Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Computational modeling”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources
PubMedDate not supplied

[Investigation of polyamine interactions with the nuclear transcription factor NF-kappa B by computer modelling].

Computer modelling is used to study interactions between polyamines and nuclear transcription factor NF-kappa B and NF-kappa B. specific DNA complex. It is shown that polyamines can regulate interaction between NF-kappa B and the specific DNA sequence by binding to p50 subunit of NF-kappa B. A possible polyamines binding site on the surface of p50 is found. Dissociation of polyamines to p50.DNA complex is modelled. Kd of spermine, spermidine and putrescine are calculated. Conformational transition of DNA.(p50)2-->DNA.p50 + p50 is simulated. Kd of complex p50.DNA is calculated in the presence and in the absence of polyamine in the binding site on the p50. It is shown that polyamines stabilizes the inter-domain interface of p50 protein due to appearance of additional electrostatic and hydrogen bonds. Shah, Thomas and Shirahata obtained the following sequence of efficiency in facilitating NF-kappa B--DNA binding: spermine > spermidine > putrescine. The sequence of affinities of polyamines to NF-kappa B that we obtained corresponds well to the former sequence from the cited work. Our results support the hypothesis that polyamines decreases the probability of spontaneous dissociation of DNA.p50 complex.

Adenocarcinoma↗
PubMed1991

Arresting tissue invasion of a parasite by protease inhibitors chosen with the aid of computer modeling.

Computer modeling of the three-dimensional structure of an enzyme, based upon its primary sequence alone, is a potentially powerful tool to elucidate the function of enzymes as well as design specific inhibitors. The cercarial (larval) protease from the blood fluke Schistosoma mansoni is a serine protease hypothesized to assist the schistosome parasite in invading the human circulatory system via the skin. A three-dimensional model of the protease was built, taking advantage of the similarity of the sequence of the cercarial enzyme to the trypsin-like class of serine proteases. A large hydrophobic S-1 binding pocket, suspected from previous kinetic studies, was located in the model and confirmed by new kinetic studies with both synthetic peptide substrates and inhibitors. Unexpected structural characteristics of the enzyme were also predicted by the model, including a large S-4 binding pocket, again confirmed by assays with synthetic peptides. The model was then used to design a peptide inhibitor with 4-fold increased solubility, and a series of synthetic inhibitors were tested against live cercariae invading human skin to confirm that predictions of the model were also applicable in a biologic assay.

Amino Acid Sequence↗
PubMed1994

Computational modelling.

Computation modelling is playing an increasingly accepted and important role in neuroscience. It is not a unitary enterprise, though, and the distinction between two different sorts of modelling, one interested in description and the other also in function, is illustrated by their application to activity-dependent developmental plasticity and adult conditioning.

Animals↗
PubMed1998

Computer modeling and computational toxicology in new chemical and pharmaceutical product development.

A theoretical basis for use of computer modeling and bioinformatics resources including the internet in decisions about whether to attempt synthesis and toxicology testing of new chemical or pharmaceutical products is described. Steps in the process include: (1) identification of a potentially efficacious chemical or pharmaceutical product; (2) structure-activity relationship (SAR) modeling; (3) synthesis methods and cost screening; (4) market screening for potential revenues; (5) regulatory impacts screening; (6) toxicology modeling and screening; (7) decision making about whether to attempt synthesis and testing. Some such computer modeling and screening processes are already in use. Others may reasonably be expected to be adopted in the near future. More development of structure-activity and structure-toxicity databases and therapeutic and toxicity molecular endpoints computerized libraries remains to be done. The internet is a rapidly developing source of information, but there are major problems with time-effectiveness, quality control, 'junk information' (misinformation), and deliberate 'disinformation'.

Computer Simulation↗
PubMed1982

Language and the brain: implications from new computer models.

Computer systems for processing and "understanding" natural language have, up to now, used semantic and syntactic procedures that provide meanings of words in terms only of other words or some structural algorithms that ultimately relate to other words. There is a long-standing and widely held belief that words, or their unknown neuronal correlates, are fundamental to verbal meaning, concepts, and thought but over the last decade, evidence has been accumulating in neurology and psychology to indicate that this is not so. We have developed a new computer system for representing the meaning of words and sentences, by which word meanings are described non-verbally in terms of sensorimotor and other modality codes. It is suggested here that the principles of this system might usefully be applied to understanding the cerebral mechanisms of some verbal and cognitive processes and their disorders. In particular the hypothesis is proposed that verbal meaning is essentially non-verbal, and that it may be represented, for both words and sentences in terms of interassociated modal percepts or their neuronal correlates.

