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PubMed1997

A computer model and program for xenobiotic disposition during pregnancy.

A physiologically based pharmacokinetic computer model and program have been developed that depict internal disposition of chemicals during pregnancy in the mother and embryo/fetus. The model is based on human physiology but has been extended to simulate laboratory animal data. The model represents the distribution, metabolism, and elimination of two chemicals in both the maternal and embryo/fetal systems; the program handles the two chemicals completely independently or interactively with the two chemicals sharing routes of metabolism and/or elimination. The FORTRAN program computes the concentration of the two chemicals in 26 organs/tissues in the pregnant mother and 15 organs/tissues in the embryo/fetus using a 486DX4 or Pentium PC. Adjustments for embryo/fetal organ and tissue volumes as a function of developmental age are made utilizing the Gompertz growth equation for the developing embryo/fetus and allometric relationships for the developing organs. Various changes in the maternal compartments which could affect the distribution of a xenobiotic during pregnancy are also included in the model. Input files require estimates of binding coefficients, first- and/or second-order metabolism constants, level of interaction between the two chemicals, and dosing information. Different possible routes of administration are included (e.g., i.v., infusion, oral, dermal, and inhalation, as well as repeated doses or exposures). Regression analysis can be conducted on any combination of these various parameters to fit actual data. Output concentration-time curves are available simultaneously from all 82 differential equations. An illustrative example compares observed data with simulations for imipramine and its demethylated metabolite, desipramine, in both the maternal rat and her fetuses. Methyl mercury data for the non-pregnant and pregnant rat also are compared with human data. Based on parameters determined from analysis of rat data, the model is readjusted for human physiology and predicts human maternal and fetal tissue concentrations as a function of time.

Animals↗
PubMed2001

Computational modelling of visual attention.

Five important trends have emerged from recent work on computational models of focal visual attention that emphasize the bottom-up, image-based control of attentional deployment. First, the perceptual saliency of stimuli critically depends on the surrounding context. Second, a unique 'saliency map' that topographically encodes for stimulus conspicuity over the visual scene has proved to be an efficient and plausible bottom-up control strategy. Third, inhibition of return, the process by which the currently attended location is prevented from being attended again, is a crucial element of attentional deployment. Fourth, attention and eye movements tightly interplay, posing computational challenges with respect to the coordinate system used to control attention. And last, scene understanding and object recognition strongly constrain the selection of attended locations. Insights from these five key areas provide a framework for a computational and neurobiological understanding of visual attention.

Animals↗
PubMedDate not supplied

Estimating exposure to volatile organic compounds from municipal water-supply systems: use of a better computational model.

The Southington, Connecticut, water-supply system is characterized by a distribution network that contains more than 1 700 pipeline segments of varying diameters and construction materials, more than 186 mi (299 km) of pipe, 9 groundwater extraction wells capable of pumping more than 4 700 gal/min (0.2965 m3/s), and 3 municipal reservoirs. Volatile organic compounds, which contaminated the underlying groundwater reservoir during the 1970s, contaminated the water-supply system and exposed the town's residents to volatile organic chemicals. We applied a computational model to the water-supply system to characterize and quantify the distribution of volatile organic compounds in the pipelines, from which we estimated the demographic distribution of potential exposure to the town's residents. Based on results from modeling analyses, we concluded the following: (a) exposure to volatile organic compound contamination may vary significantly from one census block to another, even when these census blocks are adjacent to each other within a specified radius; (b) maximum spatial spread of contamination in a water-distribution system may not occur under peak demand conditions, and, therefore, maximum spatial distribution of the exposed population also may not correspond to peak demand conditions, and (c) use of the proposed computational model allows for a more refined and rigorous methodology with which to estimate census-block-level contamination for exposure assessment and epidemiologic investigations.

Algorithms↗
PubMed2005

A computational model to define the molecular causes of type 2 diabetes mellitus.

