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At least 343 records · Page 19Linked to original sources
PubMed1987

Computer model of the absorption and distribution of colostral immunoglobulins in the newborn calf.

The transfer of immunoglobulin (Ig) isotypes (IgG1, IgG2, IgM), gamma-glutamyl transpeptidase (gamma-GT) and added D-xylose from colostrum to serum was investigated in newborn Holstein bull calves. Significant differences were observed in the time courses of the serum concentrations of these colostrum constituents following absorption from pooled colostrum. A computer model was devised to simulate the process of absorption of Ig isotypes, gamma-GT and D-xylose from colostrum in the newborn calf. A Fortran program was used to generate plots of the time course of the concentration of colostrum constituents in serum and other body fluids following a single feed of colostrum. These plots show how the changes in serum concentration of absorbed Ig isotypes, gamma-GT and D-xylose are affected by different rates of intestinal absorption, redistribution in body fluids and removal from plasma. A critical examination of data from the computer model and from the calf feeding experiments supports the view that the absorption of IgG1, IgG2 and IgM is not selective in the calf. The data were compared with earlier studies of the efficiency of the colostral transfer of Ig to the calf. In the present study the transfer efficiencies of IgG1, IgG2, IgM, gamma-GT and D-xylose were 46 per cent, 49 per cent, 47 per cent, 18 per cent and 21 per cent, respectively.

Animals↗
PubMed2005

Computational modeling of the immune response to tumor antigens.

Vaccination protocols designed to elicit anti-cancer immune responses have, many times, failed in producing tumor eradication and in prolonging patient survival. Usually in cancer vaccination, epitopes from one organism are included in the genome or linked with some protein of another in the hope that the immunogenic properties of the latter will boost an immune response to the former. However, recent results have demonstrated that injections of two different vectors encoding the same recombinant antigen generate high levels of specific immunity. Systematic comparison of the efficacy of different vaccination protocols has been hampered by technical limitations, and clear evidence that the use of multiple vectors has advantages over single carrier injections is lacking. We used a computational model to investigate the dynamics of the immune response to different anti-cancer vaccines based on randomly generated antigen/carrier compounds. The computer model was adapted for simulations to this new area in immunology research and carefully validated to the purpose. As a matter of fact, it reproduces a relevant number of experimental observations. The model shows that when priming and boosting with the same construct, competition rather than cooperation develops amongst T cell clones of different specificities. Moreover, from the simulations, it appears that the sequential use of multiple carriers may generate more robust anti-tumor immune responses and may lead to effective tumor eradication in a higher percentage of cases. Our results provide a rational background for the design of novel strategies for the achievement of immune control of cancer.

Animals↗
PubMedDate not supplied

Computer modeling of cytokeratin release in clinical oncology.

The levels of cytokeratins (CK) in serum of cancer patients have been widely used for monitoring progression of cancer growth and the effectiveness of cancer treatment. Previous studies have shown that the release of CK by tumors in patients is a complex process which depends on the rate of cell damage caused by an increasing tumor mass, or by the tumor treatment, but is not in any simple manner correlated to the number of proliferating cells or to the total tumor mass (1). The complexity of the CK-releasing process has been analyzed by a computer model which mimics the progress of tumor growth, allows the introduction of different types of treatment (i.e. irradiation, chemotherapy and surgery), and computes the amount of CK released by the tumor, and the level of CK in blood and blood clearance. The computer model can be used to obtain a better understanding of the interactions of various factors, for scheduling of treatment and CK sampling, and for analyzing the effects of treatment.

Biomarkers, Tumor↗
PubMed1990

A computer model of the heart that obeys Starling's law.

We developed a computer model of the heart that accurately reproduces human left ventricular pressure wave morphology. The model factors beat-to-beat venous return in generating cardiac output and simulates congestive heart failure when the venous return exceeds the heart's pumping capacity. The blood pressure waveform produced by our model resembles experimental data with a greater than 98% correlation and the model incorporates Starling's transfer function. The model is useful for simulations of cardiovascular hemodynamics where accurate waveforms and venous return feedback or modeling failing hearts are important.

Blood Pressure↗
PubMed2003

Computational modeling of foveal target detection.

