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PubMed2003

Allosteric regulation of the transcription factor NFAT1 by multiple phosphorylation sites: a mathematical analysis.

NFAT transcription factors are activated through dephosphorylation by the phosphatase calcineurin. Experimental data show that 13 conserved phosphorylation sites conspire to control the transition between an inactive and an active conformation. We propose a quantitative model of the underlying molecular mechanisms that may generally apply to highly phosphorylated proteins. Mathematical analysis shows that multiple phosphorylation sites result in a threshold for protein activation. Its sharpness increases with the number of sites, thus providing a rationale for the involvement of the large number of serine residues in NFAT activation. The model predicts that nuclear kinases exert a larger control on the activation threshold than cytoplasmic kinases, and that the NFAT activation kinetics can discriminate between input signals of different amplitude.

Allosteric Regulation↗

PubMed1988

Kinetics of histone gene expression during early development of Xenopus laevis.

Using literature data for transcriptional and translational rate constants, gene copy numbers, DNA concentrations, and stability constants, we have calculated the expected concentrations of histones and histone mRNA during embryogenesis of Xenopus laevis. The results led us to conclude that: (i) for X. laevis the gene copy number of the histone genes is too low to ensure the synthesis of sufficient histones during very early development, inheritance from the oocyte of either histone protein or histone mRNA (but not necessarily both) is necessary; (ii) from the known storage of histones in the oocyte and the rates of histone synthesis determined by Adamson & Woodland (1977), there would be sufficient histones to structure the newly synthesized DNA up to gastrulation but not thereafter (these empirical rates of histone synthesis may be underestimates); (iii) on the other hand, the amount of H3 mRNA recently observed during early embryogenesis (Koster, 1987, Koster et al., 1988) could direct a higher and sufficient synthesis of H3 protein, also after gastrulation. We present a quantitative model that accounts both for the observed H3 mRNA concentration as a function of time during embryogenesis and for the synthesis of sufficient histones to structure the DNA throughout early embryogenesis. The model suggests that X. laevis exhibits a major (i.e. some 14-fold) reduction in transcription of histone genes approximately 11 hours after fertilization. This reduction could be due to a decrease in the number of transcribed histone genes, a decreased rate constant of transcription with continued transcription of all the histone genes, and/or a reduction in the time during the cell cycle in which histone mRNA synthesis takes place. Alternatively, the histone mRNA stability might decrease approximately 16-fold 11 hours after fertilization.

Animals↗

PubMed1986

Functional effects of in vitro obstruction on the rabbit urinary bladder.

Bladder outlet obstruction has been the subject of numerous clinical and experimental investigations. Although these studies have demonstrated that the bladder can respond to outlet obstruction with muscular hypertrophy and hyperplasia, resulting in markedly altered morphological and functional characteristics, the nature of the direct effect of obstruction on the ability of the bladder to empty is relatively unknown. If one regards the bladder as a simple pump mechanism, decreasing the diameter of the outlet port (obstruction) would be expected to increase the work the bladder muscle would have to do in order to empty. The purpose of this present investigation is to better define the physical nature of the increased stress placed on the normal bladder via partial outlet obstruction. For these studies, the in vitro whole bladder is an appropriate model for several reasons: 1) one has complete control of initial intravesical volume, pressure, outlet diameter, and outlet resistance, and 2) this model quantitatively measures the effect of pharmacological agents and electrical stimulation on intravesical pressure and the ability of the bladder to empty. The results of these studies indicate that the obstructed bladder requires an increased pressure to empty. Although the obstructed bladder can empty completely, the rate of emptying is reduced significantly and the time required to completely empty is significantly increased. The obstructed bladder fatigues rapidly with repetitive stimulations, whereas the normal bladder is far less subject to fatigue. The physical alterations observed in these studies would play a direct role in the development of the functional alterations observed in in vivo obstruction.

