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PubMed2006

Membrane potentials in Rana temporaria muscle fibres in strongly hypertonic solutions.

Conventional microelectrode methods were used to measure variations in resting membrane potentials, E(m), of intact amphibian skeletal muscle fibres over a wide range of increased extracellular tonicities produced by inclusion of varying extracellular concentrations of sucrose. Moderate increases in extracellular tonicity to up to 2.6x normal (2.6tau) under Cl(-) free conditions produced negative shifts in E(m) that followed expectations for the K(+) Nernst equation (E(K)) applied to a perfect osmometer containing a conserved intracellular K(+) content despite any accompanying cell volume change. In contrast, E(m) remained stable in fibres studied in otherwise similar Cl(-) containing solutions, consistent with E(m) stabilization despite negative shifts in E(K) through inward cation-Cl(-) co-transport activity. Short exposures to higher tonicities (>3tau) similarly produced negative shifts in E(m) in Cl(-) free but not Cl(-) containing solutions. However, prolonged exposures to solutions of >3tau caused gradual net positive changes in E (m) in both Cl(-) containing and Cl(-) free solutions suggesting that these changes were independent of cation-Cl(-) transport. Indeed, there was no evidence of cation-Cl(-) co-transport activity in strongly hypertonic solutions despite its predicted energetic favourability, suggesting its possible regulation by E (m) in muscle. Additional findings implicated a failure to maintain greatly increased transmembrane [K(+)] gradients in these E(m) changes. Thus: (1) halving or doubling [K(+)](e) produced negative or positive shifts in E(m), respectively in isotonic or moderately hypertonic (<2.7tau), but not strongly hypertonic (>3tau) solutions; (2) subsequent restoration of isotonic extracellular conditions produced further positive changes in E(m) consistent with a dilution of the depleted [K(+)](i) by fibres regaining their original resting volumes; (3) quantitative modelling similarly predicted a gradual net efflux of K(+) as the balance between active and passive [K(+)] fluxes altered due to increased transmembrane [K(+)] gradients in hypertonic and low [K(+)](e) solutions. However, the observed positive changes in E(m) in the most strongly hypertonic solutions eventually exceeded these predictions suggesting additional limitations on Na(+)/K(+)-ATPase activity in strongly hypertonic solutions.

Animals↗
PubMed2006

Nonlocal mechanism of self-organization and centering of microtubule asters.

Fragments of fish melanophore cells can form and center aggregates of pigment granules by dynein-motor-driven transport along a self-organized radial array of microtubules (MTs). We present a quantitative model that describes pigment aggregation and MT-aster self-organization and the subsequent centering of both structures. The model is based on the observations that MTs are immobile and treadmill, while dynein-motor-covered granules have the ability to nucleate MTs. From assumptions based on experimental observations, we derive partial integro-differential equations describing the coupled granule-MT interaction. We use scaling arguments and perturbation theory to study the model in two limiting cases. The model analysis explains the mechanism of aster self-organization as a positive feedback loop between motor aggregation at the MT minus ends and MT nucleation by motors. Furthermore, the centering mechanism is explained by the spontaneous nucleation of MTs throughout the cytosol which acts as a volume sensing tool. Numerical simulations lend additional support to the analysis. The model sheds light on role of polymer dynamics and polymer-motor interactions in cytoskeletal organization.

Animals↗
PubMed1985

A logistic regression analysis of multiple noninvasive tests for the prediction of the presence and extent of coronary artery disease in men.

The incremental diagnostic yield of clinical data, exercise ECG, stress thallium scintigraphy, and cardiac fluoroscopy to predict coronary and multivessel disease was assessed in 171 symptomatic men by means of multiple logistic regression analyses. When clinical variables alone were analyzed, chest pain type and age were predictive of coronary disease, whereas chest pain type, age, a family history of premature coronary disease before age 55 years, and abnormal ST-T wave changes on the rest ECG were predictive of multivessel disease. The percentage of patients correctly classified by cardiac fluoroscopy (presence or absence of coronary artery calcification), exercise ECG, and thallium scintigraphy was 9%, 25%, and 50%, respectively, greater than for clinical variables, when the presence or absence of coronary disease was the outcome, and 13%, 25%, and 29%, respectively, when multivessel disease was studied; 5% of patients were misclassified. When the 37 clinical and noninvasive test variables were analyzed jointly, the most significant variable predictive of coronary disease was an abnormal thallium scan and for multivessel disease, the amount of exercise performed. The data from this study provide a quantitative model and confirm previous reports that optimal diagnostic efficacy is obtained when noninvasive tests are ordered sequentially. In symptomatic men, cardiac fluoroscopy is a relatively ineffective test when compared to exercise ECG and thallium scintigraphy.

