubMed2006

Non-stochastic quadratic fingerprints and LDA-based QSAR models in hit and lead generation through virtual screening: theoretical and experimental assessment of a promising method for the discovery of new antimalarial compounds.

In order to explore the ability of non-stochastic quadratic indices to encode chemical information in antimalarials, four quantitative models for the discrimination of compounds having this property were generated and statistically compared. Accuracies of 90.2% and 83.3% for the training and test sets, respectively, were observed for the best of all the models, which included non-stochastic quadratic fingerprints weighted with Pauling electronegativities. With a comparative purpose and as a second validation experiment, an exercise of virtual screening of 65 already-reported antimalarials was carried out. Finally, 17 new compounds were classified as either active/inactive ones and experimentally evaluated for their potential antimalarial properties on the ferriprotoporphyrin (FP) IX biocrystallization inhibition test (FBIT). The theoretical predictions were in agreement with the experimental results. In the assayed test compound C5 resulted more active than chloroquine. The current result illustrates the usefulness of the TOMOCOMD-CARDD strategy in rational antimalarial-drug design, at the time that it introduces a new family of organic compounds as starting point for the development of promising antimalarials.

Algorithms↗
PubMed1985

[Therapy of organic psychosyndromes of cerebrovascular origin with a vasoactive drug combination].

Concrete cross-sectional studies of the organic brain syndrome, carried out periodically, attempt to establish for the parameters evaluation of substrate damage--and different noopsychopathological rating-scales for the measurement of brain capacity impairment. Beyond the level of the purely correlative-statistical point of view of the relationship between parameter and score changes, demanding for a quantitative model which could provide not only a description, but also an explanation for such a relationship. The fact that there can only be a question here of a "quantitative causality" embracing non-specificity of toxic substances and relative to acute and chronic diffuse organic brain syndromes. It results, that quantitative causality meets the requirements of an exponential function model and that one can validate such models through correlative-statistical methods. This has already been carried out by Ball and Taylor.

Adult↗
PubMed1999

Thermal models for microwave hazards and their role in standards development.

We consider the thermal response of the body to radiofrequency (RF) energy, with emphasis on partial-body exposure, to assess potential thermal hazards. The thermal analysis is based on Pennes' bioheat equation. In this model, the thermal response is governed by two time constants. One (tau1) pertains to heat convection by blood flow and is (for physiologically normal perfusion rates) on the order of 3 min. The second (tau2) characterizes heat conduction, and varies as the square of a distance that characterizes the spatial extent of the heating. We examine three idealized cases. The first is a region of tissue with an insulated surface, subject to irradiation with an exponentially decreasing SAR, which models a large surface area of tissue exposed to microwaves. The second is a region of tissue in contact with a hemispherical electrode that passes current into it, which models exposure from contact with a conductor. The third is a region of tissue with an insulated surface, subject to heating from a dipole located close to it. In all three cases, we estimate the maximum steady-state temperature increase as a function of the relevant electrical and thermal parameters and the thresholds for thermal hazard. We conclude that thermal models are a potentially fruitful but underutilized means of analyzing thermal hazards from RF fields. A quantitative analysis of such hazards enables the development of data-based uncertainty factors, which can replace arbitrary "safety factors" in developing exposure limits. Finally, we comment on the need to marry quantitative modeling of data and risk assessment, and to incorporate contemporary approaches to risk assessment into RF standards development.

Blood Circulation↗
PubMed2000

A cell-based constitutive relation for bio-artificial tissues.

By using a combination of continuum and statistical mechanics we derive an integral constitutive relation for bio-artificial tissue models consisting of a monodisperse population of cells in a uniform collagenous matrix. This constitutive relation quantitatively models the dependence of tissue stress on deformation history, and makes explicit the separate contribution of cells and matrix to the mechanical behavior of the composite tissue. Thus microscopic cell mechanical properties can be deduced via this theory from measurements of macroscopic tissue properties. A central feature of the constitutive relation is the appearance of "anisotropy tensors" that embody the effects of cell orientation on tissue mechanics. The theory assumes that the tissues are stable over the observation time, and does not in its present form allow for cell migration, reorientation, or internal remodeling. We have compared the predictions of the theory to uniaxial relaxation tests on fibroblast-populated collagen matrices (FPMs) and find that the experimental results generally support the theory and yield values of fibroblast contractile force and stiffness roughly an order of magnitude smaller than, and viscosity comparable to, the corresponding properties of active skeletal muscle. The method used here to derive the tissue constitutive equation permits more sophisticated cell models to be used in developing more accurate representations of tissue properties.

Animals↗
PubMed1980

Activation of skeletal muscle myosin light chain kinase by calcium(2+) and calmodulin.

Many biological processes are now known to be regulated by Ca2+ via calmodulin (CM). Although a general mechanistic model by which Ca2+ and calmodulin modulate many of these activities has been proposed, an accurate quantitative model is not available. A detailed analysis of skeletal muscle myosin light chain kinase activation was undertaken in order to determine the stoichiometries and equilibrium constants of Ca2+, calmodulin, and enzyme catalytic subunit in the activation process. The analysis indicates that activation is a sequential, fully reversible process requiring both Ca2+ and calmodulin. The first step of the activation process appears to require binding of Ca2+ to all four divalent metal binding sites on calmodulin for form the complex, Ca42+-calmodulin. This complex then interacts with the inactive catalytic subunit of the enzyme to form the active holoenzyme complex, Ca42+-calmodulin-enzyme. Formation of the holoenzyme follows simply hyperbolic kinetics, indicating 1:1 stoichiometry of Ca42+-calmodulin to catalytic subunit. The rate equation derived from the mechanistic model was used to determine the values of KCa2+ and KCM, the intrinsic activation constants for each step of the activation process. KCa2+ and KCM were found to have values of 10 microM and 0.86 nM, respectively, at 10 mM Mg2+. The rate equation using these equilibrium constants accurately predicts the extent of enzyme activation over a wide range of Ca2+ and calmodulin concentrations. The kinetic model and analytical techniques employed herein may be generally applicable to other enzymes with similar regulatory schemes.

