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PubMed1985

Effect of spermidine on the conformation of bacteriophage MS2 RNA. Electron microscopy and computer modeling.

The structure of single-stranded RNA from the bacteriophage MS2 has been examined by electron microscopy in the presence of the polyamine spermidine. The molecules are found in two alternate conformations. The first of these can be characterized as a cruciform structure composed of three large loops approximately 500 to 700 nucleotides in size. The interior of the molecule has extensive base-paired regions which connect distant regions of the molecule; the farthest being 2500 nucleotides apart. In the second conformation, the molecules appear rod-like. Two of the large loops disappear, and these regions form, instead, extensive long-range helices. Computer modeling has been employed to explore the base-pairing potential of the sequence of bacteriophage MS2 RNA. Double-stranded regions identified by electron microscopy are shown to occur in local G + C-rich stretches of the RNA. Detailed models have been calculated for two regions of long-range contact. One of these includes the ribosome-binding site for the viral coat protein gene. The results are discussed in the context of the known role of RNA structure in the regulation of viral gene expression.

Bacteriophages↗

PubMed1997

A computer model for the measurement of compliance using a dual tracer technique.

AIMS: We aimed to determine whether simultaneous use of two tracer compounds with long and differing elimination half-lives may permit more precise recognition of percent compliance and discrimination among remote, intermediate, and recent patterns of daily dosing. METHODS: We have derived, through computer modelling, the potential utility of digitoxin and phenobarbitone as simultaneous tracers. From kinetic data on these reliably measured compounds with long half-lives we defined the percentage error below which this pair of tracers can be expected to discern the precise, and the approximate, pattern and number of daily doses taken over a mouth. RESULTS: The longer the half-lives of the tracers the greater the sensitivity of our model to percentage compliance. At extremely long half-lives, relative to the period of dosing being monitored, sensitivity approaches 100% if measurement error is in the 1-2% range. The ratio of the half-lives between the two tracers that is optimal for detection of percentage compliance is 0.2 to 0.8. The detection of pattern does not depend importantly either on the tracer half-lives or on their ratio to each other. The greater the percentage compliance, the more accurately our two-tracer model determines the pattern of dosing. CONCLUSIONS: Precise characterization of compliance using tracers must probably await the development of compounds with half-lives measured in weeks or months. The probability of compliance of a given degree can be derived from our two-tracer technique with best-fit analysis such as we describe.

Anti-Arrhythmia Agents↗

PubMed1994

Mathematical and computer modeling of acute normovolemic hemodilution.

BACKGROUND: Advocates of acute normovolemic hemodilution (ANH) frequently neglect to consider the decreasing hematocrit of the patient during both hemodilution and the subsequent operative procedure and the need to begin transfusion at some minimal hematocrit. STUDY DESIGN AND METHODS: For more accurate prediction of the efficacy of ANH, equations were derived and a computer model developed that allowed accounting for the decreasing hematocrit due to blood loss in an isovolemic patient and calculating the red cell volume on a minute-by-minute basis; the model also began the transfusion of ANH blood on a mL-for-mL basis when the minimal hematocrit was reached and transfused any remaining blood following completion of the case. The red cell volume saved by performing ANH for a given estimated blood volume (EBV) was expressed as either the fraction of the red cell volume of a routinely banked unit of blood (red cells stored in additive solution: volume 350 mL, hematocrit 0.65) or the number of units saved. RESULTS: The number of units saved in a typical example--EBV, 5000 mL; pre-ANH hematocrit, 0.40; minimal hematocrit at which transfusion was begun, 0.25 over a range of estimated blood losses (500-2500 mL); and 1 to 5 ANH units drawn--never exceeded 0.6. Even with extensive hemodilution, as in a child (EBV, 1500 mL; pre-ANH hematocrit, 0.40; minimal hematocrit at which transfusion was begun, 0.15; 5 units drawn; and estimated blood losses, 2500, 1500, and 1000 mL) with a postdilution hematocrit of 0.16, the savings would have been only 0.29, 0.44, and 0.49 units, respectively. CONCLUSION: Because of the decreasing hematocrit in a bleeding isovolemic patient and the need to begin transfusion at some minimal hematocrit, the theoretic savings in red cell volume attributable to ANH is less than had previously been appreciated, and additional ANH does not necessarily result in additional patient benefit.

Blood Transfusion↗

PubMed1997

A computer modeling study of the interaction between tissue factor pathway inhibitor and blood coagulation factor Xa.

Activation of blood coagulation factor X to factor Xa (FXa) is inhibited by tissue factor pathway inhibitor (TFPI). The second Kunitz-type inhibitory domain (K2) of TFPI binds a catalytic domain of FXa, whereas the first domain (K1) does not. We analyzed computer models of complexes of FXa with K1 or K2, which were made using a crystal structure of FXa. Favorable hydrophobic interaction was observed in the complex of FXa with K2. Furthermore, we constructed a tertiary structure of FXa using CHIMERA to assess the accuracy of a homology modeling method. The isolated model structure of FXa agreed well with the crystal structure, but analyses of complexes of this structure with K1 or K2 revealed that the models of complexes could not provide clear evidence of greater binding ability to K2 because of the positional difference of a few side chains interacting with the inhibitor.