Adult↗
PubMed1988

Quantitation of secretion by rat basophilic leukemia cells by measurements of quinacrine uptake.

A novel method for quantitating secretion is described based on measurements of the cellular uptake of the fluorescent aminoacridine dye quinacrine into low-pH secretory granules. The quinacrine fluorescence remaining in the medium was found to decrease after incubation with increasing numbers of the 2H3 rat basophilic leukemia line. This depletion of dye from the medium decreased after a secretory stimulus. Assuming that quinacrine partitions according to mass action, a quantitative model was derived to allow calculation of the percent secretion from dye uptake data. A good correlation was obtained when the values for the percent secretion determined by the quinacrine uptake method were compared with secretion measured by release of the granule enzyme beta-glucuronidase.

Animals↗
PubMed1979

DNA-protein crosslinking by trans-platinum(II)diamminedichloride in mammalian cells, a new method of analysis.

DNA-protien crosslinks produced in mouse leukemia L1210 cells by trans-Pt(II)diamminedichloride were quantitated using the technique of DNA alkaline elution. DNA single-strand segments that were or were not linked to protein were separable into distinct components by alkaline elution after exposure of the cells to 2--15 kR of X-ray. Protein-linked DNA strands were separated on the basis of their retention of filters at pH 12 while free DNA strands of the size generated by 2--15 kR of X-ray passed rapidly through the filters. The retention of protein-linked DNA strands was attributable to adsorption of protein to the filter under the conditions of alkaline elution. The results obeyed a simple quantitative model according to which the frequency of DNA-protein crosslinks could be calculated.

Animals↗
PubMed1985

Kinetics of conjugation and oxidation of nitrobenzyl alcohols by rat hepatic enzymes.

Previous work has suggested that quantitative differences in the in vitro and in vivo metabolism of mononitrotoluene isomers are a result of differences in the hepatic conjugation and oxidation of the first metabolic intermediates, the mononitrobenzyl alcohols. We have determined the steady-state kinetic parameters, Vmax, Km and V/K, for the metabolism of the nitrobenzyl alcohols by rat hepatic alcohol dehydrogenase, glucuronyltransferase, and sulfotransferase. 3-Nitrobenzyl alcohol was the best substrate for cytosolic alcohol dehydrogenase (Vmax = 1.48 nmoles/min/mg protein, V/K = 3.15 X 10(-3) nmoles/min/mg protein/microM, Km = 503 microM). Vmax and Km values for 4-nitrobenzyl alcohol were similar, but V/K was about 60% of that for 3-nitrobenzyl alcohol. 2-Nitrobenzyl alcohol was not metabolized by the alcohol dehydrogenase preparation used here, but it was metabolized to 2-nitrobenzoic acid by a rat liver mitochondrial preparation. 2-Nitrobenzyl alcohol was the best substrate for microsomal glucuronyltransferase (Vmax = 3.59 nmoles/min/mg protein, V/K = 11.28 X 10(-3) nmoles/min/mg protein/microM, Km = 373 microM). The Vmax for 3-nitrobenzyl alcohol was similar, but the V/K was about half and the Km was about twice that for 2-nitrobenzyl alcohol. The Vmax for 4-nitrobenzyl alcohol was about 40% and the V/K was about half that for 2-nitrobenzyl alcohol. The best substrate for cytosolic sulfotransferase was 4-nitrobenzyl alcohol (Vmax = 1.69 nmoles/min/mg protein, V/K = 37.21 X 10(-3) nmoles/min/mg protein/microM, Km = 48 microM). The Vmax values for the other two benzyl alcohols were similar, but the V/K and Km values were about 11 and 400%, respectively, of those for 4-nitrobenzyl alcohol. These data are in qualitative agreement with results obtained when the nitrobenzyl alcohols were incubated with isolated hepatocytes, but they do not allow quantitative modeling of the data from hepatocytes.