Animals↗

PubMed1998

Ethanol's effects on operant responding: differentiating reinforcement efficacy and motor performance.

The purpose of this study was to examine the effects of ethanol on operant responding in rats. Drugs may affect response rates by several mechanisms, including altering motor performance or sensitivity to reinforcement. These two processes can be dissociated by applying a quantitative model of reinforced responding the response-strength equation, to response rates obtained during multiple variable-interval (VI) schedules of reinforcement. This equation has two fitted parameters. One (k) is thought to measure changes in motor performance, and the other (Re) is thought to measure changes in reinforcement efficacy. In experimental sessions, rats earned sucrose reinforcement on a seven-component multiple VI operant schedule. The average intervals varied from 108 to 3 s and provided reinforcement rates from 30 to 1200/h. Following stable baseline performance, rats were injected intraperitoneally prior to sessions with different doses of ethanol: 0.0, 0.3, 0.6. and 0.9 g/kg. Low to moderate doses of ethanol (0.3 and 0.6 g/kg) significantly decreased response rates on several of the VI schedules but did not alter either of the fitted parameters, suggesting that these doses of ethanol did not affect motor performance or sensitivity to reinforcement. The 0.9 g/kg dose decreased responding maintained by many of the VI schedules and significantly increased the Re parameter, suggesting that the sucrose became relatively less efficacious in ethanol compared to vehicle sessions. This relatively high dose of ethanol, however, did not alter responding maintained by the richest reinforcement schedule, and it did not affect motor performance as defined by the k parameter. These results suggest that, within this paradigm, ethanol affects motivation to respond rather than ability to respond.

Analysis of Variance↗

PubMed2003

Metapopulation theory for fragmented landscapes.

We review recent developments in spatially realistic metapopulation theory, which leads to quantitative models of the dynamics of species inhabiting highly fragmented landscapes. Our emphasis is in stochastic patch occupancy models, which describe the presence or absence of the focal species in habitat patches. We discuss a number of ecologically important quantities that can be derived from the full stochastic models and their deterministic approximations, with a particular aim of characterizing the respective roles of the structure of the landscape and the properties of the species. These quantities include the threshold condition for persistence, the contributions that individual habitat patches make to metapopulation dynamics and persistence, the time to metapopulation extinction, and the effective size of a metapopulation living in a heterogeneous patch network.

Animals↗

PubMed2000

Relative contributions of sustained and transient pathways to human stereoprocessing.

It has been proposed [Hubel & Livingstone (1987) Journal of Neuroscience, 7, 3378-3415] that stereopsis is mediated solely by magnocellular pathway in primates. This hypothesis was evaluated for humans in psychophysical experiments with dynamic random-noise stimuli, based on the sustained/transient relationship of behavior mediated by the two divisions of the LGN [Merigan & Maunsell (1993) Annual Review of Neuroscience, 16, 369-402]. The stereoscopic limits show that stereoscopic system is more sensitive to sustained random-dot stimuli than to transient ones. Quantitative modeling of the result implied a weak role for magnocellular input, suggests that human stereopsis is more strongly influenced by parvocellular input through the LGN.

Adolescent↗

PubMed2000

Exploring sequential stereopsis for co-planarity tasks.

We used the sequential stereopsis paradigm and apparatus described by Enright (Vision Research, 36, (1996) 307-312). The observer's task was to set targets to equidistance in Experiments 1-3, and to make them co-planar in Experiment 4. However, it is argued that in all experiments observers exploited a co-planarity setting strategy. Sequential stereopsis produced good performance throughout in terms of low disparity thresholds when head position was varied by rotations around three axes: vertical (azimuth condition); horizontal (elevation); and midline (tilt). It also produced good performance when the targets were shifted in position so that they both lay on one side of the median plane of the head. These results cannot be accounted for by Enright's isovergence hypothesis unless it is extended to incorporate other information about eye positions. Performance was better but not greatly so in control simultaneous stereopsis conditions, nor did it deteriorate much when the observer's view was restricted solely to the targets by removing visibility of the room in which the apparatus was located. Target settings were typically located on a concave arc centred on the median plane. This effect was quantitatively modelled using disparity correction for a relief task of co-planarity (Gârding, Porrill, Mayhew, & Frisby. Vision Research, 35 (1995) 703-722). This modelling indicated over-estimations of c.10-20 cm in fixation distance for target distances in the range 71.5-112.5 cm.

