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At least 127 records · Page 7Linked to original sources
PubMed1992

A quantitative model of intracellular growth of Legionella pneumophila in Acanthamoeba castellanii.

A model of intracellular growth for Legionella pneumophila in Acanthamoeba castellanii has been developed and provides a quantitative measure of survival and replication after entry. In this model, Acanthamoeba monolayers were incubated with bacteria in tissue culture plates under nutrient-limiting conditions. Gentamicin was used to kill extracellular bacteria following the period of incubation, and the number of intracellular bacteria was determined following lysis of amebae. Intracellular growth of virulent L. pneumophila and other wild-type Legionella species was observed when the assay was performed at 37 degrees C. At room temperature, none of the Legionella strains tested grew intracellularly, while an avirulent L. pneumophila strain was unable to replicate in this assay at either temperature. The effect of nutrient limitation on A. castellanii during the assay prevented multiplication of the amebae and increased the level of infection by Legionella spp. The level of infection of the amebae was directly proportional to the multiplicity of infection with bacteria; at an inoculum of 1.03 x 10(7) bacteria added to wells containing 1.10 x 10(5) amebae (multiplicity of infection of 100), approximately 4.4% of A. castellanii cells became infected. Cytochalasin D reduced the uptake of bacteria by the amebae primarily by causing amebae to lift off the culture dish, reducing the number of target hosts; methylamine also reduced the level of initial infection, yet neither inhibitor was able to prevent intracellular replication of Legionella spp. Consequently, once the bacteria entered the cell, only lowered temperature could restrict replication. This model of intracellular growth provides a one-step growth curve and should be useful to study the molecular basis of the host-parasite interaction.

Acanthamoeba↗
PubMed1981

Experimental myocardial infarction in the rat as a quantitative model for the study of anti-ischemic interventions.

The identification of metabolic and drug interventions able to reduce myocardial injury after coronary artery occlusion requires experimental models. The rat model of ischemic injury is technically simple, unexpensive, informative and accessible to quantitative studies. In this present study, 41 rats underwent temporary myocardial ischemia of variable duration using left coronary artery ligation. They were sacrificed at 48 hours, and the heart was immediately frozen in liquid nitrogen. Serial 8 micrometer sections of known intervals were tested for succinodehydrogenase (NBT stain). Gross sectional areas measured planimetrically were utilized to calculate total myocardial volume (Vmyocardium) and infarcted myocardial volume (Vinfarct) with the aid of a programmable calculator. The data showed a linear regression for Vinfarct/Vmyocardium according to the time of ischemia (p 0,001). We suggest to test the efficiency of metabolic and drug interventions on the regression curve of the necrotic tissue using a multiple linear analysis. Since ischemic changes evolve more rapidly in this model, the intervention under study should be set up at the time of coronary artery occlusion.

Animals↗
PubMed2003

A quantitative model of the cardiac ventricular cell incorporating the transverse-axial tubular system.

The role of the transverse-axial tubular system (TATS) in electrical activity of cardiac cells has not been investigated quantitatively. In this study a mathematical model including the TATS and differential distribution of ionic transfer mechanisms in peripheral and tubular membranes was described. A model of ventricular cardiac cell described by Jafri et al. (1998) was adopted and slightly modified to describe ionic currents and Ca2+ handling. Changes of concentrations in the lumen of the TATS were computed from the total of transmembrane ionic fluxes and ionic exchanges with the pericellular medium. Long-term stability of the model was attained at rest and under regular stimulation. Depletion of Ca2+ by 12.8% and accumulation of K+ by 4.7% occurred in the TATS-lumen at physiological conditions and at a stimulation frequency of 1 Hz. The changes were transient and subsided on repolarization within 800 ms (Ca2+) and 300 ms (K+). Nevertheless, the course of action potentials remained virtually unaltered. Simulations of voltage clamp experiments demonstrated that variations in tubular ionic concentrations were detectable as modulation of the recorded membrane currents.

Action Potentials↗
PubMedDate not supplied

A spreadsheet program for modeling quantitative structure-pharmacokinetic relationships for inhaled volatile organics in humans.