Brain↗
PubMed2003

Probability models and computational models for ANOVA in multicenter clinical trials.

Multicenter trials are usually analyzed by fixed-effects, two-way analysis of variance. A mixed-effects computation with random treatment-by-center interaction may produce better results even if this interaction is considered truly to be a fixed effect. It may be more appropriate, however, to consider the treatment-by-center interaction to be a random effect, anyway.

Analysis of Variance↗
PubMed2006

In silico ADME modelling 2: computational models to predict human serum albumin binding affinity using ant colony systems.

Modelling of in vitro human serum albumin (HSA) binding data of 94 diverse drugs and drug-like compounds is performed to develop global predictive models that are applicable to the whole medicinal chemistry space. For this aim, ant colony systems, a stochastic method along with multiple linear regression (MLR), is employed to exhaustively search and select multivariate linear equations, from a pool of 327 molecular descriptors. This methodology helped us to derive optimal quantitative structure-property relationship (QSPR) models based on five and six descriptors with excellent predictive power. The best five-descriptor model is based on Kier and Hall valence connectivity index--Order 5 (path), Auto-correlation descriptor (Broto-Moreau) weighted by atomic masses--Order 4, Auto-correlation descriptor (Broto-Moreau) weighted by atomic polarizabilities--Order 5, AlogP98, SklogS (calculated buffer water solubility) [R=0.8942, Q=0.86790, F=62.24 and SE=0.2626]; the best six-variable model is based on Kier and Hall valence connectivity index of Order 3 (cluster), Auto-correlation descriptor (Broto-Moreau) weighted by atomic masses--Order 4, Auto-correlation descriptor (Broto-Moreau) weighted by atomic polarizabilities--Order 5, Atomic-Level-Based AI topological descriptors--AIdsCH, AlogP98, SklogS (calculated buffer water solubility) [R=0.9128, Q=0.89220, F=64.09 and SE=0.2411]. From the analysis of the physical meaning of the selected descriptors, it is inferred that the binding affinity of small organic compounds to human serum albumin is principally dependent on the following fundamental properties: (1) hydrophobic interactions, (2) solubility, (3) size and (4) shape. Finally, as the models reported herein are based on computed properties, they appear to be a valuable tool in virtual screening, where selection and prioritisation of candidates is required.

Algorithms↗
PubMed1991

Computer modeling of synapsin I binding to synaptic vesicles and F-actin: implications for regulation of neurotransmitter release.

Synapsin I is a neuron-specific phosphoprotein that binds to small synaptic vesicles and actin filaments in a phosphorylation-dependent fashion. It has been hypothesized that dephosphorylated synapsin I inhibits neurotransmitter release either by forming a cage around synaptic vesicles (cage model) or by anchoring them to the F-actin cytoskeleton of the nerve terminal (crosslinking model). Computer modeling was performed with the aim of testing the impact of phosphorylation on the molecular interactions of synapsin I within the nerve terminal. The results of the simulation experiments demonstrate that in the crosslinking model the phosphorylation of synapsin I causes a severalfold increase in the number of vesicles released from the cytoskeleton and that in the cage model the phosphorylation induces a 2-fold increase in the number of vesicles bearing one or more unsaturated synapsin I binding sites. These data are compatible with the view that the function of synapsin I in the short-term regulation of neurotransmitter release is to induce a phosphorylation-dependent transition of synaptic vesicles from a "reserve pool" to a readily "releasable pool" of vesicles.

Actins↗
PubMed2002

The genetic absence epilepsy rat from Strasbourg (GAERS), a rat model of absence epilepsy: computer modeling and differential gene expression.

