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PubMedDate not supplied

Computational modeling of oligonucleotide positional densities for human promoter prediction.

OBJECTIVE: The gene promoter region controls transcriptional initiation of a gene, which is the most important step in gene regulation. In-silico detection of promoter region in genomic sequences has a number of applications in gene discovery and understanding gene expression regulation. However, computational prediction of eukaryotic poly-II promoters has remained a difficult task. This paper introduces a novel statistical technique for detecting promoter regions in long genomic sequences. METHOD: A number of existing techniques analyze the occurrence frequencies of oligonucleotides in promoter sequences as compared to other genomic regions. In contrast, the present work studies the positional densities of oligonucleotides in promoter sequences. The analysis does not require any non-promoter sequence dataset or any model of the background oligonucleotide content of the genome. The statistical model learnt from a dataset of promoter sequences automatically recognizes a number of transcription factor binding sites simultaneously with their occurrence positions relative to the transcription start site. Based on this model, a continuous naïve Bayes classifier is developed for the detection of human promoters and transcription start sites in genomic sequences. RESULTS: The present study extends the scope of statistical models in general promoter modeling and prediction. Promoter sequence features learnt by the model correlate well with known biological facts. Results of human transcription start site prediction compare favorably with existing 2nd generation promoter prediction tools.

Base Sequence↗
PubMed1999

Left-ventricular pressure gradients: a computer-model simulation.

Both invasive left-ventricular pressure measurements and non-invasive colour M-mode echographic measurements have shown the existence of intraventricular pressure gradients (IVPGs) during early filling. The mechanisms responsible for these IVPG cannot be completely explained by the experiments. Therefore a one-dimensional numerical model is developed and validated. The model describes filling (both velocities and pressures) along a left ventricular (LV) base-apex axis. Blood-wall interaction in the left ventricle with moving boundaries is taken into account. The computational results for a canine heart indicate that the observed IVPGs during filling are the consequence of a complex interaction between, on the one hand, pressure waves travelling in the LV and, on the other hand, LV geometry, relaxation and compliance. The computational results indicate the pressure dependency of wavespeed (0.77-1.90 m-1 s) for different mean intraventricular pressures (0.88-5.00 mmHg) and IVPGs up to 2 mmHg, independent of the ratio of end systolic volume and equilibrium volume. Increasing relaxation rate not only decreases minimum basal pressure (2.8 instead of 3.6 mmHg) but also has a strong influence on the time delay between the minimum basal and apical pressures (14 ms instead of 49 ms). The results sustain the hypothesis that pressure-wave propagation determines IVPGs and that IVPGs are no proof of elastic recoil.

Blood Pressure↗
PubMed2002

A computational model for glycogenolysis in skeletal muscle.

A dynamic model of the glycogenolytic pathway to lactate in skeletal muscle was constructed with mammalian kinetic parameters obtained from the literature. Energetic buffers relevant to muscle were included. The model design features stoichiometric constraints, mass balance, and fully reversible thermodynamics as defined by the Haldane relation. We employed a novel method of validating the thermodynamics of the model by allowing the closed system to come to equilibrium; the combined mass action ratio of the pathway equaled the product of the individual enzymes' equilibrium constants. Adding features physiologically relevant to muscle-a fixed glycogen concentration, efflux of lactate, and coupling to an ATPase--alowed for a steady-state flux far from equilibrium. The main result of our analysis is that coupling of the glycogenolytic network to the ATPase transformed the entire complex into an ATPase driven system. This steady-state system was most sensitive to the external ATPase activity and not to internal pathway mechanisms. The control distribution among the internal pathway enzymes-although small compared to control by ATPase-depended on the flux level and fraction of glycogen phosphorylase a. This model of muscle glycogenolysis thus has unique features compared to models developed for other cell types.

Adenosine Triphosphatases↗
PubMed1992

Computer modelling of glycolipids at membrane surfaces.

Interactions of membrane anchored molecules such as glycolipids with a membrane surface are important in determining headgroup conformation. It is therefore essential to represent these membrane surface interactions in molecular modeling studies of glycolipids and other membrane bound molecules. We introduce here an energy term that represents the interaction of molecules with a membrane bilayer. This membrane interaction energy term has been added to the potential energy function of a molecular dynamics and mechanics program and has been parameterized using partition coefficients between an aqueous solution and a vesicular membrane for two model glycolipids.

Biophysical Phenomena↗
PubMed2004

A computational model for anthracycline binding to DNA: tuning groove-binding intercalators for specific sequences.

