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PubMed1996

A quantitative model of the "effective" signal processing in the auditory system. II. Simulations and measurements.

This and the accompanying paper [Dau et al., J. Acoust. Soc. Am. 99, 3615-3622 (1996)] describe a quantitative model for signal processing in the auditory system. The model combines several stages of preprocessing with a decision device that has the properties of an optimal detector. The present paper compares model predictions for a variety of experimental conditions with the performance of human observers. Simulated and psychophysically determined thresholds were estimated with a three-interval forced-choice adaptive procedure. All model parameters were kept constant for all simulations discussed in this paper. For frozen-noise maskers, the effects of the following stimulus parameters were examined: signal frequency, signal phase, temporal position and duration of the signal within the masker under conditions of simultaneous masking, masker level, and masker duration under conditions of forward masking, and backward masking. The influence of signal phase and the temporal position of the signal, including positions at masker onset, was determined for a random-noise masker and compared with corresponding results obtained for a frozen noise. The model describes all the experimental data with an accuracy of a few dB with the following exceptions: forward-masked thresholds obtained with brief maskers are too high and the change in threshold with a change in signal duration is too small. Both discrepancies have their origin in the adaptation stages in the preprocessing part of the model. On the basis of the wide range of simulated conditions we conclude that the present model is a successful approach to describing the detection process in the human auditory system.

Adult↗
PubMed1980

A quantitative model of the functional architecture of human striate cortex with application to visual illusion and cortical texture analysis.

Anatomical and physiological data from lower primates, and psychophysical data from humans, is used to construct a quantitative model of the local and global map structure (functional architecture) of human striate cortex. A series of successful estimates deriving from this model are reviewed, including a prediction for the width of human ocular dominance columns, which has recently been verified. A variety of perceptual phenomena are then discussed, from the point of view of cortical, rather than retinal, topography. It is suggested that the striate cortex may be viewed as a "cyclopean retina" whose non-linear map structure, summarized in terms of a concatenated complex logarithmic pattern, suggests insights into the nature of the Mackay complimentary image, the Frazer spiral, fortification illusions, and the relationship of the second order statistics of a visual stimulus to pre-attentive (textural) segmentation. Finally, the nature of neuronal representation is considered in the context of recent models of perceptual and cognitive function. It is suggested that anatomical re-mapping at successive stages of the CNS may provide a conceptual alternative to conventional single cell and connectionist models, and offers a viable approach towards a "field" theory of vision.

Afterimage↗
PubMed1994

"Clinical Judgment" revisited: the distraction of quantitative models.

More than 25 years ago, in a book called Clinical Judgment, each act of patient care was described as having an experimental structure. The "experiments" needed substantial scientific improvement, however, in quality of basic data, taxonomic classification of phenomena, and specifications of clinical reasoning. During the past 2 decades, these improvements have not occurred as extensively as expected because many investigators working in clinical forms of clinical research have not addressed these basic scientific challenges in data, taxonomy, and reasoning. Instead, the investigators have applied quantitative "models," derived from non-clinical domains, that focus on hard data, randomized trials, Bayes theorem, quantitative decision analysis, and psychometric strategies for clinimetric measurement. Consequently, the main challenges of clinical judgment still remain generally available for basic scientific research by investigative clinicians.

Clinical Competence↗
PubMed1989

Overview of a workshop on quantitative models for developmental toxicity risk assessment.

A workshop was held to discuss potential advancements to improve the precision of risk estimates for developmental toxicity. This paper presents an overview of the discussions at the workshop, focusing on the risk assessment process and science policy considerations important in the use of quantitative models. Some of the pertinent biological considerations are reviewed, particularly those related to the repair capacity of the developing organism and how this affects the concept of a threshold for developmental toxicity effects, as well as the maternal and litter influences on developmental toxicity outcomes. Finally, the current status of use of quantitative approaches is described, possible short-term approaches are discussed, and future research needs in this area are outlined.

Abnormalities, Drug-Induced↗
PubMed2000

Electrophoretic Deposition: A Quantitative Model for Particle Deposition and Binder Formation from Alcohol-Based Suspensions.