Adolescent↗

PubMed1998

Motion blur and motion sharpening: temporal smear and local contrast non-linearity.

Blurred images may appear sharper when drifting than when stationary. But, paradoxically, moving sharp edges may appear more blurred. To resolve this paradox, the perceived sharpness of drifting, blurred, square wave gratings was compared with that of their static analogues over a range of speeds, blurs and spatial frequencies. Both motion blur and motion sharpening occurred, depending upon the physical blur of the patterns. For large extents of blur (> 10 min arc) moving patterns always appeared sharper than their static analogues, but for small blurs (< 10 min arc) moving edges appeared more blurred than stationary ones. We present a quantitative model for the distortion of waveforms in motion based on two factors: (i) visual temporal integration that smears moving images, and (ii) a local contrast non-linearity that increasingly sharpens the effective profile of edges as speed and contrast increase. We suggest that a plausible account of the speed-dependent non-linearity is the differential recruitment of M and P cells at different speeds.

Contrast Sensitivity↗

PubMed2002

Neural control of saccades.

Quantitative models of the oculomotor plant and control of the saccadic eye movement system are presented in this chapter. Oculomotor plant models described here are linear, including a second-order model by Westheimer (1954), Bahill et al. (1980) and Enderle et al. (2000). The model of the saccade generator is initiated by the superior colliculus and terminated by the cerebellar fastigial nucleus that operates under a time optimal control strategy. A common mechanism for all types of saccades is described, including those with dynamic overshoot and glissadic behavior. Conflicting evidence exists regarding the operation of the excitatory burst neuron during saccades. The excitatory burst neuron operates within two states: complete inhibition, and without inhibition that is characterized by high firing at rates of up to 1000 Hz. While there is direct evidence of projections from the superior colliculus to the paramedian pontine reticular formation, there is conflictory evidence regarding the connections from the superior colliculus to the excitatory burst neuron, with the most recent experimental results supporting no direct connections. A model of the excitatory burst neuron is described using a Hodgkin-Huxley model of the neuron that fires at 1000 Hz automatically and without stimulation when released from inhibition. SIMULINK simulations using this neuron model have all of the characteristics of the excitatory burst neuron firing rate during a saccade. This model eliminates the need to introduce BIAS inputs that causes bursting in some models of the saccade generator. Such a model is also appropriate for modeling the Omnipause neurons.

Algorithms↗

PubMed1997

The effect of tin in the Ag-Hg phase of dental amalgam on dissolution of mercury.

OBJECTIVES: The aim of this study was to determine the relationship between the tin content in the gamma 1 phase of dental amalgam and the kinetics of mercury dissolution. METHODS: The tested materials were the same eleven commercial amalgams used by Mahler et al. (1994) to study mercury evaporation, which contained from 0.13% to 2.49% Sn in the gamma 1. In one set of tests, specimens were stabilized in air before exposure to synthetic saliva for three 24 h sampling periods. In another set of tests, they were exposed for 2 h immediately after wet-grinding. Solutions were analyzed for mercury by atomic absorption spectrophotometry. The results were analyzed by ANOVA and Turkey tests (p < 0.05). RESULTS: For air-stabilized specimens, the 24 h Hg loss was independent of the tin content in gamma 1 for 0.92 to 2.49% Sn. The loss was higher for amalgams containing 0.13% and 0.32% Sn. For abraded specimens, the 2 h Hg loss decreased with increasing tin content in gamma 1. It is proposed that tin oxide growth is initially controlled by diffusion of tin to the gamma 1/tin oxide interface, the rate of which increases with increasing Sn content in gamma 1. Later the growth becomes controlled by the electric field across the oxide. Mercury release rate, controlled by diffusion through the oxide, is inversely proportional to the oxide thickness and initially lower for high Sn content in gamma 1. For a steady state oxide thickness, tin diffusion and tin content in gamma 1 no longer affect mercury dissolution. When tin oxide film dissolves, a minimum tin content is required to maintain a barrier against mercury dissolution. SIGNIFICANCE: The results show the importance of rapid formation of a surface oxide to minimize mercury dissolution. The theoretical analysis provides a quantitative model for explanation of the effects of tin content and time.