BACKGROUND: Metabolic abnormalities associated with type 2 diabetes mellitus (DM2) are caused in part by inadequate insulin action and resulting changes in gene expression in the skeletal muscle. Two recent, independent studies of human skeletal muscle biopsies from ethnically diverse DM2 patients have identified coordinated reductions in the expression of the oxidative phosphorylation (OXPHOS) genes. Whether these reductions are a consequence or a cause of impaired insulin sensitivity remains an open question. METHODS: To address this question and to define the underlying molecular causes consistent with the expression changes reported in the muscle studies, we created a large-scale computable model to analyze the molecular actions and effects of insulin on muscle gene expression. The model enables computer-aided reasoning using over 210,000 molecular relationships assembled from the DM2 literature. RESULTS: We integrated the data from these muscle biopsy studies into the model and used computer-aided causal reasoning to discover mechanisms that can link alterations in OXPHOS genes to decreases in glucose transport, insulin signaling, and risk factors associated to post-transplant diabetes mellitus. CONCLUSIONS: The emerging hypotheses describe biologic effects in DM2 and offer important cues for molecular targeted therapy.

Algorithms↗
PubMed1988

Computer models for designing hypertension experiments and studying concepts.

This paper demonstrates how computer models along with animal experiments have been used to work out the conceptual bases of hypertensive mechanisms, especially the following: (1) The renal-fluid volume pressure control mechanism has a feed-back gain for pressure control of infinity. Therefore, the chronic level to which the arterial pressure is controlled can be changed only by altering this pressure control mechanism. (2) An increase in total peripheral resistance is not sufficient by itself to cause hypertension. The only resistances in the circulatory system that, when increased, will cause hypertension are those along a restricted axis from the root of the aorta to Bowman's capsule in the kidneys. (3) Autoregulation in the peripheral vascular beds does not increase the arterial pressure in hypertension. However, autoregulation can convert high cardiac output hypertension into high peripheral resistance hypertension. (4) In a computer simulation that cannot yet be performed in animals, a simulated hypertension caused by a combination of increased renal afferent and efferent arteriolar resistances has characteristics that match almost exactly those of essential hypertension.

Animals↗
PubMed1992

A computational model of vertical signal propagation in the primary visual cortex.

A computational model of the flow of activity in a vertically organized slab of cat primary visual cortex (area 17) has been developed. The membrane potential of each cell in the model, as a function of time, is given by the solution of a system of first order, coupled, non-linear differential equations. When firing threshold is exceeded, an action potential waveform is "pasted" in. The behavior of the model following a brief simulated stimulus to afferents from the dorsal lateral geniculate nucleus (dLGN) is explored. Excitatory and inhibitory post-synaptic potential (E and IPSP) latencies, as a function of cortical depth, were generated by the model. These data were compared with the experimental literature. In general, good agreement was found for EPSPs. Many disynaptic inhibitory inputs were found to be "masked" by the firing of action potentials in the model. To our knowledge this phenomenon has not been reported in the experimental literature. The model demonstrates that whether a cell exhibits disynaptic or polysynaptic PSP latencies is not a fixed consequence of anatomical connectivity, but rather, can be influenced by connection strengths, and may be influenced by the ongoing pattern of activity in the cortex.

Action Potentials↗
PubMed2004

Computational models of epileptiform activity in single neurons.

A series of original computational models written in NEURON of increasing physiological and morphological complexity were developed to determine the dominant causes of epileptiform behavior. Current injections to a model hippocampal pyramidal neuron consisting of three compartments produced the sustained depolarizations (SD) and simple paroxysmal depolarizing shifts (PDS) characteristic of ictal and interictal behavior in a cell, respectively. Our results indicate that SDs are the result of the semi-saturation of Na+, Ca2+ and K+ active channels, particularly the CaN, with regular Na+/K+ spikes riding atop a saturated depolarization; PDS rides on a similar semi-saturated depolarization whose shape depends more heavily on interactions between low-threshold voltage-gated Ca2+ channels (CaT) and Ca(2+)-dependent K+ channels. Our results reflect and predict recent physiological data, and we report here a cellular basis of epilepsy whose mechanisms reside mainly in the membrane channels, and not in specific morphology or network interactions, advancing a possible resolution to the cellular/network debate over the etiology of epileptiform activity.

Action Potentials↗
PubMed2005

A computational model of mitochondrial deoxynucleotide metabolism and DNA replication.