We investigated electrophoretic deposition from a suspension containing positively charged particles, isopropanol, water, and Mg(NO(3))(2), with the aim of describing the deposition rates of the particles and Mg(OH)(2), which is formed due to chemical reactions at the electrode, in terms of quantitative models. LaB(6) particles were used as a model system. The particle layer is consolidated by simultaneous precipitation of Mg(OH)(2) which acts as a binder to hold the particles together. The Mg(OH)(2) content was determined solely by the amount of charge passed through the cell. Quantitative precipitation of all OH(-) formed at the electrode was observed, except at very low current. The occurrence of a minimum current was ascribed to a threshold for Mg(OH)(2) deposition. The same minimum current was observed for particle deposition. In combination with results using NaNO(3), where no adherent layer was formed, this illustrates that Mg(OH)(2) binder is necessary for consolidation. Once the minimum current was exceeded, it was found that all particles that migrate to the electrode under the influence of the electric field contribute to the formation of the layer, i.e., the "sticking coefficient" for the particles equals 1.0. The applicability of the particle and Mg(OH)(2) deposition models was tested by variation of the Mg(NO(3))(2) concentration, pH, and water content. Copyright 2000 Academic Press.

Journal Article↗
PubMed2001

The bystander effect in radiation oncogenesis: II. A quantitative model.

There is strong evidence that biological response to ionizing radiation has a contribution from unirradiated "bystander" cells that respond to signals emitted by irradiated cells. We discuss here an approach incorporating a radiobiological bystander response, superimposed on a direct response due to direct energy deposition in cell nuclei. A quantitative model based on this approach is described for alpha-particle-induced in vitro oncogenic transformation. The model postulates that the oncogenic bystander response is a binary "all or nothing" phenomenon in a small sensitive subpopulation of cells, and that cells from this sensitive subpopulation are also very sensitive to direct hits from alpha particles, generally resulting in a directly hit sensitive cell being inactivated. The model is applied to recent data on in vitro oncogenic transformation produced by broad-beam or microbeam alpha-particle irradiation. Two parameters are used in analyzing the data for transformation frequency. The analysis suggests that, at least for alpha-particle-induced oncogenic transformation, bystander effects are important only at small doses-here below about 0.2 Gy. At still lower doses, bystander effects may dominate the overall response, possibly leading to an underestimation of low-dose risks extrapolated from intermediate doses, where direct effects dominate.

Apoptosis↗
PubMed1989

A quantitative model of reticulo-rumen particle degradation and passage.

Labelled particles were prepared by mordanting low concentrations (0.1 or 5 g/kg dry matter) of chromium to neutral-detergent-extracted stems (1-2 mm or 10 mm in length) of bromegrass (Bromus inermis). These were used in the study of reticulo-rumen particle kinetics of four steers given bromegrass hay and from the results a quantitative model of particle digestion and passage was developed. At the 0.1 g Cr/kg concentration there was minimal interference with digestibility of the feedstuff. The ratio, dry weight of the reticulo-rumen large-particle pool (greater than 3.35 mm): small-particle pool (less than 3.35 mm) was 2:1. It was derived from the model that volatile fatty acids (VFA) and carbon dioxide in the rumen were produced mainly from large particles, and that between 500 and 700 g/kg hay dry matter was digested in the reticulo-rumen. It was also derived from the model that a major portion, 200 (SE 110) g/kg, of the hay dry matter was rapidly solubilized and that the material leaving the reticulo-rumen was composed of small particles (500-840 g/kg), large particles (100-160 g/kg) and an unknown portion of soluble dry matter of hay (0-400 g/kg). Disappearance from the large-particle pool in the model involving the lowest Cr level was directed to formation of VFA and CO2 (0.68 (SE 0.04) of total flow) to the small-particle pool (0.25 (SE 0.06) of total flow) and direct passage from the reticulo-rumen (0.07 (SE 0.002) of total flow). The disappearance from the small-particle pool was to VFA and CO2 production and to the omasum accounting for 0.14 (SE 0.18) and 0.86 (SE 0.24) respectively, of the total flow. It was concluded that the low-level-mordanting technique in combination with appropriate sampling yielded a realistic quantitative description of forage breakdown and movement processes in the digestive tract of cattle.

