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At least 919 records · Page 51Linked to original sources
PubMed2004

Ligand affinity for amino-terminal and juxtamembrane domains of the corticotropin releasing factor type I receptor: regulation by G-protein and nonpeptide antagonists.

Peptide ligands bind the CRF(1) receptor by a two-domain mechanism: the ligand's carboxyl-terminal portion binds the receptor's extracellular N-terminal domain (N-domain) and the ligand's amino-terminal portion binds the receptor's juxtamembrane domain (J-domain). Little quantitative information is available regarding this mechanism. Specifically, the microaffinity of the two interactions and their contribution to overall ligand affinity are largely undetermined. Here we measured ligand interaction with N- and J-domains expressed independently, the former (residues 1-118) fused to the activin IIB receptor's membrane-spanning alpha-helix (CRF(1)-N) and the latter comprising residues 110-415 (CRF(1)-J). We also investigated the effect of nonpeptide antagonist and G-protein on ligand affinity for N- and J-domains. Peptide agonist affinity for CRF(1)-N was only 1.1-3.5-fold lower than affinity for the whole receptor (CRF(1)-R), suggesting the N-domain predominantly contributes to peptide agonist affinity. Agonist interaction with CRF(1)-J (potency for stimulating cAMP accumulation) was 12000-1500000-fold weaker than with CRF(1)-R, indicating very weak direct agonist interaction with the J-domain. Nonpeptide antagonist affinity for CRF(1)-J and CRF(1)-R was indistinguishable, indicating the compounds bind predominantly the J-domain. Agonist activation of CRF(1)-J was fully blocked by nonpeptide antagonist, suggesting antagonism results from inhibition of agonist-J-domain interaction. G-protein coupling with CRF(1)-R (forming RG) increased peptide agonist affinity 92-1300-fold, likely resulting from enhanced agonist interaction with the J-domain rather than the N-domain. Nonpeptide antagonists, which bind the J-domain, blocked peptide agonist binding to RG, and binding of peptide antagonists, predominantly to the N-domain, was unaffected by R-G coupling. These findings extend the two-domain model quantitatively and are consistent with a simple equilibrium model of the two-domain mechanism: (1) The N-domain binds peptide agonist with moderate-to-high microaffinity, substantially increasing the local concentration of agonist and so allowing weak agonist-J-domain interaction. (2) Agonist-J-domain interaction is allosterically enhanced by receptor-G-protein interaction and inhibited by nonpeptide antagonist.

Amphibian Proteins↗
PubMed1994

Solvent-induced organization: a physical model of folding myoglobin.

The essential features of the in vitro refolding of myoglobin are expressed in a solvable physical model. Alpha helices are taken as the fundamental collective coordinates of the system, while the refolding is assumed to be mainly driven by solvent-induced hydrophobic forces. A quantitative model of these forces is developed and compared with experimental and theoretical results. The model is then tested by being employed in a simulation scheme designed to mimic solvent effects. Realistic dynamic trajectories of myoglobin are shown as it folds from an extended conformation to a close approximation of the native state. Various suggestive features of the process are discussed. The tenets of the model are further tested by folding the single-chain plant protein leghemoglobin.

Models, Chemical↗
PubMed2001

Rate, timing, and cooperativity jointly determine cortical synaptic plasticity.

Cortical long-term plasticity depends on firing rate, spike timing, and cooperativity among inputs, but how these factors interact during realistic patterns of activity is unknown. Here we monitored plasticity while systematically varying the rate, spike timing, and number of coincident afferents. These experiments demonstrate a novel form of cooperativity operating even when postsynaptic firing is evoked by current injection, and reveal a complex dependence of LTP and LTD on rate and timing. Based on these data, we constructed and tested three quantitative models of cortical plasticity. One of these models, in which spike-timing relationships causing LTP "win" out over those favoring LTD, closely fits the data and accurately predicts the build-up of plasticity during random firing. This provides a quantitative framework for predicting the impact of in vivo firing patterns on synaptic strength.

Action Potentials↗
PubMed1998

Mouse model of venous bypass graft arteriosclerosis.