Animals↗
PubMed2006

Catalytically driven colloidal patterning and transport.

We recently reported the convection and pattern formation of tracers caused by a catalytically generated electric field. The electric field arises due to the heterogeneous electrochemical reduction and oxidation of hydrogen peroxide (H2O2) on silver (Ag) and gold (Au), respectively.1 Here we describe an electrokinetic model, developed in conjunction with experiments, that explains the details of the convection and pattern formation phenomenon. The model also enables the measurement of reaction kinetic parameters that are otherwise difficult to obtain. This quantitative model serves as a platform for the modeling of other catalytic redox systems and systems with broken symmetries.

Journal Article↗
PubMed2000

A modified transorbital baboon model of reperfused stroke.

BACKGROUND AND PURPOSE: Although pathophysiological studies of focal cerebral ischemia in nonhuman primates can provide important information not obtainable in rodent models, primate experimentation is limited by considerations of cost, availability, effort, and ethics. A reproducible and quantitative model that minimizes the number of animals necessary to detect differences between treatment groups is therefore crucial. METHODS: Eight male baboons (weight, 22+/-2 kg) underwent left transorbital craniectomy followed by 1 hour of temporary ipsilateral internal carotid artery occlusion at the level of the anterior choroidal artery together with bilateral temporary occlusion of both anterior cerebral arteries (A1) proximal to the anterior communicating artery. A tightly controlled nitrous oxide-narcotic anesthetic allowed for intraoperative motor evoked potential confirmation of middle cerebral artery (MCA) territory ischemia. Animals survived to 72 hours or 10 days if successfully self-caring. Outcomes were assessed with a 100-point neurological grading system, and infarct volume was quantified by planimetric analysis of both MRI and triphenyltetrazolium chloride-stained sections. RESULTS: Infarction volumes (on T2-weighted images) were 32+/-7% (mean+/-SEM) of the ipsilateral hemisphere, and neurological scores averaged 29+/-9. All animals demonstrated evidence of hemispheric infarction, with damage evident in both cortical and subcortical regions in the MCA vascular territory. Histologically determined infarction volumes differed by <3% and correlated with absolute neurological scores (r=0.9, P:=0.003). CONCLUSIONS: Transorbital temporary occlusion of the entire anterior cerebral circulation with strict control of physiological parameters can reliably produce reperfused MCA territory infarction. The magnitude of the resultant infarct with little interanimal variability diminishes the potential number of animals required to distinguish between 2 treatment regimens. The anatomic distribution of the infarct and associated functional deficits offer comparability to human hemispheric strokes.

Animals↗
PubMed2005

Intermediate care: for better or worse? Process evaluation of an intermediate care model between a university hospital and a residential home.

BACKGROUND: Intermediate care was developed in order to bridge acute, primary and social care, primarily for elderly persons with complex care needs. Such bridging initiatives are intended to reduce hospital stays and improve continuity of care. Although many models assume positive effects, it is often ambiguous what the benefits are and whether they can be transferred to other settings. This is due to the heterogeneity of intermediate care models and the variety of collaborating partners that set up such models. Quantitative evaluation captures only a limited series of generic structure, process and outcome parameters. More detailed information is needed to assess the dynamics of intermediate care delivery, and to find ways to improve the quality of care. Against this background, the functioning of a low intensity early discharge model of intermediate care set up in a residential home for patients released from an Amsterdam university hospital has been evaluated. The aim of this study was to produce knowledge for management to improve quality of care, and to provide more generalisable insights into the accumulated impact of such a model. METHODS: A process evaluation was carried out using quantitative and qualitative methods. Registration forms and patient questionnaires were used to quantify the patient population in the model. Statistical analysis encompassed T-tests and chi-squared test to assess significance. Semi-structured interviews were conducted with 21 staff members representing all disciplines working with the model. Interviews were transcribed and analysed using both 'open' and 'framework' approaches. RESULTS: Despite high expectations, there were significant problems. A heterogeneous patient population, a relatively unqualified staff and cultural differences between both collaborating partners impeded implementation and had an impact on the functioning of the model. CONCLUSION: We concluded that setting up a low intensity early discharge model of intermediate care between a university hospital and a residential home is less straightforward than was originally perceived by management, and that quality of care needs careful monitoring to ensure the change is for the better.

Aged↗
PubMed1998

Interpretation of the osmotic behavior of sickle cell hemoglobin solutions: different interactions among monomers and polymers.

It has long been known that a simple hard particle model quantitatively explains the osmotic properties of monomeric hemoglobin near its isoelectric point. However, we find that a hard particle model is not consistent with the osmotic properties of polymerized hemoglobin and that substantial soft repulsions are indicated. With allowance for different interactions among monomers and among polymers, a self-consistent quantitative fit to the experimental data is obtained. The results suggest that the decreasing "solubility" of deoxy sickle cell hemoglobin with increasing temperature from 20 to 37 degrees C is due to weaker repulsions between polymers at higher temperatures rather than stronger polymerization. The temperature dependence of these variables indicates that the aggregation of monomers is enthalpically and entropically driven (the latter effect being stronger), while the approach of polymers toward each other is enthalpically disfavored and entropically favored (with the former dominating). In both cases, the entropic contribution suggests that water is released.

Biopolymers↗