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PubMed1999

Dietary change and stable isotopes: a model of growth and dormancy in cave bears.

In order to discuss dietary change over time by the use of stable isotopes, it is necessary to sort out the underlying processes in isotopic variation. Together with the dietary signal other processes have been investigated, namely metabolic processes, collagen turnover and physical growth. However, growth and collagen turnover time have so far been neglected in dietary reconstruction based on stable isotopes. An earlier study suggested that cave bears (Ursus spelaeus) probably gave birth to cubs during dormancy. We provide an estimate of the effect on stable isotopes of growth and metabolism and discuss collagen turnover in a population of cave bears. Based on a quantitative model, we hypothesized that bear cubs lactated their mothers during their first and second winters, but were fed solid food together with lactation during their first summer. This demonstrates the need to include physical growth, metabolism and collagen turnover in dietary reconstruction. Whereas the effects of diet and metabolism are due to fractionation, growth and collagen turnover are dilution processes.

Aging↗
PubMed2004

Specific versus nonspecific binding of cationic PNAs to duplex DNA.

Although peptide nucleic acids (PNAs) are neutral by themselves, they are usually appended with positively charged lysine residues to increase their solubility and binding affinity for nucleic acid targets. Thus obtained cationic PNAs very effectively interact with the designated duplex DNA targets in a sequence-specific manner forming strand-invasion complexes. We report on the study of the nonspecific effects in the kinetics of formation of sequence-specific PNA-DNA complexes. We find that in a typical range of salt concentrations used when working with strand-invading PNAs (10-20 mM NaCl) the PNA binding rates essentially do not depend on the presence of nontarget DNA in the reaction mixture. However, at lower salt concentrations (<10 mM NaCl), the rates of PNA binding to DNA targets are significantly slowed down by the excess of unrelated DNA. This effect of nontarget DNA arises from depleting the concentration of free PNA capable of interacting with DNA target due to adhesion of positively charged PNA molecules on the negatively charged DNA duplex. As expected, the nonspecific electrostatic effects are more pronounced for more charged PNAs. We propose a simple model quantitatively describing all major features of the observed phenomenon. This understanding is important for design of and manipulation with the DNA-binding polycationic ligands in general and PNA-based drugs in particular.

Adsorption↗
PubMed1992

Similarity-scaling studies of dot-pattern classification and recognition.

Classification performance in the dot-pattern, prototype-distortion paradigm (e.g., Posner & Keele, 1968) was modeled within a multidimensional scaling (MDS) framework. MDS solutions were derived for sets of dot patterns that were generated from prototypes. These MDS solutions were then used in conjunction with exemplar, prototype, and combined models to predict classification and recognition performance. Across 3 experiments, an MDS-based exemplar model accounted for the effects of several fundamental learning variables, including level of distortion of the patterns, category size, delay of transfer phase, and item frequency. Most important, the model quantitatively predicted classification probabilities for individual dot patterns in the sets, not simply general trends of performance. There was little evidence for the existence of a prototype-abstraction process that operated above and beyond pure exemplar-based generalization.

Adult↗
PubMed1988

Interaction of amphiphiles with integral membrane proteins. I. Structural destabilization of the anion transport protein of the erythrocyte membrane by fatty acids, fatty alcohols, and fatty amines.

The effect of model amphiphiles on the structural stability of the anion exchange protein (band 3) of the human erythrocyte membrane was studied by differential scanning calorimetry. The concentration of membranes, as well as the concentration, head group, alkyl chain length, degree of unsaturation, and double bond configuration of a variety of alkane derivatives were all varied in a systematic way. The depression of the denaturation temperature of band 3 per unit membrane concentration of the amphiphile was then determined in order to quantitate the potency of each drug. Saturated fatty acids of chain length C8 to C24 displayed a monotonic decrease in potency up to C20, followed by a dramatic diminution in potency at C22 and C24. Unsaturation caused only minor increases in the abilities of fatty acids to perturb the anion exchanger, and surprisingly, there was neither a trend for the number of double bonds nor a significant cis-trans distinction. Arachidonic acid, as an exception, was much more effective than any other amphiphile in destabilizing band 3. Fatty acids were about three times more potent than fatty amines and fatty alcohols; however, the enhanced partitioning of the latter into the membrane compensated at certain membrane/buffer ratios for its reduced intrinsic potency. A quantitative model interpretation of the data is presented in an accompanying paper.

Amines↗
PubMed1998

Mechanism of separation on cholesterol-silica stationary phase for high-performance liquid chromatography as revealed by analysis of quantitative structure-retention relationships.