This paper presents the VDM2000, a computational model of target detection designed for use in military developmental test and evaluation settings. The model integrates research results from the fields of early vision, object recognition, and psychophysics. The VDM2000 is image based and provides a criterion-independent measure of target conspicuity, referred to as the vehicle metric (VM). A large data set of human responses to photographs of military vehicles in a field setting was used to validate the model. The VM adjusted by a single calibration parameter accounts for approximately 80% of the variance in the validation data. The primary application of this model is to predict detection of military targets in daylight with the unaided eye. The model also has application to target detection prediction using infrared night vision systems. The model has potential as a tool to evaluate the visual properties of more general task settings.

Calibration↗
PubMed2000

Conceptual comparison of two computer models of corpuscle sectioning and of two algorithms for correction of ploidy measurements in tissue sections.

OBJECTIVE: To compare two computer models of corpuscle sectioning and two algorithms for correction of ploidy measurements in tissue sections. STUDY DESIGN: Two models of corpuscle sectioning (the computed corpuscle sectioning program [CCSP] [Analyt Quant Cytol Histol 1997;19:376-386] and the ellipsoid sectioning program [ESP]) were run on a personal computer to generate synthetic corpuscle section data that model the sectioned nuclei in a tissue section. These synthetic data were analyzed by two algorithms for correction of ploidy measurements in tissue sections: the reference curve method (RCM) (Analyt Quant Cytol Histol 1997;19:376-386) and the method of McCready and Papadimitriou (MMP) (Analyt Quant Cytol 1983;5:117-123) for a variety of choices of section thickness and of nuclear section profile selection criteria. RESULTS: Previous recommendations (Analyt Quant Cytol Histol 1999;21:103-112) for optimization of ploidy analysis in tissue sections (selection of only center-containing sections of nuclei in ultrathin sections with a selection bias in favor of elliptical nuclear section profiles) are valid regardless of which corpuscle sectioning model and correction algorithm are employed. Perimeter correction may be desirable or necessary in some cases. The RCM has very significant advantages over the MMP, and the CCSP is more applicable to actual ploidy analysis than is the ESP. CONCLUSION: The RCM always should be used to correct ploidy measurements in tissue sections. The MMP should not be used as the sole method but, when used, should be used with and interpreted in the context of the RCM.

Algorithms↗
PubMed2002

Computer modeling of three-dimensional structure of DNA-packaging RNA (pRNA) monomer, dimer, and hexamer of Phi29 DNA packaging motor.

A striking common feature in the maturation of all linear double-stranded DNA viruses is that their lengthy genome is translocated with remarkable velocity into the limited space within a preformed protein shell and packaged into near crystalline density. A DNA-translocating motor, powered by ATP hydrolysis, accomplishes this task, which would otherwise be energetically unfavorable. DNA-packaging RNA, pRNA, forms a hexameric complex to serve as a vital component of the DNA translocating motor of bacterial virus Phi29. The sequential action of six pRNA ensures continual function in the DNA translocation process. The Phi29 motor has been assembled with purified components synthesized by chemical or biotechnological approaches and is able to pump the viral DNA into the protein shell in vitro. pRNA dimers are the building blocks of the hexamer. The computer models of the three-dimensional structure of the motor was constructed based on experimental data derived from photoaffinity cross-linking by psoralen, phenphi (cis-Rh(1,10-phenanthroline)(9,10-phenan-threnequinone diimine)Cl(2)(+)), and azidophenacyl; chemical modification and chemical modification interference with dimethyl sulfate, 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluene sulfonate, and kethoxal; complementary modification; and nuclease probing by single- and double-stranded specific RNases. The shapes of these computer models are very similar to the published pRNA images of cryo-atomic force microscopy. pRNA hexamer docking with the connector crystal structure reveals a very impressive match with the available biochemical, genetic, and physical data.

Bacteriophages↗
PubMed2006

A novel computational model of the circadian clock in Arabidopsis that incorporates PRR7 and PRR9.