Analysis of Variance↗

PubMed2000

Course of pH during the formation of amoxicillin by a suspension-to-suspension reaction.

Amoxicillin can be produced in an enzymatic suspension-to-suspension reaction in which the substrate(s) and product(s) are mainly present as solid particles, while the reaction takes place in the liquid phase. During these suspension-to-suspension reactions different subprocesses take place, such as dissolution/crystallization of substrates and products, enzymatic synthesis of the product(s), and undesired enzymatic hydrolysis of substrates and/or products. All these subprocesses are influenced by pH and also influence the pH because the reactants are weak electrolytes. This paper describes a quantitative model for predicting pH and concentrations of reactants during suspension-to-suspension reactions. The model is based on mass and charge balances, pH-dependent solubilities of the reactants, and enzyme kinetics. For the validation of this model, the kinetically controlled synthesis of amoxicillin from 6-aminopenicillanic acid and D-(p)hydroxyphenylglycine methyl ester was studied. The pH and the dissolved concentrations took a very different course at different initial substrate amounts. This was described quite reasonably by the model. Therefore, the model can be used as a tool to optimize suspension-to-suspension reactions of weak electrolytes.

Journal Article↗

PubMed1996

Macroporous poly(sucrose acrylate) hydrogel for controlled release of macromolecules.

We have studied the controlled release of proteins from poly(sucrose acrylate) hydrogels. The hydrogels were prepared by a two-step procedure in which sucrose was first acylated to sucrose-1'-acrylate followed by free radical polymerization. By adjusting the cross-link ratio and initial monomer concentration, the swelling ratio of the hydrogel was varied from five to 28. The mechanical strength of these hydrogels was comparable to that of the hydrogels with approximately the same swelling ratio. Scanning electron micrographs and mesh size calculations indicate that the hydrogel is macroporous, suggesting it may be suitable for a variety of biomedical applications. The release kinetics of beta-lactoglobulin, bovine serum albumin and gamma-globulin were studied as a function of initial monomer concentrations for the sucrose-based hydrogel. All of the release profiles were characterized by an initial burst of protein in the first 25 h followed by a long period of sustained release (> 500 h). The magnitude of the initial burst was reduced by increasing the initial monomer concentration and by increasing the molecular weight of the protein. A quantitative model based on the heterogeneous nature of hydrogel was developed to explain the observed release kinetics.

Acrylic Resins↗

PubMed2002

Significance of electrophoretic mobility distribution to bacterial transport in granular porous media.

A method is developed to obtain the electrophoretic mobility distribution of colloidal particles by microelectrophoresis. The results demonstrate that for small particles (< 1 microm), the experimental mobility distribution must be deconvoluted to remove the effect of the random Brownian motion so that the electrophoretic mobility distribution can be obtained. For bacteria-sized particles (on the order of 1 microm or larger), the random Brownian motion is not significant, and the experimental mobility distribution represents the electrophoretic mobility distribution. The significance of the electrophoretic mobility distribution to bacterial transport is demonstrated through comparison between experimental and theoretical values of collision efficiency. Using the extended Derjaguin-Landau-Verwey-Overbeek (DLVO) theory, the electrophoretic mobility distribution of bacteria is transformed to the distribution of collision efficiencies. For strain Comamonas sp. DA001, the predicted collision efficiency values span orders of magnitude, indicating that variation of surface charge density in a monoclonal bacterial population is a cause for the orders of magnitude variation of experimentally determined collision efficiencies. However, despite the fact that the predicted and experimental alpha distributions overlap, the match is not adequate. This inadequacy is ascribed to inability to probe heterogeneity of bacterial surface hydrophobicity, and the inability of the DLVO theory to quantitatively model particle deposition.