The retention characteristics of a newly synthesized stationary phase were determined for reversed-phase high-performance liquid chromatography obtained by chemical immobilization of cholesterol on spherical silica gel. For a designed series of analytes the retention factors, log k, were determined at several compositions of the methanol-water mobile phase. Logarithms of retention factor corresponding to a hypothetical pure water eluent, log k(w), were calculated by extrapolation of the linear relationships of individual log k data versus volume percent of methanol. The series of 24 test analytes were characterized structurally by means of the logarithms of n-octanol-water partition coefficients, log P, by a set of the linear solvation energy relationship (LSER)-based descriptors of the polarity and bulkiness of the analytes and by structural descriptors of analyte size and polarity acquired by molecular modelling. Quantitative structure retention relationships (QSRR) were derived by multiple regression analysis using the three groups of structural descriptors of analytes and the log k(w) data determined on the new stationary phase. For the sake of comparison the corresponding QSRR equations were also derived for retention parameters determined on a standard octadecylsilica and on the so-called immobilized artificial membrane (IAM) stationary phase. The QSRR analysis clearly proved distinctive retention properties of the new cholesterol-silica stationary phase. It has been concluded that the new phase may possess valuable analytical specificity. Its application for modelling penetration of xenobiotics through biological membranes appears rather unlikely.

Cholesterol↗
PubMed1989

The structure of the cuticular plate, an in vivo actin gel.

The cuticular plate is a network of actin filaments found in hair cells of the cochlea. In the alligator lizard, it consists of rootlets, emanating from the stereocilia, and of cross-connecting actin filaments that anchor these rootlets. In thin sections, this network displays striking patches of 650 +/- 110-A striae. By quantitative analyses of the images, the mystery of the striae can be explained. They are due in part to the rootlets which are sets of flat ribbons of actin filaments. The ribbons in each set are separated by approximately 650 A. Numerous whiskers 30 A in diameter extend from each ribbon's face, interconnecting adjacent ribbons. The nonrootlet filaments, except at the margins of the cell, occur primarily as single filaments. Like the ribbons, they are bristling with whiskers. The patches of striae are explained by ribbons and filaments held at a 650-A separation by the whiskers that project from them. A simple model for regions of bewhiskered filaments is a box crammed full of randomly oriented test-tube brushes. A thin slice through the box will show regions of dark lines or striae due to the wire backbones of the brushes separated from one another by the bristle length. Using the computer instead of test-tube brushes, we have been able to model quantitatively the filament distribution and pattern of striae seen in the cuticular plate of the lizard. The organization of actin filaments we have deduced from our simulations differs from that found in macrophages or in the terminal web of intestinal epithelial cells.

Actin Cytoskeleton↗
PubMed1994

A possible interpretation of some colony forming assays: 'developmental tree' model.

The characteristic form of the probability distributions of in vitro grown colonies is analysed and experimental results are shown to be well approximated by an exponential dependence. It is argued that this type of dependence is very frequent in nature and does not provide sufficient evidence to resolve the dilemma whether the development of haemopoietic lineages proceeds according to a schema of 'progressive and stochastic restriction' or more limiting 'developmental tree' with some random control process involved. Detailed analysis of the experimental conditions and results is needed to provide insight into collective phenomena in cellular proliferation and differentiation. At present, the complexity of the phenomena involved prevents unique interpretation of the experimental distributions. Nevertheless, one particular quantitative model, based on a developmental tree concept, yields a set of the theoretical probability distributions, which are in a very good agreement with the experimental results.

Animals↗
PubMed2006

Near-infrared imaging for studying homogeneity of protein-sugar mixtures.

PURPOSE: To investigate the applicability of near-infrared (NIR) imaging for assessing the homogeneity of dried protein-sugar formulations. METHODS: Physical mixtures of lysozyme and trehalose in different ratios were prepared and analyzed by near-infrared (NIR) imaging with a spatial resolution of 10 or 40 microm. To define and select the best imaging strategy, besides visual inspection of the images, several approaches for data processing were tested: single wavelength intensity, peak/height ratio of two specific wavelengths, correlation coefficient with a reference spectrum and principal component analysis (PCA). In order to relate the contrast directly to concentration differences of lysozyme and trehalose, quantitative models were created based on correlation coefficient and partial least squares (PLS) regression. The selected imaging method was applied to compare the homogeneity of a supercritical fluid (SCF) dried and a freeze-dried lysozyme-trehalose mixture. RESULTS: All tested methods confirmed each other and showed spatial heterogeneity in the lysozyme and trehalose contents of the physical mixtures. However, multivariate data processing methods (correlation coefficient and PCA/PLS) resulted in more distinct contrasts than univariate approaches (single wavelength analysis) and allowed a quantitative estimation of the homogeneity. As shown by NIR imaging in combination with the correlation coefficient or the PLS method, the SCF dried lysozyme-trehalose formulation was at least as homogeneous as its lyophilized counterpart, at 10 microm pixel size resolution. CONCLUSIONS: NIR imaging is a useful tool for studying the homogeneity of dried protein-sugar formulations.