In plants, as in animals, the core mechanism to retain rhythmic gene expression relies on the interaction of multiple feedback loops. In recent years, molecular genetic techniques have revealed a complex network of clock components in Arabidopsis. To gain insight into the dynamics of these interactions, new components need to be integrated into the mathematical model of the plant clock. Our approach accelerates the iterative process of model identification, to incorporate new components, and to systematically test different proposed structural hypotheses. Recent studies indicate that the pseudo-response regulators PRR7 and PRR9 play a key role in the core clock of Arabidopsis. We incorporate PRR7 and PRR9 into an existing model involving the transcription factors TIMING OF CAB (TOC1), LATE ELONGATED HYPOCOTYL (LHY) and CIRCADIAN CLOCK ASSOCIATED (CCA1). We propose candidate models based on experimental hypotheses and identify the computational models with the application of an optimization routine. Validation is accomplished through systematic analysis of various mutant phenotypes. We introduce and apply sensitivity analysis as a novel tool for analyzing and distinguishing the characteristics of proposed architectures, which also allows for further validation of the hypothesized structures.

Arabidopsis↗
PubMed1990

Population dynamics of Trichostrongylus colubriformis in sheep: computer model to simulate grazing systems and the evolution of anthelmintic resistance.

A computer model was developed to simulate Trichostrongylus colubriformis populations, their level of resistance to the common anthelmintics, host mortalities and acquired immunity. Predictions were based on sheep management practices such as lambing, weaning, sheep/paddock rotation, anthelmintic treatment, the use of controlled release devices (capsules) for anthelmintic delivery and daily meteorological records to determine the development and survival of infective larvae (L3) on pasture. Evolution of drug resistance was determined by a simple genetic system which allowed for up to three genes, each with two alleles, to give a maximum of 27 genotypes associated with one drug or three genotypes for each of three drugs. The model was validated against egg counts, L3 counts on pasture and host mortalities observed in a grazing trial, however, aspects of the model such as the development of drug resistance and use of the model in a variety of climatic zones have yet to be tested against field observations. The model was used to examine the impact of grazing management and capsule use on anthelmintic resistance and sheep production over 20 years using historical weather data. Predictions indicated that grazing management can play a dominant role in parasite control and that capsule use will reduce sheep mortalities and production losses, and in some circumstances will not cause a substantial increase in anthelmintic resistance for up to 5 years.

Animals↗
PubMed2003

Computational modeling and experimental analysis of nonsense-mediated decay in yeast.

A conserved mRNA surveillance system, referred to as nonsense-mediated decay (NMD), exists in eukaryotic cells to degrade mRNAs containing nonsense codons. This process is important in checking that mRNAs have been properly synthesized and functions, at least in part, to increase the fidelity of gene expression by degrading aberrant mRNAs that, if translated, would produce truncated proteins. Using computational modeling and experimental analysis, we define the alterations in mRNA turnover triggered by NMD in yeast. We demonstrate that the nonsense-containing transcripts are efficiently recognized, targeted for deadenylation-independent decapping, and show NMD triggered accelerated deadenylation regardless of the position of the nonsense codon. We also show that 5' nonsense codons trigger faster rates of decapping than 3' nonsense codons, thereby providing a mechanistic basis for the polar effect of NMD. Finally, we construct a computational model that accurately describes the process of NMD and serves as an explanatory and predictive tool.

Adenine↗
PubMed1998

The design, computer modeling, solution structure, and biological evaluation of synthetic analogs of bryostatin 1.

The bryostatins are a unique family of emerging cancer chemotherapeutic candidates isolated from marine bryozoa. Although the biochemical basis for their therapeutic activity is not known, these macrolactones exhibit high affinities for protein kinase C (PKC) isozymes, compete for the phorbol ester binding site on PKC, and stimulate kinase activity in vitro and in vivo. Unlike the phorbol esters, they are not first-stage tumor promoters. The design, computer modeling, NMR solution structure, PKC binding, and functional assays of a unique class of synthetic bryostatin analogs are described. These analogs (7b, 7c, and 8) retain the putative recognition domain of the bryostatins but are simplified through deletions and modifications in the C4-C14 spacer domain. Computer modeling of an analog prototype (7a) indicates that it exists preferentially in two distinct conformational classes, one in close agreement with the crystal structure of bryostatin 1. The solution structure of synthetic analog 7c was determined by NMR spectroscopy and found to be very similar to the previously reported structures of bryostatins 1 and 10. Analogs 7b, 7c, and 8 bound strongly to PKC isozymes with Ki = 297, 3.4, and 8.3 nM, respectively. Control 7d, like the corresponding bryostatin derivative, exhibited weak PKC affinity, as did the derivative, 9, lacking the spacer domain. Like bryostatin, acetal 7c exhibited significant levels of in vitro growth inhibitory activity (1.8-170 ng/ml) against several human cancer cell lines, providing an important step toward the development of simplified, synthetically accessible analogs of the bryostatins.