Comamonas↗

PubMed2002

Microscopic kinetics and structure-function analysis in the vesicular acetylcholine transporter.

The vesicular acetylcholine transporter (VAChT) resides in synaptic vesicles of cholinergic nerve terminals. It carries out vesicular storage of ACh. The amount of ACh stored determines, along with other factors, the amount of ACh released. Knowledge of the structure-function relationship in VAChT might enable pharmacological regulation of ACh storage and release at the level of VAChT. To this end, a quantitative model for the individual steps in the overall transport cycle of VAChT has been developed. Because of the particular values of the microscopic rate constants in the model, structure-function analysis of VAChT can be misleading. Attempts to devise a pro-storage strategy to increase ACh release from cholinergic nerve terminals should take into account the microscopic kinetics of this transporter.

Animals↗

PubMed1999

Synapse formation molecules in muscle and autonomic ganglia: the dual constraint hypothesis.

In 1970 it was thought that if the motor-nerve supply to a muscle was interrupted and then allowed to regenerate into the muscle, motor-synaptic terminals most often formed presynaptic specializations at random positions over the surface of the constituent muscle fibres, so that the original spatial pattern of synapses was not restored. However, in the early 1970s a systematic series of experiments were carried out showing that if injury to muscles was avoided then either reinnervation or cross-reinnervation reconstituted the pattern of synapses on the muscle fibres according to an analysis using the combined techniques of electrophysiology, electronmicroscopy and histology on the muscles. It was thus shown that motor-synaptic terminals are uniquely restored to their original synaptic positions. This led to the concept of the synaptic site, defined as that region on a muscle fibre that contains molecules for triggering synaptic terminal formation. However, nerves in developing muscles were found to form connections at random positions on the surface of the very short muscle cells, indicating that these molecules are not generated by the muscle but imprinted by the nerves themselves; growth in length of the cells on either side of the imprint creates the mature synaptic site in the approximate middle of the muscle fibres. This process is accompanied at first by the differentiation of an excess number of terminals at the synaptic site, and then the elimination of all but one of the terminals. In the succeeding 25 years, identification of the synaptic site molecules has been a major task of molecular neurobiology. This review presents an historical account of the developments this century of the idea that synaptic-site formation molecules exist in muscle. The properties that these molecules must possess if they are to guide the differentiation and elimination of synaptic terminals is considered in the context of a quantitative model of this process termed the dual-constraint hypothesis. It is suggested that the molecules agrin, ARIA, MuSK and S-laminin have suitable properties according to the dual-constraint hypothesis to subserve this purpose. The extent to which there is evidence for similar molecules at neuronal synapses such as those in autonomic ganglia is also considered.

Animals↗

PubMed2003

Differentiating between local cytotoxicity, mitogenesis, and genotoxicity in carcinogen risk assessments: the case of vinyl acetate.