Animal Feed↗
PubMed1999

A quantitative model of the Simpson-Baldwin Effect.

G. G. Simpson was the first to explain the Baldwin Effect completely in terms of the theory of natural selection. A genetic version of a seemingly non-hereditary adaptation may arise when natural selection acts on the likelihood of having an adaptive trait not just on the trait itself. We present a quantitative model of the Simpson-Baldwin Effect. Organisms in the model have mutable ranges of phenotypic plasticity. The distribution of phenotypes in a population depends largely on the extent of environmental stochasticity. When the environment undergoes intermediate rates of fluctuation, the Simpson-Baldwin effect arises through the interaction of natural selection and mutation on norms of reaction. In a highly volatile environment, organisms benefit from plasticity, and consequently do not experience a Simpson-Baldwin channeling of phenotypic possibility.

Animals↗
PubMed1989

Lateral feedback from monophasic horizontal cells to cones in carp retina. II. A quantitative model.

About half of the monophasic horizontal cells in carp retina receive input from both red- and green-sensitive cones. Since the horizontal cells feed back to cones, the color and feedback pathways result in wavelength- and intensity-dependent changes of the dynamics and of the receptive field amplitude profile of the horizontal cell responses. In this paper we present a quantitative model that describes adequately the color and spatial coding and the dynamics of the responses from monophasic horizontal cells in carp. Lateral feedback plays a distinct role in this model.

Animals↗
PubMed2002

High-throughput SELEX SAGE method for quantitative modeling of transcription-factor binding sites.

The ability to determine the location and relative strength of all transcription-factor binding sites in a genome is important both for a comprehensive understanding of gene regulation and for effective promoter engineering in biotechnological applications. Here we present a bioinformatically driven experimental method to accurately define the DNA-binding sequence specificity of transcription factors. A generalized profile was used as a predictive quantitative model for binding sites, and its parameters were estimated from in vitro-selected ligands using standard hidden Markov model training algorithms. Computer simulations showed that several thousand low- to medium-affinity sequences are required to generate a profile of desired accuracy. To produce data on this scale, we applied high-throughput genomics methods to the biochemical problem addressed here. A method combining systematic evolution of ligands by exponential enrichment (SELEX) and serial analysis of gene expression (SAGE) protocols was coupled to an automated quality-controlled sequence extraction procedure based on Phred quality scores. This allowed the sequencing of a database of more than 10,000 potential DNA ligands for the CTF/NFI transcription factor. The resulting binding-site model defines the sequence specificity of this protein with a high degree of accuracy not achieved earlier and thereby makes it possible to identify previously unknown regulatory sequences in genomic DNA. A covariance analysis of the selected sites revealed non-independent base preferences at different nucleotide positions, providing insight into the binding mechanism.

Base Sequence↗
PubMed2003

Forces for morphogenesis investigated with laser microsurgery and quantitative modeling.

We investigated the forces that connect the genetic program of development to morphogenesis in Drosophila. We focused on dorsal closure, a powerful model system for development and wound healing. We found that the bulk of progress toward closure is driven by contractility in supracellular "purse strings" and in the amnioserosa, whereas adhesion-mediated zipping coordinates the forces produced by the purse strings and is essential only for the end stages. We applied quantitative modeling to show that these forces, generated in distinct cells, are coordinated in space and synchronized in time. Modeling of wild-type and mutant phenotypes is predictive; although closure in myospheroid mutants ultimately fails when the cell sheets rip themselves apart, our analysis indicates that beta(PS) integrin has an earlier, important role in zipping.

Animals↗
PubMed1985

Formulating and evaluating quantitative models of control of sodium stores.