We present a computational model of mitochondrial deoxynucleotide metabolism and mitochondrial DNA (mtDNA) synthesis. The model includes the transport of deoxynucleosides and deoxynucleotides into the mitochondrial matrix space, as well as their phosphorylation and polymerization into mtDNA. Different simulated cell types (cancer, rapidly dividing, slowly dividing, and postmitotic cells) are represented in this model by different cytoplasmic deoxynucleotide concentrations. We calculated the changes in deoxynucleotide concentrations within the mitochondrion during the course of a mtDNA replication event and the time required for mtDNA replication in the different cell types. On the basis of the model, we define three steady states of mitochondrial deoxynucleotide metabolism: the phosphorylating state (the net import of deoxynucleosides and export of phosphorylated deoxynucleotides), the desphosphorylating state (the reverse of the phosphorylating state), and the efficient state (the net import of both deoxynucleosides and deoxynucleotides). We present five testable hypotheses based on this simulation. First, the deoxynucleotide pools within a mitochondrion are sufficient to support only a small fraction of even a single mtDNA replication event. Second, the mtDNA replication time in postmitotic cells is much longer than that in rapidly dividing cells. Third, mitochondria in dividing cells are net sinks of cytoplasmic deoxynucleotides, while mitochondria in postmitotic cells are net sources. Fourth, the deoxynucleotide carrier exerts the most control over the mtDNA replication rate in rapidly dividing cells, but in postmitotic cells, the NDPK and TK2 enzymes have the most control. Fifth, following from the previous hypothesis, rapidly dividing cells derive almost all of their mtDNA precursors from the cytoplasmic deoxynucleotides, not from phosphorylation within the mitochondrion.

Animals↗
PubMed2001

Computational modeling of RBC and neutrophil transit through the pulmonary capillaries.

A computational model of the pulmonary microcirculation is developed and used to examine blood flow from arteriole to venule through a realistically complex alveolar capillary bed. Distributions of flow, hematocrit, and pressure are presented, showing the existence of preferential pathways through the system and of large segment-to-segment differences in all parameters, confirming and extending previous work. Red blood cell (RBC) and neutrophil transit are also analyzed, the latter drawing from previous studies of leukocyte aspiration into micropipettes. Transit time distributions are in good agreement with in vivo experiments, in particular showing that neutrophils are dramatically slowed relative to the flow of RBCs because of the need to contract and elongate to fit through narrower capillaries. Predicted neutrophil transit times depend on how the effective capillary diameter is defined. Transient blockage by a neutrophil can increase the local pressure drop across a segment by 100--300%, leading to temporal variations in flow and pressure as seen by videomicroscopy. All of these effects are modulated by changes in transpulmonary pressure and arteriolar pressure, although RBCs, neutrophils, and rigid microspheres all behave differently.

Blood Flow Velocity↗
PubMed1984

A computer model for learning processes and the role of the cerebral commissures.

A computer model of the two brain hemispheres is constructed of discrete populations of neurons, and it is shown to exhibit the characteristics of the great cerebral commissures, as has been pointed out by Sperry and others. For the range of parameters used we find that such systems respond in a specific manner to specific stimuli, and furthermore, whatever memory is transferred to one simulated hemisphere is also transferred to the other. However, this behavior changes when the two hemispheres are separated. We find that memory is not transferred from one hemisphere to the other when the interconnecting commissures are severed. The above findings verify Sperry's experimental observation that the split brain behaves as if it were indeed two separate brains, each performing concurrently and simultaneously diametrically opposite tasks.

Computers↗
PubMed2001

Automating the segmentation of medical images for the production of voxel tomographic computational models.

Radiation dosimetry for the diagnostic medical imaging procedures performed on humans requires anatomically accurate, computational models. These may be constructed from medical images as voxel-based tomographic models. However, they are time consuming to produce and as a consequence, there are few available. This paper discusses the emergence of semi-automatic segmentation techniques and describes an application (iRAD) written in Microsoft Visual Basic that allows the bitmap of a medical image to be segmented interactively and semi-automatically while displayed in Microsoft Excel. iRAD will decrease the time required to construct voxel models.

Computer Simulation↗
PubMed2000

Radiotracer and computer modeling evidence that phospho-base methylation is the main route of choline synthesis in tobacco.