Alcohol Dehydrogenase↗
PubMed1985

Structure-activity relationships of benzimidazole carbamates as inhibitors of mammalian tubulin, in vitro.

The structure-activity relationships of thirty-two methyl (5(6)-substituted benzimidazol-2yl) carbamates as inhibitors of the rate of polymerisation of mammalian tubulin have been investigated. The size or some colinear physico-chemical characteristic of the substituent in the 5 (or 6)-position has a profound effect on potency. The presence of branching with or without a commensurate increase in the polarity of the 5(6)-substituent adjacent to the benzimidazole ring (alpha-position) resulted in a loss of activity. The nature of the overall site, as reflected by the quantitative models, could relate to either the hydrophobicity or molar volume of the 5 (or 6)-substituents.

Animals↗
PubMed1995

Inhibition of monoamine oxidase by isoquinoline derivatives. Qualitative and 3D-quantitative structure-activity relationships.

A series of isoquinolines, N-methyl-1,2-dihydroisoquinolines, N-methyl-1,2,3,4-tetrahydroisoquinolines, 1,2,3,4-tetrahydroisoquinolines, and N-methylisoquinolinium ions were tested as inhibitors of monoamine oxidases A and B. All compounds were found to act as reversible and time-independent MAO inhibitors, often with a distinct selectivity towards MAO-A. As a class, the N-methylisoquinolinium ions were found to be the most active MAO-A inhibitors, with N-methyl-6-methoxyisoquinolinium ion emerging as a potent (IC50 = 0.81 microM) and competitive MAO-A inhibitor. Comparative molecular field analysis (CoMFA, a 3D-QSAR method) of MAO-A inhibition was performed using the data reported here and in the literature. Using the steric and lipophilic fields of the inhibitors, quantitative models with reasonable predictive power were obtained that point to the importance of steric, lipophilic, and polar interactions in modulating MAO-A inhibitory activity.

Binding Sites↗
PubMed1989

Knowledge management as a decision support method: a diagnostic workup strategy application.

We have explored the potential of a computer-based approach called "knowledge management" to aid in clinical problem solving and education. The major features of the approach are its ability to support flexible and immediate access by a user to relevant knowledge and annotation and organization of the knowledge for personal use and subsequent retrieval. We illustrate this approach with its application to diagnostic workup strategy problems. In this application, knowledge may be in the form of static narrative text, diagrams, pictures, graphs, tables, flow charts, or bibliographic citations. Other more dynamic forms of knowledge may be the result of simulations, "what if" analyses or modeling, quantitative mathematical or statistical calculation, or heuristic inference. User assessment has demonstrated the system's ease of use and user perception of its desirability, but underscores the need for a "critical mass" of knowledge before such an approach will be widely utilized.

Decision Support Techniques↗
PubMed1990

Experimental dissection of devitrification in aqueous solutions of 1,3-butanediol.

Devitrification is a major problem which must be overcome for successful organ cryopreservation. Devitrification can be initiated on fracture planes and on bubbles, but the focus of attention here is on devitrification by ordinary heterogeneous and homogeneous mechanisms, which are the most relevant for organ preservation by vitrification. The purpose of the present studies was to define the devitrification process: to determine nucleation rates, ice-crystal growth rates, and the distribution of ice-crystal size and to evaluate the applicability of existing quantitative models of these processes which have successfully approximated the behavior of other aqueous systems. The present work was done using differential scanning calorimetry and cryomicroscopy. The amount of ice formed has been estimated for highly concentrated solutions. Kinetic parameters are presented here for isothermal conditions and continuous heating rate experiments. The classical theory based on the Johnson-Avrami equation has been evaluated and the results are compared with the theory of Boutron. The agreement is good for the continuous heating rate conditions, but results differ for the isothermal conditions.

Butylene Glycols↗
PubMed1987

Growth and differentiation during myogenesis in the chick embryo.