Amino Acid Sequence↗

PubMedDate not supplied

A computer model comparing normovolemic hemodilution, hypervolemic hemodilution, and neither on intraoperative blood loss and final hematocrit.

Homologous blood transfusion, while frequently life-saving, is attended by risks and complications. Autologous blood transfusions have become an increasingly common alternative. Volume expansion, which is simpler, also is used. This study was designed to construct computer models of hypervolemic hemodilution and normovolemic hemodilution to compare them with each other and with normal (neither hypervolemic nor normovolemic hemodilution). Each model started with blood volume (BV) equal to 5,000 mL. Initial hematocrits (HCTs) were varied from 25% to 50%. Following phlebotomy and hemodilution or volume expansion, which ranged from 0 to 2,500 mL (50% of initial BV), the models were then bled 250 to 2,500 mL (5% to 50% of initial BV). In the phlebotomy model, the autologous blood was then returned. Final HCTs were then calculated. Preoperative phlebotomy of 500 to 1,000 mL, an amount commonly withdrawn, provides a minimally higher final HTC. Volume expansion by hypervolemic hemodilution provides almost the same low level of benefit. Benefits (3% higher HCT) are not seen until larger volumes are phlebotomized or hemodiluted and accompanied by large intraoperative blood losses. Autologous blood drawn by preoperative phlebotomy for intraoperative transfusion should not be used until studies show that these large volumes are safe and actually save blood.

Blood Loss, Surgical↗

PubMed1988

Maturation of the immune response: a computational model.

Experimental studies of the effect on antibody affinity of antigen dose and time after immunization show that average affinity increases progressively with time after immunization, and that this increase is greater at lower doses of antigen. In this paper we describe a polyclonal computer model of the immune system that yields all the essential phenomena of affinity maturation, including dose-dependency. Our main findings are (1) the dose-dependency relationship is not produced when typical assumptions regarding B-cell populations and binding reactions are employed, and (2) it is possible to reproduce this dependency by assuming two classes of lymphocytes: generalists and specialists. Generalists have a low threshold for response and produce antibody of low effectiveness, whereas specialists have a high threshold for response, and produce highly effective antibody. We make an analogy between the generalists and a pioneer species in ecological succession, and suggest how the generalists may contribute to a more effective defense against real infections.

Antibody Affinity↗

PubMed2006

Measurement of cardiac output by open-circuit acetylene uptake: a computer model to quantify error caused by ventilation-perfusion inequality.

The ability to assess cardiac output (Q(T)) noninvasively has been the focus of interest for many researchers. While the open-circuit acetylene (C2H2) method seems promising, it is prone to error due to ventilation-perfusion (V/Q) inequality. Measurements during exercise, at high altitude or in patients with chronic obstructive pulmonary disease (COPD) could be unreliable and further validation studies under these circumstances may be needed. We used a computer model based on formulae derived from the multiple inert gas elimination technique to quantify error in Q(T) measurements resulting from V/Q inequality at rest, during exercise or at high altitude. Moreover, potential errors encountered in patients with COPD were quantified. In healthy subjects, V/Q inequality related measurement error seems negligible, under both normoxic and hypoxic conditions and especially during exercise. In COPD, errors up to 20% at rest and up to 15% during exercise are expected. It is therefore concluded from our model that the open-circuit C2H2 uptake method is expected to be accurate in normal subjects. Its validity in COPD needs further study.

Acetylene↗

PubMed2001

Interaction between first- and second-order orientation channels revealed by the tilt illusion: psychophysics and computational modelling.

This paper examines the interaction between first- and second-order contours in the orientation domain. Using the simultaneous tilt illusion (TI), we show that the apparent rotation of a vertical test grating away from that of a surrounding inducing grating (repulsion effect) occurs when both the inducing and test grating are either first- or second-order. Furthermore, a significant repulsion effect is obtained when a first-order inducing grating surrounds a second-order test. If lateral inhibitory interactions between populations of orientation selective neurons provides a plausible explanation for orientation repulsion effects [Blakemore, C. B. Carpenter, R. H. S. & Georgeson, M. A. (1970) Nature, 228, 37-39], it is likely that the cue-invariant mechanisms that encodes the orientation of first- and second-order contours also exhibit inhibitory interactions. A two-channel computational model of orientation encoding is presented where one channel encodes only first-order stimuli while the second channel encodes both first- and second-order contours. In addition to predicting the orientation repulsion effects we observed, the model also provides a functional account of orientation attraction effects in terms of the responses of populations of orientation-tuned neurons.

Chi-Square Distribution↗

PubMed2005

Error estimation of geometrical data obtained by histomorphometry of oblique vessel sections: a computer model study.