PURPOSE: We present results obtained by computer modeling of the thalamic network and differential gene expression analysis in a rat strain with absence epilepsy, the genetic absence epilepsy rat from Strasbourg (GAERS). METHODS: (a) Computer modeling used equations from the Hodgking-Huxley model with a circuit of 13 reticular thalamic (nRt) and 39 thalamocortical (TC) neurons; (b) gene-expression analysis using differential mRNA display (DD), in situ hybridization, Northern blotting, and competitive reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS: (a) Computer modeling showed an increased network synchrony in the thalamic circuit as the value of conductance of low-voltage activated calcium channel (LVACC) is increased. (b) Using differential mRNA display, a 40% upregulation of the H-ferritin mRNA in the hippocampus was demonstrated. Looking for some candidate genes of the VACC family, no difference was found in the alpha1G mRNA expression between GAERS and control animals, whereas a decreased expression of the alpha1E subunit was observed in the cerebellum and the brainstem of the GAERS. This phenomenon was not observed in young animals when the epileptic phenotype is not expressed. CONCLUSIONS: The use of computer modeling appeared to be an efficient way to evaluate the impacts of electrophysiologic findings in vivo from single cells on an entire circuit. No clear single gene defect was revealed so far in GAERS. More information could arise from linkage analysis. However, some brain structures like hippocampus or cerebellum classically not known to be involved in the production of absence spike-and-wave discharges could in fact participate in the development of this phenotype.

Animals↗
PubMedDate not supplied

Studies of reproductive cyclicity: evaluation of computer modeling as a tool.

Assessment of toxic effects on human reproductive function using fetal health or teratogenic criteria presumes the conditions of parental fertility. Toxins that compromise fecundity through derangement of the menstrual cycle may require quite different models and criteria. Nonlinear dynamic interactions of the hormonal and morphological components of the menstrual cycle add to the difficulty of such studies. With appropriate mathematical models, computer simulation can provide a useful guide to the design and conduct of in vivo experiment.

Computer Simulation↗
PubMed2002

Energy and phase orientation mechanisms: a computational model.

A computational model is proposed for spatial orientation processing beyond the initial stage of linear filtering in visual cortex. The model accounts for orientation pop-out, edge location and orientation, and bar location and orientation. It naturally extends to higher order orientation symmetries. The model is consistent with much of the current understanding of early processing in mammalian visual cortex. It builds on the notions of orientation and spatial frequency specific simple cells, any subsequent non-linearity, and orientation 'pooling'. The processing treats simple cell energy, real, and imaginary responses in a unified way to generate 'feature maps'. The 'pooling' operation in each case is a discrete Fourier transform of the simple cell responses over orientation. The suggested processing has implications for psychophysics (e.g. providing an explanation of why orientation discrimination thresholds are more than an order of magnitude less than simple cell orientation bandwidths), provides some understanding of the variety of 'complex-cell' properties found in visual cortex, and provides a plausible starting point for subsequent processing.

Computer Simulation↗
PubMed2006

Dimerization of the lutropin receptor: insights from computational modeling.

A computational approach based upon rigid-body docking, ad hoc filtering, and cluster analysis has been carried out to predict likely interfaces in LHR homodimers. Quaternary structure predictions emphasize the role of helices 4, 5 and 6, with prominence to helix 4, in mediating inter-monomer interactions. Intermolecular interactions essentially involve the transmembrane domains rather than the hydrophilic loops and do not implicate disulfide bridges.Collectively, molecular dynamics simulations on the isolated receptor and computational modeling of LHR homodimerization suggest that mutation-induced LHR activation favors H4-H4 contacts involving the highly conserved W491 from both the receptors monomers.

Amino Acid Sequence↗
PubMed2001

Basic principles of synaptic physiology illustrated by a computer model.

A computer model is described that simulates many basic aspects of chemical synapse physiology. The model consists of two displays, the first being a pictorial diagram of the anatomical connections between two presynaptic neurons and one postsynaptic neuron. Either or both of the presynaptic cells can be stimulated from a control panel with variable control of the number of pulses and firing rate; the resulting presynaptic action potentials are animated. The second display plots the membrane potential of the postsynaptic cell versus time following presynaptic stimulation. The model accurately simulates temporal and spatial summation when the presynaptic cells are arranged and stimulated in parallel and simulates presynaptic inhibition when they are arranged and stimulated in series. Excitatory and inhibitory postsynaptic potentials can be demonstrated by altering the nature of the ionic conductance change occurring on the postsynaptic cell. The effects on summation of changing length constant or time constant of the postsynaptic cell can also be illustrated. The model is useful for teaching these concepts to medical, graduate, or undergraduate students and can also be used as a self-directed computer laboratory exercise. It is available for free download from the internet.

Computer Simulation↗
PubMed2006

Auditory-nerve first-spike latency and auditory absolute threshold: a computer model.