A general method for describing the complex dynamics of cell populations over an extended period of growth and differentiation in a developing tissue is presented. The measurements required to produce a unique description are defined. Skeletal muscle development in the thigh and breast of the chick embryo is analyzed, using this method, during the period of embryonic development between Day 7 and Day 17. A unique quantitation of growth and differentiation for the period from Day 11 to Day 17 is developed. The pectoralis major is compared with the averaged behavior of the thigh musculature. In each case, a single partitioning rule holds for more than 10 generations during the main myogenic period. In the pectoralis, approximately 51% of the cells entering G1 in each generation continue in the cell cycle; in the thigh, which experiences substantially greater overall growth, approximately 58% of the cells entering G1 in each generation continue in the cell cycle. No significant cell death is detected. Thus, in each case, the absolute number of myoblasts is increasing while the fractional value of myoblasts in the population is decreasing over a fivefold range. These results are discussed in terms of several quantitative models for the possible basis of the observed population dynamics.

Animals↗
PubMed1991

Are prions misfolded molecular chaperones?

A theory has been developed that could explain prion infection. Prions could be molecular chaperones that are required for their own assembly. The theory has been deduced from an analysis of protein folding and consequences explored by computer simulations. Thermo-kinetic analysis of protein folding shows that a misfolded chaperone gives rise to new misfolded chaperones. Consequently such a protein could behave as a new kind of informative molecule and replicate misfolding according to a process similar to infection. A quantitative model has been derived from this hypothesis that displays the characteristics of prion infections. This hypothesis satisfactorily explains the three manifestations - infection, familial and sporadic - that are the characteristic features of all prion diseases.

Animals↗
PubMed1991

Characterization of the fluorescent morphological structures in human arterial wall using ultraviolet-excited microspectrofluorimetry.

In this study, the fluorescent morphological structures in normal coronary artery, normal aorta, and atherosclerotic aorta were histochemically identified and spectroscopically characterized in situ using ultraviolet-excited microspectrofluorimetry. Excitation wavelengths of 290 nm and 310/312 nm were employed to observe two distinct fluorescence bands, with peak emission wavelengths near 335 nm and 380 nm, respectively. Emission of the short wavelength 335 nm band, previously assigned to tryptophan residues in tryptophan-containing proteins, was observed from all the morphological structures in the vessel walls and was isolated in groups of smooth muscle cells in aorta and coronary artery media. The long wavelength 380 nm band was assigned to distinct fluorophores associated with the structural proteins collagen and elastin and was observed in collagen fibers and elastic fibers, respectively. The corresponding morphological structures in normal aorta, normal coronary artery, and atherosclerotic aorta exhibited similar fluorescence lineshapes. In atherosclerotic plaque, a distinct fluorescence band, peaking near 370 nm, was observed in the emission from both ceroid granules and necrotic core. Using a simple, quantitative model, differing contributions of collagen, elastin, and tryptophan-containing protein fluorescence were shown to account for over 95% of the emission from the intima, media, and adventitia layers of non-necrotic aorta and coronary artery.

Aorta↗
PubMed1988

Estimation of in-vivo miscoding rates.

The replication of premutagenic DNA lesions generates mutant progeny in patterns that distinguish lesions that rarely produce a mutation per DNA replication from those that frequently do so. The quantitative aspects of this distinction were tested in studies of heat-mutagenized bacteriophage T4. Previous T4 studies had demonstrated that transition mutations produced at G.C base-pairs depended upon heat-induced DNA lesions distinct from those responsible for transversions at G.C pairs. In this study the transversion mutations are shown to arise in patterns predicted for mutations produced from lesions that miscode rarely (fewer than 10% per replication). In contrast, the transition mutations arise in patterns predicted for mutations produced from lesions that miscode at about 20 to 60% per replication. The fact that the two classes of DNA lesions are distinguishable as predicted by the quantitative model suggests that such studies may in general be useful in quantifying the behavior of mutation-generating DNA lesions. The method employed also estimates the frequency of premutagenic lesions in DNA.

DNA Damage↗
PubMed1984

Feeding rate and meal patterns in the laboratory rat.