Numerous factors that influence sodium handling have been identified, and many have been studied in minute detail; however, relatively little information is available regarding either the steady-state relationship between dietary sodium intake and sodium stores or the transient response of intact animals to challenges to sodium homeostasis. In this paper the principles of elementary feedback control theory have been used both to obtain and analyze quantitative models of the feedback control of sodium stores. It has been assumed that the sodium content of the body determines the rate of urinary sodium excretion, and a mass balance has been used to obtain differential equations that describe the dynamics of sodium stores. Both first- and second-order models are considered, and their predictions for both steady states and transients are compared critically with observations from the literature, using data from human studies whenever possible. The results indicate that a relatively simple proportional feedback controller describes most available data well; however, gaps in the available information are identified, and opportunities for future experimental investigation are described.

Feedback↗
PubMed1999

Quantitative modeling of visual attention processes in patients with Parkinson's disease: effects of stimulus integrality on selective attention and dimensional integration.

Parkinson's disease (PD) patients and normal controls (NCs) were administered a series of visual attention tasks. The dimensional integration task required integration of information from 2 stimulus dimensions. The selective attention task required selective attention to 1 stimulus dimension while ignoring the other stimulus dimension. Both integral- and separable-dimension stimuli were examined. A series of quantitative models of attentional processing was applied to each participant's data. The results suggest that (a) PD patients were not impaired in integrating information from 2 stimulus dimensions, (b) PD patients were impaired in selective attention, (c) selective attention deficits in PD patients were not due to perceptual interference, and (d) PD patients were affected by manipulations of stimulus integrality and separability in much the same way as were NCs.

Aged↗
PubMed1996

A quantitative model for the cdc2 control of S phase and mitosis in fission yeast.

In this article we consider the role of the cyclin-dependent protein kinase cdc2 in regulating progression through the fission yeast cell cycle. The onset of mitosis is governed by cdc2 in partnership with the B-type cyclin, cdc13. Recent evidence shows that the cdc2-cdc13 complex can also control the onset of S phase and, in addition, ensures that there is only one S phase per cell cycle. This leads us to propose a novel quantitative model in which different levels of cdc2 activity regulate cell-cycle progression: S phase is initiated when protein kinase activity increases from a very low to a moderate level; maintenance of this moderate level prevents re-initiation of S phase, and a further increase of activity to a high level initiates mitosis. Inactivation of the kinase activity at the end of mitosis resets the cell for a new cell cycle.

Animals↗
PubMed1981

A quantitative model of the Hoffmann reflex.

Electrical stimulation of the human posterior tibial nerve elicits two separate electromyographic responses. The shorter latency response results from electrical activation of motor axons and is termed the direct motor (M) response, while the longer latency response results from activation of stretch receptor afferents of the monosynaptic reflex arc and is termed the Hoffmann (H) reflex. At high stimulus intensities, the H reflex is either greatly reduced in size or completely extinguished, presumably by antidromic impulses elicited by stimulation of the motor nerve. In most subjects, a simple quantitative model appears to account for this extinction. In this model: (1) the M response is used to estimate the number of antidromic impulses; (2) the H reflex is used to estimate the number of orthodromic impulses which escape collision; (3) the maximum size of the M response is used to indicate the size of the motoneuron pool; and (4) it is assumed that antidromic impulses collide in a random fashion with orthodromic impulses in the motor nerve.

Electromyography↗
PubMed1996

Quantitative model of antibody- and soluble CD4-mediated neutralization of primary isolates and T-cell line-adapted strains of human immunodeficiency virus type 1.

Primary isolates (PI) of human immunodeficiency virus type 1 (HIV-1) are considerably less sensitive than T-cell line-adapted strains to neutralization by soluble CD4 and by most cross-reactive monoclonal antibodies to the viral envelope (Env) glycoprotein, as well as by postinfection and postvaccination sera (J. P. Moore and D. D. Ho, AIDS 9 [suppl. A]:5117-5136, 1995). We developed a quantitative model to explain the neutralization resistance of PI. The factors incorporated into the model are the dissociation constants for the binding of the neutralizing agent to native Env oligomers, the number of outer Env molecules on the viral surface (which decreases by shedding), and the minimum number of Env molecules required for attachment and fusion. We conclude that modest differences in all these factors can, when combined, explain a relative neutralization resistance of PI versus T-cell line-adapted strains that sometimes amounts to several orders of magnitude. The hypothesis that neutralization of HIV is due to the reduction below a minimum number of the Env molecules on a virion available for attachment and fusion is at odds with single- and few-hit neutralization theories. Our analysis of these ideas favors the hypothesis that neutralization of HIV is instead a competitive blocking of interactions with cellular factors, including adsorption receptors.