Among flowering plants, the synthesis of choline (Cho) from ethanolamine (EA) can potentially occur via three parallel, interconnected pathways involving methylation of free bases, phospho-bases, or phosphatidyl-bases. We investigated which pathways operate in tobacco (Nicotiana tabacum L.) because previous work has shown that the endogenous Cho supply limits accumulation of glycine betaine in transgenic tobacco plants engineered to convert Cho to glycine betaine. The kinetics of metabolite labeling were monitored in leaf discs supplied with [(33)P]phospho-EA, [(33)P]phospho-monomethylethanolamine, or [(14)C]formate, and the data were subjected to computer modeling. Because partial hydrolysis of phospho-bases occurred in the apoplast, modeling of phospho-base metabolism required consideration of the re-entry of [(33)P]phosphate into the network. Modeling of [(14)C]formate metabolism required consideration of the labeling of the EA and methyl moieties of Cho. Results supported the following conclusions: (a) The first methylation step occurs solely at the phospho-base level; (b) the second and third methylations occur mainly (83%-92% and 65%-85%, respectively) at the phospho-base level, with the remainder occurring at the phosphatidyl-base level; and (c) free Cho originates predominantly from phosphatidylcholine rather than from phospho-Cho. This study illustrates how computer modeling of radiotracer data, in conjunction with information on chemical pool sizes, can provide a coherent, quantitative picture of fluxes within a complex metabolic network.

Choline↗
PubMed1990

Kinematics of the patellofemoral joint. Investigations on a computer model with reference to patellar fractures.

Patellofemoral kinematics were studied on a computer model. The articulating point of the patella moves from distal to proximal during flexion, until the quadriceps tendon starts to turn around the femur tendo-femoral gliding. The pattern of patellofemoral movement consists of a gliding and rolling component, the latter at its maximum at the beginning of flexion. The pathway of the instant centers of motion moves from dorsal to ventral during flexion. Stress analysis shows that the contact area is at all times the area of maximum bending stress. The distal part of the patella is the part with mechanical stress at all angles of flexion. The conclusions to be drawn for treatment are that fractures within the proximal and central part of the patella need a very high stability of internal fixation, the distal part of the patella less so. Postoperative treatment must take into account the changing contact area, because the peak stress is always at the contact area.

Biomechanical Phenomena↗
PubMed1986

A computer model of neck muscle endurance and fatigue as a function of helmet loading.

A series of experiments were conducted in which the neck muscles of volunteer subjects were dynamically and statistically loaded by systematic variations of twenty-four headgear configurations consisting of eight different centers-of-gravity (CGs) times three different weights. Six subjects would rotate their heads laterally (from side-to-side) for 30 min with each of the headgear loading combinations. Immediately thereafter, the subject would position his head in an isometric head dynamometer and exert a sustained right lateral neck contraction or forward neck contraction at 70% of his maximum strength, during which endurance time (to fatigue) was recorded. The results indicate that the computer model makes reasonable predictions within the boundary conditions. Input data outside the boundary conditions is rejected. The assumption of insensitivity to vertical loading is demonstrated. The assumption of bilateral symmetric response was confirmed for the 1.45 kg and 2.27 kg helmet loads. However, this assumption was not confirmed for the 4.09 kg helmet load. It is concluded from the computer model that aftward, midline loading is the optimal CG location (i.e. maximal endurance) for heavier helmets in the 3-4 km range.

Adult↗
PubMed1997

A computer model with surface friction for the prediction of total knee kinematics.

A computer model was generated which modelled the bearing surfaces of total knees, and predicted the kinematics for a set of input forces and moments. The model included friction at the bearing surfaces and soft tissue restraint forces, including the effect of cruciate resection. Predictions from the model were compared with data from a Knee Simulating Machine. There was close agreement in the shapes of the curves and in the magnitudes of the displacements and rotations under most conditions. The model predicted major differences in kinematics when friction between metal and polyethylene was included, the differences being even greater at the friction levels associated with small embedded acrylic particles. Soft tissue restraint was shown to reduce the displacements and rotations for tibial surfaces of low constraint but for moderate to high constraint, the soft tissues affected the kinematics only slightly. When the model was used to predict the motions for different condylar geometries, widely different contact paths on the tibial surface were determined. This suggested that condylar geometries which appeared to be generally similar, could have important differences in kinematics, function and wear.

Acrylic Resins↗
PubMed2004

A computational model of the mechanics of growth of the villous trophoblast bilayer.

We present a computational model of the mechanics of growth of the trophoblast bilayer in a chorionic villous, the basic structure of the placenta. The placental trophoblast is modeled as a collection of elastic neutrally buoyant membranes (mononuclear cytotrophoblasts and multinucleated syncytiotrophoblast) filled with a viscous, incompressible fluid (cytoplasm) with sources of growth located inside cells. We show how this complex, dynamic fluid-based structure can be modeled successfully using the immersed boundary method. The results of our research presented here include simulations of two processes-cell proliferation and cell fusion which both play a crucial role in the growth and development of the trophoblast tissue. We present the computed results of simulations of both processes running independently as well as simultaneously, along with comparisons with clinically obtained results.