Animals↗
PubMed1994

Refractory period prolongation by biphasic defibrillator waveforms is associated with enhanced sodium current in a computer model of the ventricular action potential.

Mechanisms through which biphasic waveforms lower defibrillation threshold are unknown. Previous work showed that low-intensity biphasic shocks (BS2), delivered during the refractory period of a control action potential (S1), produced significantly longer responses than monophasic shocks (MS2). To test the hypothesis that longer responses are due to hyperpolarization-induced excitation channel recovery during the first portion of the biphasic waveform, we used the Beeler-Reuter ventricular action potential computer model with the Drouhard-Roberge (BRDR) modification to study refractory period stimulation with MS2 (10 msec) and symmetrical BS2 (10 msec each pulse). At 1.5 times diastolic threshold, BS2 prolonged action potential duration when delivered 50 msec into the S1 refractory period, and produced a maximum BS2 versus MS2 response duration difference of 62 msec. Longer BS2 responses corresponded to enhanced BS2-induced sodium current compared to MS2. Maximum BS2 vs MS2 sodium current difference was 400 uA/cm2. These results show that, in a computer model of the ventricular action potential, hyperpolarization by the first phase of a biphasic waveform enhances S2 sodium current and prolongs duration of refractory-period responses. This effectively shortens the cellular refractory period. Prolonged refractory period responses, produced by biphasic defibrillator waveforms, may underlie enhanced defibrillating efficacy at low shock intensities.

Action Potentials↗
PubMed2000

Two-phase computational model training long-term memories in the entorhinal-hippocampal region.

The computational model described here is driven by the hypothesis that a major function of the entorhinal cortex (EC)-hippocampal system is to alter synaptic connections in the neocortex. It is based on the following postulates: (1) The EC compares the difference between neocortical representations (primary input) and feedback information conveyed by the hippocampus (the "reconstructed input"). The difference between the primary input and the reconstructed input (termed "error") initiates plastic changes in the hippocampal networks (error compensation). (2) Comparison of the primary input and reconstructed input requires that these representations are available simultaneously in the EC network. We suggest that compensation of time delays is achieved by predictive structures, such as the CA3 recurrent network and EC-CA1 connections. (3) Alteration of intrahippocampal connections gives rise to a new hippocampal output. The hippocampus generates separated (independent) outputs, which, in turn, train long-term memory traces in the EC (independent components, IC). The ICs of the long-term memory trace are generated in a two-step manner, the operations of which we attribute to the activities of the CA3 (whitening) and CA1 (separation) fields. (4) The different hippocampal fields can perform both nonlinear and linear operations, albeit at different times (theta and sharp phases). We suggest that long-term memory is represented in a distributed and hierarchical reconstruction network, which is under the supervision of the hippocampal output. Several of these model predictions can be tested experimentally.

Computer Simulation↗
PubMedDate not supplied

The maintained discharge of neurons in the cat lateral geniculate nucleus: spectral analysis and computational modeling.

The maintained discharge of neurons along the early visual pathway in mammals constitutes the "noise" from which the visual signal must be discriminated. The statistics of this background noise in cat retinal ganglion cells (RGCs) have been shown to conform to that of a gamma-distributed renewal process (Kuffler et al., 1957; Barlow & Levick, 1969), and power spectrum analysis reveals that this property allows for low noise levels at the temporal-frequency range (0-10 Hz) most important for visual performance (Troy & Robson, 1992). In this study, we compare the statistics of the maintained discharge of cat lateral geniculate neurons with those of its RGC input by simultaneous recordings of spikes and S-potentials in single relay cells of the cat lateral geniculate nucleus (LGN). We demonstrate that, during primarily tonic spiking activity, the LGN maintained discharge preserves the renewal process statistics of its RGC input and also generates relatively little noise at the temporal frequencies important for vision. However, during burst spiking activity, the renewal process model breaks down and increased noise is generated at 2-10 Hz. This suggests that optimization of the visual signal/noise ratio is not a prime consideration in the behavioral states associated with bursting activity in the LGN. The occurrence of burst spikes in LGN relay cells is dependent on the activity of T-type calcium channels in their plasma membranes (Jahnsen & Llinas, 1984a,b). We show that a computational model of LGN relay cells that incorporates T-channel kinetics (Mukherjee & Kaplan, 1995) can correctly simulate LGN maintained discharge statistics during both tonic and bursty firing conditions, and indicates an essential role for this ion channel in determining the dynamic noise properties of the LGN. We also use the computational model to predict how the burstiness of the LGN maintained discharge is affected by the statistics of its RGC input.