A computer model of the auditory periphery was used to address the question of what constitutes the physiological substrate of absolute auditory threshold. The model was first evaluated to show that it is consistent with experimental findings that auditory-nerve fiber spikes can be predicted to occur when the running integral of stimulus pressure reaches some critical value [P. Heil and H. Neubauer, J. Neurosci. 15, 7404-7415 (2001)]. It was then modified to examine two ways in which the accumulation and clearance of receptor presynaptic calcium might explain this effect. Both methods gave results that matched the animal data. It was also shown how the rate of clearance of presynaptic calcium could be used to explain the origin of differences between low and high spontaneous-rate fiber types. When spiking activity is aggregated across a number of similar high spontaneous-rate fibers and used as the input to a model of a cochlear nucleus coincidence neuron, its response can be used to judge whether or not a stimulus is present. A simulated psychophysical experiment then demonstrated that this simple decision procedure can reproduce measurements of absolute auditory threshold for tones in quiet where the threshold is a joint function of both time and level.

Acoustic Stimulation↗
PubMed1994

Antiresorptive drugs and trabecular bone turnover: validation and testing of a computer model.

A computer model of trabecular bone turnover has been developed, based on concepts of Jonathan Reeve [1]. This model predicts changes in bone volume by summing bone resorption and formation over a large number of remodeling sites. Clinical data [histomorphometry and bone mineral content (BMC)] from two clinical studies using an antiresorptive drug (etidronate disodium, EHDP) in postmenopausal osteoporosis were used to test the model. The results for BMC obtained from the EHDP and placebo groups in each study at 60 and 120 weeks were correctly predicted by the model from the histomorphometric data obtained from baseline and week 60 biopsies. The parameter in this model having the greatest influence on predicted changes in bone volume was found by sensitivity analysis to be activation frequency. These results suggest that the contribution of bone turnover to BMC can be predicted solely by considering the cell kinetics of the basic multicellular unit (BMU), and that, in the case of antiresorptive drugs, maximal effects on bone volume may be achieved by pharmacological reduction of activation frequency. The results also suggest that the present model may be useful in predicting in clinical studies the effects of EHDP and similar drugs on bone turnover.

Absorptiometry, Photon↗
PubMedDate not supplied

Wideband inhibition of dorsal cochlear nucleus type IV units in cat: a computational model.

A computational model of a portion of dorsal cochlear nucleus neural circuitry was used to investigate relationships between connectivity and response properties of type IV units. The model in this study consists of four neural populations. The pattern of convergence from one population to another and the strengths of those connections are the most important model parameters. Lumped parameter electrical circuit models represent individual cells. Interconnections are achieved by activating variable conductances in post-synaptic cells according to spike activity in pre-synaptic cells. Auditory nerve fibers are incorporated as a bank of logarithmically spaced gammatone filters that drive compartmental models of inner hair cell function. While it might be possible to configure the model without wideband inhibition to simulate type IV unit notch noise responses, the resulting parameters would likely be physiologically implausible. The model with wideband inhibition, however, shows the appropriate notch noise behavior. A wide variety of simulated rate versus cutoff-frequency plots are achieved varying three model parameters. The model was fit to physiological data by finding values of these three parameters that minimize the sum of squared errors. The results show that wideband inhibition can quantitatively account for the responses of type IV units to notch noise.

Acoustic Stimulation↗
PubMed1992

A computer model to predict the effects of level of nutrition on composition of empty body gain in beef cattle: II. Evaluation of the model.

A computer model developed to predict composition of empty body gain of beef cattle fed at different levels of nutrition was evaluated with data from one unpublished and seven published experiments. These experiments used several breeds of beef cattle growing at rates that varied from negative to fast and various combinations of these growth rates. There was close agreement between observed and simulated absolute treatment means for fatness, except when animals were fed diets low in protein. In this case, experimental animals fed inadequate protein grew at slower rates and became fatter than contemporaries fed adequate protein, whereas the model predicted the opposite. Ability of the model to predict effects of nutrition not associated with changes in BW was evaluated using the proportion of residual variation in experimental fat percentage accounted for by the model, after fitting linear and quadratic terms for empty BW. The model accounted for 13.8 to 56.2% of the residual variation in observed fatness in four experiments in which significant differences in fatness were observed among nutritional treatments after accounting for differences in empty BW. Regression of observed fatness on model-simulated fatness resulted in regression coefficients that were positive and close to 1 in these four experiments. This suggests that the model can accurately predict some of the effects of nutrition on fatness that are not associated with changes in empty BW.

Adipose Tissue↗