Anthracycline antibiotics such as doxorubicin and its analogues have been in common use as anticancer drugs for almost half a century. There has been intense interest in the DNA binding sequence specificity of these compounds in recent years, with the hope that a compound could be identified that could possibly modulate gene expression or exhibit reduced toxicity. To computationally analyze this phenomenon, we have constructed molecular models of 65 doxorubicin analogues and their complexes with eight distinct DNA octamer sequences. The HINT (Hydropathic INTeractions) program was utilized to describe binding, including differences in the functional group contributions as well as sequence selectivity. Of these 65 compounds, two compounds were calculated to have a selectivity (the calculated DeltaDeltaG(sel) between the sequence with the strongest binding and the second strongest binding sequence) greater than -0.75 kcal mol(-1) for one sequence over all others, 10 compounds were specific between -0.50 and -0.74 kcal mol(-1), 18 compounds were specific between -0.25 and -0.49 kcal mol(-1), and 35 compounds were virtually nonspecific with a DeltaDeltaG below -0.24 kcal mol(-1). Several compounds have been identified from this study that include features which may enhance sequence selectivity, including several with a halogen in lieu of the 4'-OH in the daunosamine sugar, one compound with a nonaromatic six-membered ring (pirarubicin) in place of the 4'-OH, and a compound with an aromatic ring in the vicinity of the C(14) region (zorubicin). Removal of the methoxy group at the C(4) position on the aglycone portion also appears to add potency and selectivity (idarubicin). Overall, efficient computational methods are presented that can be utilized to analyze the free energy of binding and sequence selectivity of both known and designed analogues of doxorubicin to identify future lead compounds for further experimental research.

Anthracyclines↗
PubMed2002

Computer modelling of the chemical speciation of caesium, uranium(VI) and neptunium(V) in human duodenal fluids under fasting conditions.

A model simulating the human duodenal contents under physiologically realistic, fasting conditions was developed using the joint expert speciation system (JESS) computer program and database and used to investigate the chemical speciation of caesium, uranium(VI) and neptunium(V). Over the pH range 5.0-9.0, and the concentration range 5 x 10(-15) x 10(-5) mol dm(-3), caesium was predicted to occur predominantly as the absorbable free monovalent cation Cs+ (approximately 95%) with species such as CsHPO4- and CsCl representing the remainder. The presence or absence of sulphate at 2.1 x 10(-3) mol dm(-3) did not influence the predicted speciation. Uranium was predicted to be present entirely as a soluble, highly charged species, both in the absence and in the presence of sulphate. Between pH 5.0 and approximately 6.5 the UO2H2(PO4)2(2-) predominated, above this pH carbonate species, either UO2(CO3)4(6-) or, possibly, UO2(CO3)5(8-). At pH 8.0, and in the presence of sulphate, neptunium(V) was predicted to exist solely as the tetrasulphate species, whilst in the absence of sulphate, an array of negatively charged soluble carbonate species predominated. Studies over the pH range 5.0-9.0 predicted the formation of a spectrum of negatively charged carbonate and phosphate species, approximately 40% of the total neptunium was predicted to be present as the electrically net-neutral species NpO2HCO3 at pH6.0, approximately 20% at pH 7.0, approximately 10% at pH 7.5 and approximately 1% at pH 8.0. The observed speciation patterns of uranium and neptunium did not change over the concentration range 5 x 10(-15) - 5 x 10(-5) mol dm(-3) and no solid species were predicted to occur under the conditions simulated. Whether the predicted electrically net-neutral neptunium species or the uranium pentacarbonate species do actually occur under true physiological conditions remains to be established. The observed speciation patterns for caesium and uranium are consistent with the observed absorption of these elements by humans; however, the observations for neptunium appear to be equivocal.

Cesium Radioisotopes↗
PubMed1998

A computer model to predict composition of empty body weight changes in cattle at all stages of maturity.

We developed methods to integrate two published models that partitioned gains in empty body weight (EBW) to fat and fat-free matter. These models were based on separate mathematical formulations for growing and mature cattle. We assumed that as cattle grow from birth to maturity a transition would occur at some point in the life cycle from the growing to the mature mathematical formulation. This transition point and the rate at which the transition occurs between the two mechanisms were estimated from published data. Evaluation results with data on steers that were full-fed to grow from birth to 815 kg EBW showed that the methods used to integrate the two models provided an accurate prediction of empty body composition at final slaughter. Evaluation results with full-fed growing cattle that were slaughtered at market weights suggest that partitioning of EBW gains can be fully described by the mathematical formulation used for growing cattle. However, for cattle that were restricted in growth, then realimented, the results showed that a model with a transition to the mathematical formulation for mature cattle, during the realimentation phase, accurately predicted the observed final composition. These results suggest that the integrated model would accurately predict the changes in body composition of cattle of all ages, under different systems of nutritional management.