Saphenous vein grafts are widely used for treatment of severe atherosclerosis via aortocoronary bypass surgery, a procedure often complicated by later occlusion of the graft vessel. Because the molecular mechanisms of this process remain largely unknown, quantitative models of venous bypass graft arteriosclerosis in transgenic mice could be useful to study this process at the genetic level. We describe herein a new model of vein grafts in the mouse that allows us to take advantage of transgenic, knockout, or mutant animals. Autologous or isogeneic vessels of the external jugular or vena cava veins were end-to-end grafted into carotid arteries of C57BL/6J mice. Vessel wall thickening was observed as early as 1 week after surgery and progressed to 4-, 10-, 15-, and 18-fold original thickness in grafted veins at age 2, 4, 8, and 16 weeks, respectively. The lumen of grafted veins was significantly narrowed because of neointima hyperplasia. Histological and immunohistochemical analyses revealed three lesion processes: marked loss of smooth muscle cells in vein segments 1 and 2 weeks after grafting, massive infiltration of mononuclear cells (CD11b/18+) in the vessel wall between 2 and 4 weeks, and a significant proliferation of vascular smooth muscle cells (alpha-actin+) to constitute neointimal lesions between 4 and 16 weeks. Similar vein graft lesions were obtained when external jugular veins or vena cava were isografted into carotid arteries of C57BL/6J mice. Moreover, no significant intima hyperplasia in vein-to-vein isografts was found, although there was leukocyte infiltration in the vessel wall. Thus, this model, which reproduces many of the features of human vein graft arteriosclerosis, should prove useful for our understanding of the mechanism of vein graft disease and to evaluate the effects of drugs and gene therapy on vascular diseases.

Anastomosis, Surgical↗
PubMed2000

Population risk and physiological rate parameters for colon cancer. The union of an explicit model for carcinogenesis with the public health records of the United States.

The relationship between the molecular mechanisms of mutagenesis and the actual processes by which most people get cancer is still poorly understood. One missing link is a physiologically based but quantitative model uniting the processes of mutation, cell growth and turnover. Any useful model must also account for human heterogeneity for inherited traits and environmental experiences. Such a coherent algebraic model for the age-specific incidence of cancer has been developing over the past 50 years. This development has been spurred primarily by the efforts of Nordling [N.O. Nordling, A new theory on the cancer-inducing mechanism, Br. J. Cancer 7 (1953) 68-72], Armitage and Doll [P. Armitage, R. Doll, The age distribution of cancer and a multi-stage theory of carcinogenesis, Br. J. Cancer 8 (1) (1954) 1-12; P. Armitage, R. Doll, A two-stage theory of carcinogenesis in relation to the age distribution of human cancer, Br. J. Cancer 9 (2) (1957) 161-169], and Moolgavkar and Knudson [S.H. Moolgavkar, A.G. Knudson Jr., Mutation and cancer: a model for human carcinogenesis. JNCI 66 (6) (1981) 1037-1052], whose work defined two rate-limiting stages identified with initiation and promotion stages in experimental carcinogenesis. Unfinished in these efforts was an accounting of population heterogeneity and a complete description of growth and genetic change during the growth of adenomas. In an attempt to complete a unified model, we present herein the first means to explicitly compute the essential parameters of the two-stage initiation-promotion model using colon cancer as an example. With public records from the 1930s to the present day, we first calculate the fraction at primary risk for each birth year cohort and note historical changes. We then calculate the product of rates for n initiation-mutations, the product of rates for m promotion-mutations and the average growth rate of the intermediate adenomatous colonies from which colon carcinomas arise. We find that the population fraction at primary risk for colon cancer risk was historically invariant at about 42% for the birth year cohorts from 1860 through 1930. This was true for each of the four cohorts we examined (European- and African-Americans of each gender). Additionally, the data indicate an historical increase in the initiation-mutation rates for the male cohorts and the promotion-mutation rates for the female cohorts. Interestingly, the calculated rates for initiation-mutations are in accord with mutation rates derived from observations of mutations in peripheral blood cells drawn from persons of different ages. Adenoma growth rates differed significantly between genders but were essentially historically invariant. In its present form, the model has also allowed us to calculate the rate of loss of heterozygosity (LOH) or loss of genomic imprinting (LOI) in adenomas to result in the high LOH/LOI fractions in tumors. But it has not allowed us to specify the number of events m required during promotion.