The extent and profile of target tissue exposure to toxicants depend upon the pharmacokinetic processes, namely, absorption, distribution, metabolism and excretion. The present study developed a spreadsheet program to simulate the pharmacokinetics of inhaled volatile organic chemicals (VOCs) in humans based on information from molecular structure. The approach involved the construction of a human physiologically-based pharmacokinetic (PBPK) model, and the estimation of its parameters based on quantitative structure-property relationships (QSPRs) in an Excel spreadsheet. The compartments of the PBPK model consisted of liver, adipose tissue, poorly perfused tissues and richly perfused tissues connected by circulating blood. The parameters required were: human physiological parameters such as cardiac output, breathing rate, tissue volumes and tissue blood flow rates (obtained from the biomedical literature), tissue/air partition coefficients (obtained using QSPRs developed with rat data), blood/air partition coefficients (Pb) and hepatic clearance (CL). Using literature data on human Pb and CL for several VOCs (alkanes, alkenes, haloalkanes and aromatic hydrocarbons), multi-linear additive QSPR models were developed. The numerical contributions to human Pb and CL were obtained for eleven structural fragments (CH3, CH2, CH, C, C [double bond] C, H, Cl, Br, F, benzene ring, and H in the benzene ring structure). Using these data as input, the PBPK model written in an Excel spreadsheet simulated the inhalation pharmacokinetics of ethylbenzene (33 ppm, 7 h) and dichloromethane (100 ppm, 6 h) in humans exposed to these chemicals. The QSPRs developed in this study should be useful for predicting the inhalation pharmacokinetics of VOCs in humans, prior to testing and experimentation.

Animals↗
PubMed2002

Quantitative model studies on the efficiency of precursors in the formation of cooling-active 1-pyrrolidinyl-2-cyclopenten-1-ones and bitter-tasting cyclopenta-[b]azepin-8(1H)-ones.

The yields of the cooling-active compounds 3-methyl-2-(1-pyrrolidinyl)-2-cyclopenten-1-one (1) and 5-methyl-2-(1-pyrrolidinyl)-2-cyclopenten-1-one (2) as well as the bitter tastants 7-methyl-2,3,6,7-tetrahydrocyclopenta-[b]azepin-8(1H)-one (3) and 7-methyl-2,3,4,5,6,7-hexahydrocyclopenta-[b]azepin-8(1H)-one (4) obtained by heating mixtures of possible Maillard-type precursors in model systems varying in temperature, pH value, or water content were determined quantitatively. The results showed that hexose-derived cyclotene is the common precursor for all four tastants and that the formation of each individual tastant is strongly determined by the structure of the nitrogen-containing precursor, e.g., reaction of cyclotene with pyrrolidine formed by thermal decarboxylation of L-proline produced the cooling compounds 1 and 2 only, whereas in the presence of 1-pyrroline formed upon Strecker reactions of L-proline, the bitter tasting azepinone 3 was produced exclusively. In contrast, the structure of the secondary amino acid L-proline enabled the formation of compound 4, whereas the pyrrolidine and 1-pyrroline, respectively, do not generate this tastant. In addition, a nonvolatile, tasteless intermediate, (S)-3-methyl-2-[(2'-carboxy)-1-pyrrolidinyl]-2-cyclopenten-1-one (5), was isolated from the cyclotene/L-proline reaction mixture and could be confirmed as an efficient precursor for the cooling compound 1. The data, obtained by these studies, are the scientific basis to tailor the desired overall flavor of foods by means of a more controlled Maillard-type technology.

Amino Acids↗
PubMed2004

Quantitative modeling of DNA-protein interactions: effects of amino acid substitutions on binding specificity of the Mnt repressor.

Understanding DNA-protein recognition quantitatively is essential to developing computational algorithms for accurate transcriptional binding site prediction. Using a quantitative, multiple fluorescence, relative affinity (QuMFRA) assay, we determine the binding specificity of 11 different position 6 variants of the Mnt repressor for operators containing all 16 possible dinucleotides at operator positions 16 and 17. We show that the wild-type and all variant proteins interact with the two positions in a non-independent manner, but that a simple independent model provides a close approximation to the true binding affinities. The wild-type His at amino acid 6 is the only protein to prefer the AC sequence of the wild-type operator, whereas most of the variant proteins prefer TA. H6R is unique in having a strong preference for C at position 16. A comparison of the quantitative binding data for all of the protein variants with a model for recognition of the early growth response (EGR) zinc finger family suggests that interactions of Mnt with positions 16 and 17 are similar to interactions of EGR with positions 1 and 2, respectively. This information leads to an augmented model for the interaction of Mnt with its operator.