Animals↗
PubMed1994

Fast and efficient computer modeling of ferromagnetic seed arrays of arbitrary orientation for hyperthermia treatment planning.

PURPOSE: Effective hyperthermia treatment planning requires an ability to predict temperatures quickly and accurately from an arbitrary distribution of power. Our purpose was to design such a fast executing computer code, MGARRAY, to compute steady-state temperatures from ferromagnetic seed heating, allowing seeds to have arbitrary orientations and to be curved to permit more realistic modeling of clinical situations. We further required flexibility for the tissue domain, allowing inhomogeneity with respect to thermal conductivity and blood perfusion, as well as an arbitrary shaped boundary. METHODS AND MATERIALS: MGARRAY uses multigrid methods and a finite volume discretization to solve the Pennes bioheat transfer equation in three dimensions. We used MGARRAY to compare temperature distributions that result from an array of straight, parallel seeds and from an array of seeds that were curved and tilted randomly by 13 degrees. RESULTS: On a personal workstation the Central Processing Unit (CPU) time of MGARRAY was under 4 min. We found that the median temperature in a predetermined target volume was approximately 0.8 degrees C higher in the straight array than in the curved array. At specific locations within the target volume temperature differed by approximately 0.5-0.9 degrees C, but could differ by up to several degrees, depending on proximity to a seed and the level of blood perfusion. CONCLUSION: These differences can impact on retrospective analyses whereby temperatures at a few locations are used to infer the overall temperature field and blood perfusion levels. The flexibility and computational speed of MGARRAY could potentially lead to a substantial improvement in both retrospective and prospective hyperthermia treatment planning.

Computer Simulation↗
PubMed2000

Comparison of different computer models of the neural control system of the lower urinary tract.

This paper presents a series of five models that were formulated for describing the neural control of the lower urinary tract in humans. A parsimonious formulation of the effect of the sympathetic system, the pre-optic area, and urethral afferents on the simulated behavior are included. In spite of the relative simplicity of the five models studied, behavior that resembles normal lower urinary tract behavior as seen during an urodynamic investigation could be simulated. The models were tested by studying their response to disturbances of the afferent signal from the bladder. It was found that the inhibiting reflex that results from including the sympathetic system or the pre-optic area (PrOA) only counteracts the disturbance in the storage phase. Once micturition has started, these inhibiting reflexes are suppressed. A detrusor contraction that does not result in complete micturition similar to an unstable detrusor contraction could be simulated in a model including urethral afferents. Owing to the number of uncertainties in these models, so far no unambiguous explanation of normal and pathological lower urinary tract behavior can be given. However, these models can be used as an additional tool in studies of the mechanisms of the involved neural control.

Computer Simulation↗
PubMed1997

A simple computer model of excitable synaptically connected neurons.

The space-lumped two-variable neuron model is studied. Extension of the neural model by adding a simple synaptic current allows the demonstration of neural interactions. The production of synchronous burst activity in this simple two-neuron excitatory loop is modeled, including the influence of random background excitatory input. The ability of the neuron model to integrate inputs spatially and temporally is shown. Two refractory periods after stimuli were identified and their role in burst cessation is demonstrated. Our findings show that simple neural units without long-lasting membrane processes are capable of generating long lasting patterns of activity. The results of simulation of simple background activity suggest that an increase in background activity tends to cause decreased activity of the network. This phenomenon, as well as the existence of two refractory periods, allows for burst cessation without inhibition in this simple model.

Neural Networks, Computer↗
PubMed1996

Computer modelling of human alpha 1-antitrypsin reactive site loop behaviour under mild conditions.

Human alpha 1-antitrypsin (alpha 1-PI) is a member of the serpin superfamily of proteins. The reactive site loop (RSL) of the serpin binds to the active site of its target proteinase. Deficiency of alpha 1-antitrypsin is associated with a spontaneous conformational transition in the molecule which leads to a polymer formation. Mild conditions (1 M guanidinium.HCl), temperature and point mutations within the RSL are the factors that induce polymerisation. Initiation of this process has been associated with the disruption of a salt bridge Glu342-->Lys290. In this paper the interaction of guanidinium ion with Glu342 and Lys290 as well as the effect of this interaction on the mobility of RSL is studied by molecular modelling.

Binding Sites↗