Adenoma↗
PubMed2006

Quantitative and predictive model of transcriptional control of the Drosophila melanogaster even skipped gene.

Here we present a quantitative and predictive model of the transcriptional readout of the proximal 1.7 kb of the control region of the Drosophila melanogaster gene even skipped (eve). The model is based on the positions and sequence of individual binding sites on the DNA and quantitative, time-resolved expression data at cellular resolution. These data demonstrated new expression features, first reported here. The model correctly predicts the expression patterns of mutations in trans, as well as point mutations, insertions and deletions in cis. It also shows that the nonclassical expression of stripe 7 driven by this fragment is activated by the protein Caudal (Cad), and repressed by the proteins Tailless (Tll) and Giant (Gt).

Animals↗
PubMed2005

Evolutionary approach for determining first-principles hamiltonians.

Modern condensed-matter theory from first principles is highly successful when applied to materials of given structure-type or restricted unit-cell size. But this approach is limited where large cells or searches over millions of structure types become necessary. To treat these with first-principles accuracy, one 'coarse-grains' the many-particle Schrodinger equation into 'model hamiltonians' whose variables are configurational order parameters (atomic positions, spin and so on), connected by a few 'interaction parameters' obtained from a microscopic theory. But to construct a truly quantitative model hamiltonian, one must know just which types of interaction parameters to use, from possibly 10(6)-10(8) alternative selections. Here we show how genetic algorithms, mimicking biological evolution ('survival of the fittest'), can be used to distil reliable model hamiltonian parameters from a database of first-principles calculations. We demonstrate this for a classic dilemma in solid-state physics, structural inorganic chemistry and metallurgy: how to predict the stable crystal structure of a compound given only its composition. The selection of leading parameters based on a genetic algorithm is general and easily applied to construct any other type of complex model hamiltonian from direct quantum-mechanical results.

Journal Article↗
PubMed2026

Improving insurance deduction identification: a hybrid artificial intelligence model using machine learning and expert systems.

PURPOSE: Financial challenges in healthcare systems worldwide, especially in low- and middle-income countries like Iran, have increased hospitals' reliance on insurance reimbursements. Unrecognized insurance deductions often cause severe financial shortages, making efficient deduction management crucial. This study aimed to design a hybrid intelligent system for identifying and predicting insurance deductions by combining machine learning and expert system frameworks. DESIGN/METHODOLOGY/APPROACH: A mixed-methods design was applied in four stages. First, a scoping review identified the causes and patterns of insurance deductions. Second, interviews with 15 insurance experts produced a validated checklist and a dataset from inpatient billing records. Third, using the CRISP-DM methodology, machine learning algorithms were developed and tested in SPSS Modeler alongside a fuzzy expert system developed in MATLAB. Finally, the model was validated using the holdout method. FINDINGS: Four categories of deduction drivers were identified: service provision, registration errors, document submission issues, and revenue conversion processes. The CHAID decision tree outperformed other algorithms with a 99% precision rate and the lowest Mean Absolute Error (9.43). A brief assessment of potential overfitting was conducted to ensure that the CHAID model's high accuracy was interpreted cautiously and supported by the validation results. The fuzzy expert system with validated rules was adaptable for deduction classification, especially for cases unsuitable for quantitative modeling. ORIGINALITY/VALUE: The hybrid model improves detection and prevention of deductions, offering actionable insights for hospital administrators, insurers, and policymakers. Its implementation can enhance hospital information systems, streamline claims processing, and optimize revenue management amid financial constraints.

Machine Learning↗
PubMed1998

Physiologically-based pharmacokinetic model for trichloroethylene considering enterohepatic recirculation of major metabolites.