Amino Acid Substitution↗
PubMed1985

Some issues in the quantitative modeling portion of cancer risk assessment.

Several questions should be asked in order to determine the relevance and scientific merit of a quantitative cancer risk assessment. Twenty such questions are formulated here and briefly discussed. These questions are intended to identify important issues and serve as a checklist for risk managers and developers of quantitative risk assessments. Among the many factors involved in these questions are the carcinogenic response, quantal response models, time to response, competing risks, model shapes, goodness of fit, dose scale, high-to-low-dose extrapolation, consistency across different subjects, animal-to-human extrapolation, route-to-route extrapolation, exposure durations and patterns, short-term tests, consistency with human epidemiological data, human exposures, statistical variability, impacts of assumptions and policy decisions and value judgments, risk characterization, upper and lower bounds, and keeping pace with scientific advances.

Animals↗
PubMed1980

A quantitative model for subcutaneous abscess formation in mice.

The purpose of this experiment was to develop an experimental model of s.c. encapsulated abscesses in which abscess formation could be assessed by quantitative measurements. Inocula were composed of bacterial broth cultures, autoclaved mouse caecal contents or both in combination. These inocula were injected s.c. on the flank in 2 strains of mice. Large encapsulated abscesses formed in all recipients by Day 4 when the inoculum contained either B. fragilis or S. aureus combined with caecal contents. Bacterial concentrations per ml of pus at Day 6 were 10(10.1+/-0.02) for B. fragilis and 10(8.4+/-0.1) for S. aureus. Spontaneous external drainage began by 10--15 days, and complete healing of the lesion occurred by 4--6 weeks. The typical histological pattern consisted of a collagen capsule surrounding a rim of neutrophils, enclosing a central area of necrotic cells and fibre from the inoculum. The cross-sectional areas of the capsule, the neutrophil band and the entire abscess were measured in a reproducible manner by planimetry, and abscess volumes were calculated. Values for these measurements varied with different inocula and different times after inoculation, but were highly consistent for a specified time and inoculum.

Abscess↗
PubMed2005

Quantitative modeling of single atom high harmonic generation.

It is shown by comparison with numerical solutions of the Schrödinger equation that the three step model (TSM) of high harmonic generation (HHG) can be improved to give a quantitatively reliable description of the process. Excellent agreement is demonstrated for the H atom and the H2(+) molecular ion. It is shown that the standard TSM heavily distorts the HHG spectra, especially of H2(+), and an explanation is presented for this behavior. Key to the improvement is the use of the Ehrenfest theorem in the TSM.

Journal Article↗
PubMed2006

Dynamics of electron transport by elastic bending of short DNA duplexes. Experimental study and quantitative modeling of the cyclic voltammetric behavior of 3'-ferrocenyl DNA end-grafted on gold.

The dynamics of electron transport within a molecular monolayer of 3'-ferrocenylated-(dT)(20) strands, 5'-thiol end-grafted onto gold electrode surfaces via a short C2-alkyl linker, is analyzed using cyclic voltammetry as the excitation/measurement technique. It is shown that the single-stranded DNA layer behaves as a diffusionless system, due to the high flexibility of the ss-DNA chain. Upon hybridization by the fully complementary (dA)(20) target, the DNA-modified gold electrode displays a highly unusual voltammetric behavior, the faradaic signal even ultimately switching off at a high enough potential scan rate. This remarkable extinction phenomenon is qualitatively and quantitatively justified by the model of elastic bending diffusion developed in the present work which describes the motion of the DNA-borne ferrocene moiety as resulting from the elastic bending of the duplex DNA toward and away from the electrode surface. Its use allows us to demonstrate that the dynamics of electron transport within the hybridized DNA layer is solely controlled by the intrinsic bending elasticity of ds-DNA. Fast scan rate cyclic voltammetry of end-grafted, redox-labeled DNA layers is shown to be an extremely efficient method to probe the bending dynamics of short-DNA fragments in the submillisecond time range. The persistence length of the end-anchored ds-DNA, a parameter quantifying the flexibility of the nanometer-long duplex, can then be straightforwardly and accurately determined from the voltammetry data.

DNA↗
PubMed2000

A quantitative model for the dependence of solute permeability on peptide and cholesterol content in biomembranes.