Cell Division↗
PubMed2006

Experimental and computer modelling speciation studies of the effect of pH and phosphate on the precipitation of calcium and magnesium salts in urine.

BACKGROUND: pH and phosphate concentration are the major determinants of precipitation in urine of the salts of calcium and magnesium. This study aims to model the process of salt precipitation and establish whether the acidification of urine samples is necessary for the accurate measurement of calcium and magnesium in a clinical laboratory setting. METHODS: Urine samples were collected from 21 patients, aliquots were taken from each patient sample and the pH was adjusted to cover the range 2.0-10.0. The analytical and biological variation for each analyte was established and used to calculate percentage changes and critical differences. The critical difference was used to assess whether there was a significant difference between acidified and un-acidified samples. The JESS (Joint Expert Speciation System) thermodynamic computer-modelling program was used to predict the distribution of salt species formed with varying pH values and phosphate levels in simulated urine. RESULTS: The results showed that at a pH greater than 6.5, measured calcium, magnesium and phosphate significantly decreased as a result of precipitation (p<0.0001), although the critical difference was generally not exceeded. Computer modelling showed that both pH and phosphate concentration affected the distribution of salt species formed, as well as the precipitation patterns of calcium and magnesium phosphates. Overall, calcium phosphate precipitation tends to predominate at lower phosphate concentrations and at pH values below about 6.5, while both calcium and magnesium phosphate precipitation occur at higher phosphate concentrations and pH values greater than 6.5. CONCLUSIONS: For accurate analysis of these analytes in urine, the pH should be routinely measured and acidification should be undertaken prior to analysis if the pH is greater than 6.5. Based on the findings of this study, acidification or the lack of it does not result in a clinically significant change in calcium, magnesium and phosphate measured in urine. This study also predicted the likely salt species formed at varying urinary pH values and phosphate concentrations.

Calcium↗
PubMed1999

Molecular characterization of binding of substrates and inhibitors to DT-diaphorase: combined approach involving site-directed mutagenesis, inhibitor-binding analysis, and computer modeling.

The molecular basis of the interaction of DT-diaphorase with a cytotoxic nitrobenzamide CB1954 [5-(aziridin-1-yl)-2, 4-dinitrobenzamide] and five inhibitors was investigated with wild-type DT-diaphorase (human and rat) and five mutants [three rat mutants (rY128D, rG150V, rH194D) and two human mutants (hY155F, hH161Q)]. hY155F and hH161Q were generated to evaluate a hypothesis that Tyr155 and His161 participate in the obligatory two-electron transfer reaction of the enzyme. The catalytic properties of hY155F and hH161Q were compared with a naturally occurring mutant, hP187S. Pro187 to Ser mutation disturbs the structure of the central parallel beta-sheet, resulting in a reduction of the binding affinity of the flavin-adenine dinucleotide prosthetic group. With NADH as the electron donor and menadione as the electron acceptor, the k(cat) values for the wild-type human DT-diaphorase, hY155F, hH161Q, and hP187S were measured as 66 +/- 1, 23 +/- 0, 5 +/- 0 and 8 +/- 2 x 10(3) min(-1), respectively. Because hY155F still has significant catalytic activity, the hydroxyl group on Tyr155 may not be as important as proposed. Interestingly, hY155F was found to be 3. 3 times more active than the human wild-type DT-diaphorase in the reduction of CB1954. Computer modeling based on our results suggests that CB1954 is situated in the active site, with the aziridinyl group pointing toward Tyr155 and the amide group placed near a hydrophobic pocket next to Tyr128. Dicoumarol, Cibacron blue, chrysin, 7,8-dihydroxyflavone, and phenindone are competitive inhibitors of the enzyme with respect to nicotinamide coenzymes. The binding orientations of dicoumarol, flavones, and phenindone in the active site of DT-diaphorase were predicted by results from our inhibitor-binding studies and computer modeling based on published X-ray structures. Our studies generated results that explain why dicoumarol is a potent inhibitor and binds differently from flavones and phenindone in the active site of DT-diaphorase.

Antineoplastic Agents↗