Trichloroacetic acid (TCA) is a major metabolite of trichloroethylene (TRI) thought to contribute to its hepatocarcinogenic effects in mice. Recent studies have shown that peak blood concentrations of TCA in rats do not occur until approximately 12 hours following an oral dose of TRI. However, blood concentrations of TRI reach a maximum within an hour and are nondetectable after 2 hours. The results of a study which examined the enterohepatic recirculation (EHC) of the principle TRI metabolites was used to develop a physiologically-based pharmacokinetic model for TRI, which includes enterohepatic recirculation of its metabolites. The model quantitatively predicts the uptake, distribution and elimination of TRI, trichloroethanol, trichloroethanol-glucuronide, and TCA and includes production of metabolites through the enterohepatic recirculation pathway. Physiologic parameters used in the model were obtained from the literature. Parameters for TRI metabolism were taken from Fisher et al. Other kinetic parameters were found in the literature or estimated from experimental data. The model was calibrated to data from experiments of an earlier study where TRI was orally administered. Verification of the model was conducted using data on the enterohepatic recirculation of TCEOH and TCA, chloral hydrate data (infusion doses) from Merdink, and TRI data from Templin and Larson and Bull.

Animals↗
PubMed1998

Transient cavities in liquids and the nature of the hydrophobic effect.

The size distributions of transient cavities in water and organic liquids, obtained from computer simulations, have provided a new means to analyze the nature of the hydrophobic effect and to evaluate the adequacy of different analytical models of this effect. The poor solubility of non-polar solutes in water is attributed to a low probability of finding in water cavities of atomic and molecular size. It has been shown that water applies more force per unit area of cavity surface than do hydrocarbon liquids. Models that successfully capture the main characteristics of the hydrophobic effect must at least include information about the density and the radial distribution of oxygen atoms in liquid water. One such model, quantitatively accurate for molecular solutes of arbitrary shape, is presented.

Butanes↗
PubMedDate not supplied

[A mathematical model of the seasonal morbidity of shigellosis].

A new epidemiologically significant mathematical model for the prognosis of seasonal morbidity in dysentery caused by S. flexneri and S. sonnei has been developed. This model may be used for solving problems on the epidemiology of Shigella infections. In this model quantitative ratios are determined by means of the system of nonlinear integral-differential equations in partial derivatives of the first order with edge conditions of the integral type. This model makes it possible to make multiple calculations with a view to obtaining the most probable picture of the development of the epidemic process at individual territories, to ascertain and make prognosis the terms and peaks of morbidity rises year after year in succession. The model permits the evaluation of specific features of the course of dysentery in patients of different ages in different groups of the population, affected by various nosological forms of shigellae. The relationships indicated by the model have been realized in the form of the computer program "SHIGELLA C" permitting multiple calculations of dysentery morbidity by means of an IBM PC/AT.

Dysentery, Bacillary↗
PubMed2002

Bayesian probabilistic network modeling of remifentanil and propofol interaction on wakeup time after closed-loop controlled anesthesia.

OBJECTIVE: Until now, the knowledge of combining anesthetics to obtain an adequate level of anesthesia and to economize wakeup time has been empirical and difficult to represent in quantitative models. Since there is no reason to expect that the effect of non-opioid and opioid anesthetics can be modeled in a simple linear manner, the use of a new computational approach with Bayesian belief network software is demonstrated. METHODS: A data set from a pharmacodynamic study was used where remifentanil was randomly given in three fixed target concentrations (2, 4, and 8 ng/ml) to 62 subjects. Target concentrations of propofol were controlled according to the closed-loop system feedback of the auditory evoked potential index to render modeling unbiased by the level of anesthesia. Time to open eyes was measured to represent wakeup time after surgery. The NETICA version 1.37 software was used on a personal computer for network building, validation, and prediction. RESULTS: After the learning phase, the network was used to generate a series of random cases whose probability distribution matches that of the compiled network. The sampling algorithms used are precise, so that the frequencies of the simulated cases will exactly approach the probabilities of the network and that of the data learned. The graphical display of the predicted wakeup time shows less variability but a more complex interaction pattern than with the unadjusted original data. CONCLUSIONS: Model building and evaluation with Bayesian networks does not depend on underlying linear relationships. Bayesian relationships represent true features of the represented data sample. Data may be sparse, uncertain, stochastic, or imprecise. Multiple platform software that is easy to use is increasingly available. Bayesian networks promise to be versatile tools for building valid, nonlinear, predictive instruments to further gain insight into the complex interaction of anesthetics.