The influence of varying concentrations of a transmembrane peptide, gramicidin A (gA), and cholesterol (Chol) on the passive permeation of p-methylhippuric acid (MHA) and alpha-carbamoyl-p-methylhippuric acid (CMHA) across egg-lecithin membranes (EPC) has been investigated in vesicle efflux experiments. Incorporation of 0.25 volume fraction of gA in its nonchannel conformation increased the permeability coefficient (Pm) for CMHA by a factor of 6.0 +/- 1.8 but did not alter Pm for MHA, a more lipophilic permeant. In contrast, incorporation of 0.26 volume fraction Chol with no added protein decreased the Pm values for both CMHA and MHA by similar factors of 4.2 +/- 1.1 and 3.5 +/- 1.2, respectively. A quantitative structure-transport model has been developed to account for the dependence of Pm on the membrane concentrations of gA and Chol in terms of induced changes in both membrane chain ordering and hydrophobicity. Chain ordering is assumed to affect Pm for both permeants similarly since they are comparable in molecular size, while changes in Pm ratios in the presence of gA or Chol are attributed to alterations in membrane hydrophobicity. Changes in lipid chain ordering were detected by monitoring membrane fluidity using fluorescence anisotropy of 1-[4-(trimethylamino)phenyl]-6-phenylhexa-1,3,5-triene incorporated into the membranes. The influence of additives on membrane hydrophobicity, which governs Pm ratios through effects on solute partitioning into the barrier domain, were rationalized within the framework of regular solution theory using solubility parameters as a measure of membrane hydrophobicity. Fits of the Pm ratios using the theoretical model yielded solubility parameters for gA and Chol in EPC membranes of 13.2 and 7.7 (cal/ml)(1/2), respectively, suggesting that gA decreases the barrier domain hydrophobicity while Chol has a minimal effect on barrier hydrophobicity. After correcting for barrier domain hydrophobicity, permeability decrements due to membrane ordering induced by gA or Chol were found to exhibit a strong correlation with membrane order as predicted by free-surface-area theory, regardless of whether gA or Chol is used as the ordering agent.

Cholesterol↗
PubMed2002

A quantitative model for predicting enzyme enantioselectivity: application to Burkholderia cepacia lipase and 3-(aryloxy)-1,2-propanediol derivatives.

We describe a new approach for predicting the enantioselectivity of enzymes towards racemic compounds. It is based on comparative binding energy (COMBINE) analysis. The approach is used to rationalise the enantioselectivity of Burkholderia cepacia lipase (BCL) towards thirteen racemic 3-(aryloxy)-1,2-propanediols in the process of acylation. According to our molecular modelling study the two 3-(aryloxy)-1,2-propanediols enantiomers bind in the BCL active site in different orientations. To derive a quantitative structure-activity relationship (QSAR), the difference in the interaction energy between two enantiomers with each amino acid residue was computed. These residue-based energy differences were then subjected to chemometric analysis and 3D QSAR models were derived. The models were able to unambiguously predict the fast-reacting enantiomer and the approximate magnitude of the enantioselectivity. The study enabled identification of interactions between the substrate and the lipase amino acid residues that play key roles in secondary alcohol enantiodifferentiation. From the results, it was possible to propose modifications of both, substrate and protein, which would directionally modify enantioselectivity of BCL towards secondary aryl-alcohols.

Acetylation↗
PubMed1987

A simple quantitative model of the molecular clock.

We present the ideas, and their motivation, at the basis of a simple model of nucleic acid evolution: the stationary Markov process, or Markov clock. After a brief review of its relevant mathematical properties, the Markov clock is applied to nucleotide sequences from mitochondrial and nuclear genes of different species. Particular emphasis is given to the necessity of carrying out a correct statistical analysis, which allows us to check quantitatively the applicability of our model. We find evidence that the Markov clock ticks in many different processes, and that its limitations can be understood in terms of a simple idea that we call the "base-drift" hypothesis. This hypothesis correlates the deviations from the stationarity of the Markov process to the evolutionary distance dAB(p) of two species A and B, relative to the process P. We conclude by discussing the implications of our findings for future work.

Animals↗
PubMed2005

On the computations analyzing natural optic flow: quantitative model analysis of the blowfly motion vision pathway.