Algorithms↗
PubMed1975

Kinetics and thermodynamics of the slow hydrophobic deactivation of alpha-chymotrypsin.

A quantitative model for the slow reversible hydrophobic deactivation of alpha-chymotrypsin (alpha-CT) is proposed. Kinetic results are obtained for (1) the situation in which the inhibitor concentration, although remaining constant during the course of a run, can be varied independently of the concentration of nonself-inhibiting substrate, and for (2) the situation in which the self-inhibiting substrate concentration decreases during the course of a run, and independent variation of inhibitor and substrate concentrations is not possible. Excellent quantitative agreement between theory and experiment is obtained for a wide range of conditions using 3-(n-hexanoyl-O-benzoate (with dodecylsulfate as the inhibitor), and 3-(n-decanoyl)-O-benzoate as the self-inhibiting substrate. Activation enthalpies and entropies for the hydrophobic deactivation of alpha-CT by dodecylsulfate and tetradecyltrimethylammonium are determined. For comparison, activation enthalpies and entropies for the alpha-CT hydrolysis of 3-(n-heptanoyl)-O-benzoate are determined; evidence for a thermally induced conformational transition in alpha-CT at 30 degrees C is obtained.

Benzoates↗
PubMedDate not supplied

Oocyte selection: a new model for the maternal-age dependence of Down syndrome.

Previously proposed mechanisms for Down syndrome (trisomy 21) have generally invoked a progressive increase in meiotic nondisjunction to explain maternal-age dependence, but models of this sort have failed to predict the observed patterns of marker segregation. Here we propose instead that age-dependent trisomy 21 results primarily from a mechanism that favors maturation and utilization of euploid oocytes in preference to the pre-existing aneuploid products of mitotic (premeiotic) nondisjunction. The increased utilization of aneuploid oocytes at later stages of maternal life would result from their increased proportion following many progressive cycles of selection against their maturation in earlier stages. Derivation of a quantitative model and evaluation of existing data indicate that the pattern of marker segregation associated with age-dependent trisomy 21 supports the proposed mechanism.

Aging↗
PubMed1995

The inositol trisphosphate receptor of Xenopus oocytes.

Xenopus laevis oocytes (stages V and VI) are a widely used model system for the study of Ca2+ signaling. The properties of the Xenopus oocyte InsP3 receptor (InsP3R) are of paramount importance for our thinking about this system and for our efforts to model Ca2+ dynamics in the oocyte cytosol. The recent data regarding the molecular structure, the regulation and the functional properties of the Xenopus oocyte InsP3R are summarized in this review. The main properties of the Xenopus oocyte InsP3R are compared with the properties of the cerebellar InsP3R and are shown to be remarkably similar. The density of the InsP3R in Xenopus oocyte cytoplasm is estimated to a value between 1.1-4.1 x 10(14) tetrameric InsP3R/l. The use of these numbers in a quantitative model of Ca2+ wave propagation leads to values of Ca2+ wave amplitude (0.8-1.5 microM Ca2+) and velocity of the wave propagation (12-24 microns/s) that are in excellent agreement with the values observed experimentally. The density of InsP3Rs in Purkinje cells of the cerebellum is estimated to be about 20,000-fold higher, but in other types of neurons and in peripheral tissues the InsP3R density is estimated to be of the same order of magnitude as, or up to 20-fold higher than, in Xenopus oocytes. The implications of differences in InsP3R density for Ca2+ signaling are discussed.

Animals↗
PubMed2000

Theoretical investigation of substrate specificity for cytochromes P450 IA2, P450 IID6 and P450 IIIA4.

Three-dimensional models of the cytochromes P450 IA2, P450 IID6 and P450 IIIA4 were built by means of comparative modeling using the X-ray crystallographic structures of P450 CAM, P450 BM-3, P450 TERP and P450 ERYF as templates. The three cytochromes were analyzed both in their intrinsic structural features and in their interaction properties with fifty specific and non-specific substrates. Substrate/enzyme complexes were obtained by means of both automated rigid and flexible body docking. The comparative analysis of the three cytochromes and the selected substrates, in their free and bound forms, allowed for the building of semi-quantitative models of substrate specificity based on both molecular and intermolecular interaction descriptors. The results of this study provide new insights into the molecular determinants of substrate specificity for the three different eukaryotic P450 isozymes and constitute a useful tool for predicting the specificity of new compounds.