Anesthesia Recovery Period↗
PubMed1983

A mathematical model of the vagally driven primary pacemaker.

Information regarding the electrical behavior of cells in the sinoatrial (SA) node of the heart is by no means complete; yet sufficiently detailed information is available in the literature to allow the formulation of a reasonably quantitative model of the membrane of the primary pacemaker cell (P-cell) and its parasympathetic innervation. In a previous study [Am. J. Physiol. 243 (Heart Circ. Physiol. 12): H207-H218, 1982], the well-known McAllister-Noble-Tsien model of the cardiac Purkinje fiber is modified to account for the electrical activity of the SA node. In the present study, the effects of vagal activity on sinus rhythm are considered by adding a special acetylcholine-sensitive "muscarinic channel" to the membrane model for the P-cell. The resulting model mimics published data quite well and is capable of characterizing the free-running SA node cell as well as its responses to electrotonic and vagal stimulation.

Acetylcholine↗
PubMed1996

The hydration of globular proteins as derived from volume and compressibility measurements: cross correlating thermodynamic and structural data.

We report the first thermodynamic characterization of protein hydration that does not depend on model compound data but rather is based exclusively on macroscopic (volumetric) and microscopic (X-ray) measurements on protein molecules themselves. By combining these macroscopic and microscopic characterizations, we describe a quantitative model that allows one for the first time to predict the partial specific volumes, v(zero), and the partial specific adiabatic compressibilities, ks(zero), of globular proteins from the crystallographic coordinates of the constituent atoms, without using data derived from studies on low-molecular-mass model compounds. Specifically, we have used acoustic and densimetric techniques to determine v(zero) and ks(zero) for 15 globular proteins over a temperature range from 18 to 55 degrees C. For the subset of the 12 proteins with known three-dimensional structures, we calculated the molecular volumes as well as the solvent-accessible surface areas of the constituent charged, polar and nonpolar atomic groups. By combining these measured and calculated properties and applying linear regression analysis, we determined, as a function of temperature, the average hydration contributions to v(zero) and ks(zero) of 1 A2 of the charged, polar, and nonpolar solvent-accessible protein surfaces. We compared these results with those derived from studies on low-molecular-mass compounds to assess the validity of existing models of protein hydration based on small molecule data. This comparison revealed the following features: the hydration contributions to v(zero) and ks(zero) of charged protein surface groups are similar to those of charged groups in small organic molecules. By contrast, the hydration contributions to v(zero) and ks(zero) of polar protein surface groups are qualitatively different from those of polar groups in low-molecular-mass compounds. We suggest that this disparity may reflect the presence of networks of water molecules adjacent to polar protein surface areas, with these networks involving waters from second and third coordination spheres. For nonpolar protein surface groups, we find the ability of low-molecular-mass compounds to model successfully protein properties depends on the temperature domain being examined. Specifically, at room temperatures and below, the hydration contribution to ks(zero) of protein nonpolar surface atomic groups is close to that of nonpolar groups in small organic molecules. By contrast, at higher temperatures, the hydration contribution to ks(zero) of protein nonpolar surface groups becomes more negative than that of nonpolar groups in small organic molecules. We suggest that this behaviour may reflect nonpolar groups on protein surfaces being hydrated independently at low temperatures, while at higher temperatures some of the solvating waters become influenced by neighboring polar groups. We discuss the implications of our aggregate results in terms of various approaches currently being used to describe the hydration properties of globular proteins, particularly focusing on the limitations of existing additive models based on small molecule data.

Crystallography, X-Ray↗
PubMed2005

A simulation study on the Ca2+-independent but voltage-dependent exocytosis and endocytosis in dorsal root ganglion neurons.