Action Potentials↗
PubMed2006

Neighborhood effects in reading aloud: new findings and new challenges for computational models.

A word from a dense neighborhood is often read aloud faster than a word from a sparse neighborhood. This advantage is usually attributed to orthography, but orthographic and phonological neighbors are typically confounded. Two experiments investigated the effect of neighborhood density on reading aloud when phonological density was varied while orthographic density was held constant, and vice versa. A phonological neighborhood effect was observed, but not an orthographic one. These results are inconsistent with the predominant role ascribed to orthographic neighbors in accounts of visual word recognition and reading aloud. Consistent with this interpretation, 6 different computational models of reading aloud failed to simulate this pattern of results. The results of the present experiments thus provide a new understanding of some of the processes underlying reading aloud, and new challenges for computational models.

Attention↗
PubMed2004

Computational modeling of retinotopic map development to define contributions of EphA-ephrinA gradients, axon-axon interactions, and patterned activity.

The topographic projection of retinal ganglion cell (RGC) axons to mouse superior colliculus (SC) or chick optic tectum (OT) is formed in three phases: RGC axons overshoot their termination zone (TZ); they exhibit interstitial branching along the axon that is topographically biased for the correct location of their future TZ; and branches arborize preferentially at the TZ and the initial exuberant projection refines through axon and branch elimination to generate a precise retinotopic map. We present a computational model of map development that demonstrates that the countergradients of EphAs and ephrinAs in retina and the OT/SC and bidirectional repellent signaling between RGC axons and OT/SC cells are sufficient to direct an initial topographic bias in RGC axon branching. Our model also suggests that a proposed repellent action of EphAs/ephrinAs present on RGC branches and arbors added to that of EphAs/ephrinAs expressed by OT/SC cells is required to progressively restrict branching and arborization to topographically correct locations and eliminate axon overshoot. Simulations show that this molecular framework alone can develop considerable topographic order and refinement, including axon elimination, a feature not programmed into the model. Generating a refined map with a condensed TZ as in vivo requires an additional parameter that enhances branch formation along an RGC axon near sites that it has a higher branch density, and resembles an assumed role for patterned neural activity. The same computational model generates the phenotypes reported in ephrinA deficient mice and Isl2-EphA3 knockin mice. This modeling suggests that gradients of counter-repellents can establish a substantial degree of topographic order in the OT/SC, and that repellents present on RGC axon branches and arbors make a substantial contribution to map refinement. However, competitive interactions between RGC axons that enhance the probability of continued local branching are required to generate precise retinotopy.

Animals↗
PubMed1978

A computer model in the selection of multiple channel analysers.

1. A simple computer model is described which was used to study possible test combinations on automated multichannel analysers. Specific objectives were minimisation of manpower and maximisation of throughput of the specimen preparation process. 2. In our case, by appropriate test combination selection, a staff saving of 50% in the aliquotting process is predicted. For tests that are available on multichannel analysers, a reduction from 198 to 121 aliquots per 100 patient specimens is expected on an 18 channel machine. With the use of filter separation systems, manual aliquotting would be required for 21 specimens per 100.

Autoanalysis↗
PubMedDate not supplied

[Computer modeling the cytochrome P450 three-dimensional structure: problems and prospects].

The review is devoted to the description of basic approaches, problems and prospects of computer modelling of 3D structures of cytochromes P450 (P450s). The following questions have been are considered in the review: (1) the role of computer molecular modelling in P450s research; (2) basic stages of homology modelling of protein 3D structures; (3) purposes and tasks of molecular modelling; (4) problems of P450s homology modelling; (5) criteria for successful P450s homology modelling; (6) methods of P450s models refinement, verification of correctness and reliability.

Amino Acid Sequence↗