Amino Acid Sequence↗
PubMed2006

Guard cells elongate: relationship of volume and surface area during stomatal movement.

Stomata in the epidermis of photosynthetically active plant organs are formed by pairs of guard cells, which create a pore, to facilitate CO2 and water exchange with the environment. To control this gas exchange, guard cells actively change their volume and, consequently, surface area to alter the aperture of the stomatal pore. Due to the limited elasticity of the plasma membrane, such changes in surface area require an exocytic addition or endocytic retrieval of membrane during stomatal movement. Using confocal microscopic data, we have reconstructed detailed three-dimensional models of open and closed stomata to precisely quantify the necessary area to be exo- and endocytosed by the guard cells. Images were obtained under a strong emphasis on a precise calibration of the method and by avoiding unphysiological osmotical imbalance, and hence osmocytosis. The data reveal that guard cells of Vicia faba L., whose aperture increases by 111.89+/-22.39%, increase in volume and surface area by 24.82+/-6.26% and 14.99+/-2.62%, respectively. In addition, the precise volume to surface area relationship allows quantitative modeling of the three-dimensional changes. While the major volume change is caused by a slight increase in the cross section of the cells, an elongation of the guard cells achieves the main aperture change.

Cell Movement↗
PubMed1991

Quantitation of natural killer cell function and risk of metastatic poorly differentiated head and neck cancer.

Previous laboratory studies have suggested that natural immunity is a primordial defense mechanism against blood-borne metastatic cancer, its function being most effective against dedifferentiated, low-major-histocompatibility-complex-class-I-antigen-expressing tumors. In this clinical study, 263 previously untreated patients with squamous cell carcinoma of the upper aerodigestive tract were evaluated for natural killer (NK) cell cytotoxicity mediated by peripheral blood lymphocytes against K562 target cells. All patients were evaluated before treatment, underwent subsequent attempts at curative therapy in which they were initially rendered disease-free, and then followed longitudinally for clinical outcome. Using a Cox proportional hazards model, quantitated NK cell cytotoxicity was inversely related to subsequent death with disease (p = 0.05), regional metastases (p = 0.008) and distant metastases (p = 0.03). No relationship between NK cell function and local recurrence could be identified (p = 0.81). Patients were further stratified by degree of differentiation of their respective primary cancer. The prognostic implication provided as to risk of death with disease and progressive metastatic growth was confined to the population with moderate-to-poorly differentiated cancers. Conversely, its function was nonpredictive in patients with well-differentiated cancers; the latter cancers were observed to express higher levels of major histocompatibility complex-class I framework antigens. Results of this clinical study are consistent with previous laboratory investigations and suggest that, within humans, the NK cell functions in metastatic sites against more primitive cancers. Such findings may have implications in designing therapeutic strategies.

Adult↗
PubMed2000

Utility of decompressive surgery in the prophylaxis and treatment of cisplatin neuropathy in adult rats.

Cisplatin produces a dose-dependent and dose-limiting peripheral neuropathy in patients. This study tested the hypothesis that this clinical neuropathy results from the chronic compression of peripheral nerves rendered susceptible to injury because of cisplatin-induced microtubular dysfunction. A quantitative model of cisplatin neurotoxicity was developed by administering cisplatin to rats and measuring the neuropathy by hindlimb walking track assay. The study aims were: (1) to characterize neuropathy induced by cisplatin in the adult rat; (2) to evaluate the role of decompressive surgery in the prevention of cisplatin neuropathy; and (3) to determine whether decompressive surgery was an effective treatment for established neuropathy. The assay demonstrated an increased print length in animals after 8 weeks of cisplatin (p < 0.01). This neuropathy progressed for 6 weeks after cisplatin was stopped, and reversed slowly over 3 months. These abnormalities were prevented by early tarsal tunnel decompression. Decompressive surgery was also beneficial, if performed early in the course of the neuropathy; abnormalities reversed in 5 weeks and remained normal for the remainder of the study. Control animals had progressive abnormalities which slowly resolved over a period of 18 weeks after discontinuing cisplatin. However, decompressive surgery performed after the neuropathy was established did not alter the neuropathic walking-track pattern. These studies provide insight into the etiology and possible therapeutic approaches to cisplatin neuropathy. Although further studies are required, they suggest that, in selected patients, decompressive surgery may have a role in the prevention or early treatment of cisplatin-induced neuropathy. Patients with underlying clinical or subclinical compressive neuropathies could be at high risk for the development of cisplatin neuropathy, and quantitative monitoring of neuropathies may be useful.