In patch-clamped somata of dorsal root ganglion (DRG) neurons, two types of secretion have been proposed: Ca(2+)-dependent secretion and Ca(2+)-independent but voltage-dependent secretion (CIVDS). The Ca(2+)-induced and the depolarization-induced membrane capacitance (C(m)) increases contribute 80 and 20% to the total C(m) increase, respectively (Zhang and Zhou in Nat Neurosci 5:425, 2002). In order to explore the mechanism of the voltage-dependent C(m) change (DeltaC(m)), we constructed a model with sequential states. The simulation with this model closely approximates all the experimental data. The model predicts that the majority of fusion events (approximately 80%) are so-called "kiss-and-run" events, which account for the fast recovery or the rapid retrieval feature of the signals. The remaining 20% are attributed to full fusion events, which account for a slow retrieval feature. On the basis of the model, one mechanism of the activity-dependent endocytosis has revealed a differential distribution of vesicles between the kiss-and-run and full fusion states at different stimulation frequencies. The quantitative model presented in this study may help us to understand the mechanism of the CIVDS and the tightly coupled endocytosis found in mammalian DRG neurons.

Animals↗
PubMed2003

Animal colour vision--behavioural tests and physiological concepts.

Over a century ago workers such as J. Lubbock and K. von Frisch developed behavioural criteria for establishing that non-human animals see colour. Many animals in most phyla have since then been shown to have colour vision. Colour is used for specific behaviours, such as phototaxis and object recognition, while other behaviours such as motion detection are colour blind. Having established the existence of colour vision, research focussed on the question of how many spectral types of photoreceptors are involved. Recently, data on photoreceptor spectral sensitivities have been combined with behavioural experiments and physiological models to study systematically the next logical question: 'what neural interactions underlie colour vision?' This review gives an overview of the methods used to study animal colour vision, and discusses how quantitative modelling can suggest how photoreceptor signals are combined and compared to allow for the discrimination of biologically relevant stimuli.

Animals↗
PubMed2002

Searching for quantitative entropy-enthalpy compensation among protein variants.

Entropy-enthalpy (SH) compensation occurs when a small change in DeltaG is caused by large, and nearly compensatory, changes in DeltaH and DeltaS. It is considered a ubiquitous property of reactions in water. Because water is intimately involved in protein stability, SH compensation among protein variants, if it exists, could lead to important knowledge about protein-water interactions. In light of recent theoretical work on SH compensation, we gathered thermodynamic data for >200 protein variants to seek evidence for the simplest quantitative model of SH compensation (i.e., The van't Hoff denaturation enthalpy divided by the van't Hoff denaturation entropy is a constant). We conclude that either the data are insufficient to support the idea that quantitative SH compensation is a general feature of variant proteins or that such compensation does not exist. This study reinforces the idea that DeltaH-versus-DeltaS plots should not be used to provide evidence for SH compensation.

Cytochrome c Group↗
PubMed2001

The mechanisms of stone fragmentation in ESWL.

Currently, several mechanisms of kidney stone fragmentation in extracorporal shockwave lithotripsy (ESWL) are under discussion. As a new mechanism, the circumferential quasistatic compression or "squeezing" by evanescent waves in the stone has been introduced. In fragmentation experiments with self-focussing electromagnetic shock-wave generators with focal diameters comparable to or larger than the stone diameter, we observed first cleavage surfaces either parallel or perpendicular to the wave propagation direction. This is in agreement with the expectation of the "squeezing" mechanism. Because, for positive pulse pressures below 35 MPa and stones with radii of 15 mm or smaller, cleavage into only two fragments was observed, we developed a quantitative model of binary fragmentation by "quasistatic squeezing." This model predicts the ratio of the number of pulses for the fragmentation to 2-mm size and of the number of pulses required for the first cleavage into two parts. This "fragmentation-ratio" depends linearly alone on the stone radius and on the final size of the fragments. The experimental results for spherical artificial stones of 5 mm, 12 mm and 15 mm diameter at a pulse pressure of 11 MPa are in good agreement with the theoretical prediction. Thus, binary fragmentation by quasistatic squeezing in ESWL as a new efficient fragmentation mechanism is also quantitatively verified.

Humans↗