Many manipulations used in the study of feeding (e.g., changes of food taste or texture, anorectic drugs) affect the rate of food consumption. Consequent changes in meal patterning might reflect either direct effects of the manipulation or alternatively might result from indirect effects of the changed rate of intake. In the experiment reported here a direct reduction in the permitted rate of food intake resulted in a clear reduction of meal size and an increase in meal frequency in rats. We explore the extent to which this finding is predicted by quantitative models of the regulation of food intake.

Animals↗
PubMed1978

Analysis of the effects of pulsatile capillary blood flow and volume on gas exchange.

Blood flow into the pulmonary capillaries and the volume of blood within the capillary bed are both pulsatile with the cardiac cycle. We have developed a quantitative model of diffusional gas exchange in the lung to investigate the effects of coupling between these two time-varying parameters on lung O2 and CO2 exchange. For normal man breathing room air at rest, the computed results agree well with previous predictions for the constant flow and volume case, and for the case of pulsatile flow alone. When coupled time-varying pulmonary capillary blood flow and volume are included, using the best data available in the literature to define these parameters, diffusional O2 exchange is improved over the cases of pulsatile flow or volume alone, and closely approximates that obtained for the hypothetical constant flow and volume case. CO2 exchanges, and O2 exchange during hypoxia, are not affected by pulsatile flow and/or volume. These results suggest that O2 exchange is efficient in the presence of coupled blood flow and blood volume pulsations as they exist in the lung capillaries, and that these conditions may be optimal for gas exchange under certain physiological (or pathological) conditions.

Blood Volume↗
PubMed1982

Measles in the tropics and public health practice.

Measles shows three distinct transmission patterns in the tropics, one each in urban, rural and insular or very remote areas. The characteristics of measles transmission are reviewed for each area, both with and without immunization. Planning must be based on the best use of currently underused infrastructure in the light of epidemiology. Mass mobile campaigns are not advised for urban areas. Vaccination of the sick and the well as part of episodic medical care is proposed, and vaccination of the sick is supported as safe and effective. Age floors and ceilings should be set with reference to the local situation; adoption of international "rules of thumb", without reference to local conditions, is inadvisable." A mixed strategy is urged for rural areas, with routine immunization against measles as part of a multi-antigen programme. Routine immunization should be complemented by annual surveillance and containment during the seasonal trough. Research and development needs in measles control include better understanding of measles epidemiology, more operationally useful quantitative models, and trials of new control strategies. Control, elimination and eradication are defined and discussed.

Adolescent↗
PubMed1989

On the evolution of genetic incompatibility systems. V. Origin of sporophytic self-incompatibility in response to overdominance in viability.

Conditions for the origin of partial sporophytic self-incompatibility (SSI) are obtained from two quantitative models, which differ with respect to the determination of offspring viability. Offspring viability depends solely on the source (self or nonself) of the fertilizing pollen in the first model, which describes changes only at a primitive S-locus itself. Two loci evolve in the second model: overdominant viability selection maintains an arbitrary number of alleles at one locus, with SSI under the control of a separate locus. In both cases, the origin of SSI requires that the relative change in the numbers of offspring derived by the two reproductive modes compensate for the twofold cost of outcrossing. In the first model studied, the viability of inbred offspring fully determines the relative change in the numbers of inbred and outbred offspring produced. In the second model, the relative change in offspring numbers depends in addition on associations between the S-locus and the viability locus. Because these two-locus associations are comparable in magnitude to the differences between the viabilities of inbred and outbred offspring, SSI can arise under less restrictive conditions than expected from the one-locus model. Greater allelic multiplicity at the viability locus facilitates the origin of SSI by reducing the relative viability of inbred offspring. Tight linkage between the S-locus and the viability locus and high rates of receipt of self-pollen promote the generation and maintenance of associations between the S-locus and the viability locus. In populations in which more than two viability alleles are maintained, the active S-allele can invade even in the absence of linkage with the viability locus. The present study establishes that incompatibility systems can arise in response to identity disequilibrium between a modifier of incompatibility and a locus subject to overdominant viability selection; in particular, compensation for the twofold cost of outcrossing does not require preexisting gametic level disequilibria.

Alleles↗