For many animals, including humans, the optic flow generated on the eyes during locomotion is an important source of information about self-motion and the structure of the environment. The blowfly has been used frequently as a model system for experimental analysis of optic flow processing at the microcircuit level. Here, we describe a model of the computational mechanisms implemented by these circuits in the blowfly motion vision pathway. Although this model was originally proposed based on simple experimenter-designed stimuli, we show that it is also capable to quantitatively predict the responses to the complex dynamic stimuli a blowfly encounters in free flight. In particular, the model visual system exploits the active saccadic gaze and flight strategy of blowflies in a similar way, as does its neuronal counterpart. The model circuit extracts information about translation velocity in the intersaccadic intervals and thus, indirectly, about the three-dimensional layout of the environment. By stepwise dissection of the model circuit, we determine which of its components are essential for these remarkable features. When accounting for the responses to complex natural stimuli, the model is much more robust against parameter changes than when explaining the neuronal responses to simple experimenter-defined stimuli. In contrast to conclusions drawn from experiments with simple stimuli, optimization of the parameter set for different segments of natural optic flow stimuli do not indicate pronounced adaptational changes of these parameters during long-lasting stimulation.

Adaptation, Physiological↗
PubMed1982

A phalangeal fracture model--quantitative analysis of rigidity and failure.

Nine types of internal fixation techniques were tested in 4-point bending using a pig metacarpal model for phalangeal fractures. Levels of bending rigidity and bending moments at failure were determined, and the modes of failure are described. Plate and screw fixation afforded the greatest rigidity, and epiphyseal fractures occurred, leaving intact the test section. Flexible wire loop fixation failed by wire cutting into bone when a square knot was used. Twisted wire unraveled when placed in tension. Depending on the fracture type and the wire placement. Kirschner wires failed either by slipping in the bone, twisting in the bone cortex, or bending at the bone cortex interface. Rigidity varied widely depending on the way in which the wires were employed.

Animals↗
PubMed1984

A quantitative model for the in vivo assessment of drug binding sites with positron emission tomography.

We propose an in vivo method for use with positron emission tomography (PET) that results in a quantitative characterization of neuroleptic binding sites using radiolabeled spiperone. The data are analyzed using a mathematical model that describes transport, nonspecific binding, and specific binding in the brain. The model demonstrates that the receptor quantities Bmax (i.e., the number of binding sites) and KD-1 (i.e., the binding affinity) are not separably ascertainable with tracer methodology in human subjects. We have, therefore, introduced a new term, the binding potential, equivalent to the product BmaxKD-1, which reflects the capacity of a given tissue, or region of a tissue, for ligand-binding site interaction. The procedure for obtaining these measurements is illustrated with data from sequential PET scans of baboons after intravenous injection of carrier-added [18F]spiperone. From these data we estimate the brain tissue nonspecific binding of spiperone to be in the range of 94.2 to 95.3%, and the regional brain spiperone permeability (measured as the permeability-surface area product) to be in the range of 0.025 to 0.036 cm3/(s X ml). The binding potential of the striatum ranged from 17.4 to 21.6; these in vivo estimates compare favorably to in vitro values in the literature. To our knowledge this represents the first direct evidence that PET can be used to characterize quantitatively, locally and in vivo, drug binding sites in brain. The ability to make such measurements with PET should permit the detailed investigation of diseases thought to result from disorders of receptor function.

Animals↗
PubMed2005

A quantitative model of purinergic junctional transmission of calcium waves in astrocyte networks.

A principal means of transmitting intracellular calcium (Ca2+) waves at junctions between astrocytes involves the release of the chemical transmitter adenosine triphosphate (ATP). A model of this process is presented in which activation of purinergic P2Y receptors by ATP triggers the release of ATP, in an autocrine manner, as well as concomitantly increasing intracellular Ca2+. The dependence of the temporal characteristics of the Ca2+ wave are shown to critically depend on the dissociation constant (K(R)) for ATP binding to the P2Y receptor type. Incorporating this model astrocyte into networks of these cells successfully accounts for many of the properties of propagating Ca2+ waves, such as the dependence of velocity on the type of P2Y receptor and the time-lag of the Ca2+ wave behind the ATP wave. In addition, the conditions under which Ca2+ waves may jump from one set of astrocytes across an astrocyte-free lane to another set of astrocytes are quantitatively accounted for by the model. The properties of purinergic transmission at astrocyte junctions may determine many of the characteristics of Ca2+ propagation in networks of these cells.

Action Potentials↗