Antibodies, Monoclonal↗
PubMed1986

Visuomotor fields of the superior colliculus: a quantitative model.

Electrophysiological and electrical stimulation studies in the monkey have disclosed that both the retinal surface and the metrics of saccades are topographically represented in the superior colliculus. This mapping of sensory and motor space onto the colliculus is nonhomogeneous in that the central region is over-represented in both the visual and the motor map. Single unit studies have revealed that visual receptive fields of collicular neurons are typically quite large and are characterized by a skewed (asymmetrical) sensitivity profile. Analyses by McIlwain [J. Neurophysiol. 38, 219-230 (1975)] in the cat have suggested that this skewness property reflects mainly the spatial distortion inherent in the afferent mapping. In this paper we describe a quantitative model, based on a logarithmic mapping function combined with a Gaussian connectivity function in the colliculus, which can account for the extent and the shape of collicular receptive fields. Collicular neurons in the deeper layers have movement-related bursts of activity for saccades in a limited amplitude and direction range related to their location in the collicular map. These movement fields, like visual receptive fields, may be quite extensive and typically have a skewed profile. In our model, an efferent-mapping function is defined, which relates the locus of a population of recruited cells to the metrics of the ensuing saccade. The parameters of this function, which was taken to be identical with the afferent mapping function, were estimated from Robinson's [Vision Res. 12, 1795-1808 (1972)] electrical stimulation data. Based on the assumption that the population-activity profile resembles a two-dimensional Gaussian function, the shape and the size of movement fields can then be described with just 2 or 3 free parameters. Electrophysiological data recorded from a small sample of collicular visuomotor neurons were used to illustrate the procedure, which we designed to enable application of our model to the experimental data. The best fit was obtained when the mapping function was slightly anisotropic. Suggestions on how the model could be improved and extended are offered in the Discussion.

Action Potentials↗
PubMed1991

A quantitative model for translational control of the GCN4 gene of Saccharomyces cerevisiae.

Expression of the GCN4 gene of Saccharomyces cerevisiae is regulated at the translational level by short open reading frames (uORFs) present in the leader sequence of its mRNA. Under conditions of amino acid sufficiency, these sequences restrict the flow of initiating ribosomes to the GCN4 AUG start codon. Mutational analysis of GCN4 has led to a model in which ribosomes must translate the 5'-proximal uORF1 and reassemble an initiation complex in order to translate GCN4. This reassembly process is thought to be rapid when amino acids are abundant, such that reinitiation occurs at uORF2, uORF3, or uORF4. Reinitiation at these sites prevents translation of GCN4, presumably because ribosomes dissociate from the mRNA following termination at uORFs 2 to 4. Because of reduced initiation factor activity under starvation conditions, a substantial fraction of ribosomal subunits scanning downstream from uORF1 are not ready to reinitiate when they reach uORFs 2 to 4, but become competent to do so while scanning the additional sequences between uORF4 and GCN4. Examination of the effects of point mutations in the ATG codons of the different uORFs suggests a quantitative model for this control mechanism that describes the probability of reinitiation as a function of the distance scanned downstream from uORF1. This model accounts for the phenotypes of a number of deletion and insertion mutations that alter the intercistronic spacing between the uORFs and GCN4. The correspondence between observed and predicted results implies that the differential rates of reinitiation at GCN4 versus uORFs 2 to 4 are determined largely by the different scanning times required to reach each of these start sites following translation of uORF1. In addition, it supports the notion that an increased scanning-time requirement for reinitiation in amino acid-starved cells forms the basis for translational derepression of GCN4 expression.

Amino Acids↗