Animals↗
PubMed2001

Why are cancers acidic? A carrier-mediated diffusion model for H+ transport in the interstitial fluid.

31P MRS studies have shown that the intracellular compartment ot tumours is kept near neutrality, whereas the interstitial fluid is acidic (pH 6.5-6.8). Why is this compartment acidic? Balance studies confirm that tumours produce excessive lactic acid, although less than usually supposed, but this cannot be the whole story, since Tannock and co-workers have shown interstitial acidity in glycolysis-deficient tumours. Another major acid load is caused by hydration of CO2 molecules to carbonic acid, catalysed by carbonic anhydrase. The distance that H+ must diffuse from cancer cells to capillaries is further than in normal tissue and this will increase acidification near the cells. We show that previous quantitative models based on simple H+ diffusion are unsatisfactory. This is because most H+ ions cross the interstitial space bound to buffers such as inorganic phosphate. Although these protonated buffers (i.e. conjugate acids) diffuse much more slowly than H+ ions they carry most of the protons, so the pH predicted by this model is closer to neutrality for a given proton production rate than that predicted by the dissolved H+ model. We have developed a mathematical model of this carrier-mediated system that predicts pHe values as low as those observed in some tumours.

Diffusion↗
PubMed1997

Surface Precipitation of Co(II)(aq) on Al2O3

Surface precipitation is an important process in many areas of science and technology, including modeling contaminant segregation from groundwater to solid phases and dispersion of active phases on catalyst supports. XAFS, TEM, and XPS measurements of Co(II) sorbed on Al2O3 demonstrate that surface precipitates have formed from solutions that are undersaturated with respect to any known bulk solid phase. The precipitates have a structure similar to that of Co(OH)2(s), but are disordered and have a high concentration of Co vacancies. The data plus thermodynamic reasoning have been used to analyze the plausibility of various models for surface precipitation and to show that for Co(II)/Al2O3 it occurs by forming a double-hydroxide phase containing substrate-derived Al(III) ions. This idea was corroborated by mixing aqueous solutions of Al(III) and Co(II) at the pH and concentration of the sorption samples, forming a stable colloidal precipitate that is less soluble than either Al(OH)3 or Co(OH)2. The Co XAFS of this material was similar to that of the sorption samples. Successful quantitative models of metal ion transport in groundwater need to include the possibility of forming ternary and higher order precipitates that include ions derived from sparingly soluble solids. For catalyst impregnation, surface coprecipitation can prevent production of a well-dispersed precursor material.

Journal Article↗
PubMed2003

Analysis of excess Gibbs energy of electrolyte solutions: a new model for aqueous solutions.

This paper presents an analysis of the excess Gibbs free energy of aqueous electrolytes. The analysis of experimental data leads to the conclusion that the equilibrium state for dilute univalent electrolytes in water involves an intercalation of water and ionic liquid crystal domains. Excess free energy of the solution is determined by the Madelung energy of hydrated ion-pair liquid crystals, and the energy associated with a shift in the structural equilibrium of water. The data that point to such a model include: molecular orbital-molecular dynamics applied to electrolyte water systems; Raman spectra; infrared spectra; magnetic resonance spectra of ions; the apparent density of water; and the excess free energy of electrolytes in aqueous solutions. Molecular orbital-molecular dynamics calculations of relatively large water clusters containing a molecule of sodium iodide show that the solvent separated ion pair exists in a substantial potential well compared to other possible structures. Raman spectra of univalent electrolyte solutions as a function of concentration can be quantitatively modeled using only the spectra of pure water and electrolyte solution at the concentration of the solvent separated ion pair. The other observations are consistent with the structures proposed from the Raman spectral study. The new model provides a satisfactory account of the fact that the excess free energy of dilute (<0.2 mol/l) solutions is generally more negative than anticipated on the basis of Debye-Hückel theory, and that the equilibrium evidence points to the same functional behavior at very low concentrations as is seen at 0.05 mol/l. We present a testable hypothesis that the excess free energy, and other thermodynamic properties of the solutions do not follow the Debye-Hückel limiting law. The tests of this hypothesis must involve only equilibrium measurements at concentrations between 0.05 and 0.0005 mol/l. This hypothesis concerning the structure of aqueous electrolyte solutions is not in conflict in any way with the Debye-Hückel-Onsager theory of electrical conductivity.

Electrolytes↗