Understanding the mode of action of carcinogens is critical to scientifically assessing exposure-related risk. Regulatory hazard classification schemes and dose-response assessment paradigms generally require basic knowledge of genotoxic potential to guide decisions on which scheme or paradigm is most appropriate. Although convention suggests that classification and dose-response assessment of genotoxic chemicals should be assessed using conservative assumptions of no threshold, several examples, such as vinyl acetate, exist that challenge this assumption. Vinyl acetate is carcinogenic at portals of entry (nasal cavity and upper gastrointestinal tract). Local metabolism of vinyl acetate produces DNA-reactive acetaldehyde but also produces acetic acid and protons, which contribute to intracellular acidification, cytotoxicity and cell proliferation. This paper reviews their relative contributions to the overall mode of action. Elevated cellular proliferation, well understood to be a risk factor for carcinogenesis, is observed at concentrations associated with tumor formation. Cytotoxicity and compensatory tissue regeneration is one pathway for stimulating cellular proliferation while intracellular acidification is a mitogenic stimulus. Both of these pathways may be operative in nasal tissues while mitogenic proliferation alone appears to be induced in the upper gastrointestinal tract. Using a physiologically-based pharmacokinetic model, quantitative relationships between critical tissue dosimeters and tissue responses are developed to assess the relative importance of genotoxicity and cell proliferation in the overall mode of action of vinyl acetate. This approach supports the concept that intracellular acidification is the sentinel response that precedes cytotoxicity and cellular proliferation. Secondarily, the carcinogenic potential of vinyl acetate is expressed only when tissue exposure to acetaldehyde is high and when cellular proliferation is simultaneously elevated. This mode of action suggests that exposure levels that do not increase intracellular acidification beyond homeostatic bounds will be adequately protective of adverse downstream responses including cancer. These mechanistic insights provide the scientific basis for a cancer classification that incorporates thresholds for cytotoxic and/or mitogenic cell proliferation secondary to intracellular acidification.

Animals↗

PubMed1998

Commercial toxicology prediction systems: a regulatory perspective.

The use of commercial toxicity prediction systems in a regulatory setting must consider both the limitations and capabilities of the methods, as well as the ultimate use of the predictions, e.g. for testing prioritization, screening, or supporting regulatory decisions. Current systems are better suited to hazard identification (i.e. positive identification of activity-conferring features) than to ruling out hazard. Two recent examples (an EPA testing prioritization exercise for water disinfection byproducts and a regulatory action on 2,4,6-tribromophenol) illustrate issues involved in regulatory applications of SAR and commercial prediction systems. The challenge for the future will be to improve technologies for prediction within the constraints of available data, make optimal use of new test data, and better integrate elements of quantitative modeling (QSAR), empirical association, and biological and chemical mechanisms towards the goal of toxicity prediction.

Disinfection↗

PubMed1997

Anatomy of the normal human cochlear aqueduct with functional implications.

There is great variation in published descriptions of the shape, size, and patency of the human cochlear aqueduct. The first part of this paper describes the anatomy of the normal human cochlear aqueduct as determined from a study of 101 temporal bones. Nineteen bones aged 0-1 years and approximately 10 bones per decade of life until age 100 years were examined. The aqueduct was found to have a funnel shaped aperture at the cranial end with a dural sheath extending into it for a varying distance. The rest of the aqueduct was filled with a meshwork of loose connective tissue, often with a central lumen within it. Four types of patencies were noted: central lumen patent throughout length of aqueduct (34%), lumen filled with loose connective tissue (59%), lumen occluded by bone (4%), and obliteration of the aqueduct (3%). The mean value (+/- SD) of the narrowest portion was 138 (+/- 58) microns which occurred 200-300 microns from the cochlear end of the aqueduct. There was no correlation between age and narrowest diameter, or between age and category of patency. In the second part of this paper, we propose quantitative models of aqueduct function, based on measurements of ductal dimensions and known acoustical properties of the inner ear. Our model analyses suggest that in normal ears, the aqueduct (1) cannot support fluid flows large enough to explain stapedectomy gushers, (2) does filter out cardiac- and respiration-induced pulses in CSF and prevents them from affecting cochlear function, and (3) has little effect on normal ossicular transmission of sound for frequencies above 20 Hz. In pathological ears, such as those with ossicular disruption or after a type IV tympanoplasty, a patent aqueduct might affect hearing for frequencies below 150 Hz.

Acoustics↗