The errors of radius and wall thickness of a single vessel due to oblique sectioning in histomorphometry are expressed as a function of the circular shape factor (CSF) of the section's lumen, assuming cylindrical geometry and the absence of tissue deformation. Using computer model trees generated by constrained constructive optimization, mean errors are estimated for an ensemble of vessel segments. A geometrical exclusion criterion for segments cut too obliquely is defined on the basis of a CSF-cutoff value. It is shown that CSF-values ranging from 0.95 to 0.9 are reasonable choices for a cutoff and lead to mean errors of the same order of magnitude (9.6% [9.3%] to 15.4% [14.8%] for the radius [wall thickness]) as errors due to histological tissue processing.

Animals↗

PubMed1998

Computer modeling of prostate biopsy: tumor size and location--not clinical significance--determine cancer detection.

PURPOSE: Sampling error is an inherent problem of prostate biopsy, and the determination of clinical significance based on biopsy results is problematic. We quantify the dimensions of these problems by computer simulation. MATERIALS AND METHODS: We constructed 3-dimensional solid computer models of 59 autopsy prostates containing clinically undetected prostate cancer, and performed simulations of the standard prostate biopsy method. RESULTS: Biopsy simulation detected 19 tumors from the 59 prostates, the majority of which were in the most accessible portion of the prostate, the posterior peripheral zone. Using 0.5 cc or greater tumor volume or less than 0.5 cc and Gleason sum 7 or greater as criteria of significance, the model detected 58% (11 of 19) significant tumors and 20% (8 of 40) insignificant tumors. With 0.25 cc or greater tumor volume or less than 0.25 cc and Gleason sum 7 or greater as criteria 15 of 29 significant (52%) and 4 of 30 insignificant (13%) tumors were detected. Among significant tumors defined by either volume criterion there was a statistical difference between detected and undetected tumors in terms of mean tumor volume and mean ratio of tumor volume-to-prostate volume. Among insignificant tumors defined by either criterion there was no such difference. CONCLUSIONS: As much as 20 to 40% of currently detected prostate cancer may be histologically insignificant, as 4 of 19 cancers were detected when 0.25 cc was used as volume determinant of clinical significance and 8 of 19 were detected when 0.5 cc volume was used. These tumors are detected randomly. On the other hand, perhaps only one-half to three-fourths of clinically significant prostate cancers are being detected, and then only because the volume and anatomic location make them hard to miss.

Adult↗

PubMed1992

A computational model of the amplitude and implicit time of the b-wave of the human ERG.

To improve the usefulness of the ERG in identifying the sites and mechanisms of adaptation, development, and disease processes, a theoretical framework based upon Granit's analysis of the ERG was evaluated. The framework assumes that the ERG is the sum of two potentials, one, P3, generated by the receptors and the other, P2, generated by the cells of the INL. Hood and Birch (1990a, b) demonstrated that the leading edge of the a-wave can be quantitatively described by a model used to describe the response from single rod receptors. This model provides P3(t), a theoretical receptor response as a function of time, for any given flash intensity. The ERGs from normal observers and patients with retinal diseases were analyzed in this framework, first by deriving P2 by computer subtracting the predicted P3(t) responses. This analysis was successful and a computational model of the ERG was then derived. The model of P2(t) was constructed with linear filters and a static nonlinearity and using P3(t) as the input. The ERG for any given flash intensity is then P3(t) + P2(t). The model describes (1) the change both in implicit times and in trough-to-peak b-wave amplitudes with flash intensity for the normal, dark-adapted observers; and (2) the changes in b-wave implicit times and amplitudes for three patients with retinal diseases. Among the implications drawn from these analyses were as follows: (1) The fits of the Naka-Rushton equation to trough-to-peak b-wave amplitudes must be interpreted with great care. (2) When the INL is affected by retinal disease, the b-wave may be a very poor reflection of INL activity. (3) The implicit time of the b-wave can provide a measure of receptor sensitivity.

Adult↗

PubMed1993

Computer modelling of estrogenic transcriptional activation can account for different types of dose-response curves of estrogens.

Estrogenic activity of diphenylethanes and -ethenes was determined by uterine growth in immature mice and analyzed by weighed regression of logit-transformed effect on log dose values. This resulted in a range of Hill coefficients nH from 0.3 to 2 corresponding to the molecular mechanism of estrogenic transcriptional activation. Binding of agonists (hormones, H) to estrogen receptors (ER) leads to receptor dimerization depending on the structure of the ligand. Three hormone-receptor complexes, H-ER, H-ER-ER, and H-ER-ER-H, which bind with different affinity to short palindromic DNA sequences (estrogen responsive elements), can be proposed. Transcriptional activating functions of the DNA-bound ER are subsequently induced. We have derived an equilibrium model including these steps. Computer simulations of Hill plots based on the model have completely reproduced the range of observed nH values. Hill coefficients are > 1.5 if the homodimer H-ER-ER-H and < 0.7 if the heterodimer H-ER-ER strongly predominates. If ER dimerization is disturbed (H-ER monomer predominant), nH is closer to 1. Hill coefficients and pD2 values (negative decadic logarithms of molar estrogen doses causing 50% of the maximal effects) are related to parameters of ER dimerization and the two steps of hormone-receptor dissociation. When a series of 1,2-bis(3'-or 4'-hydroxyphenyl)ethanes and -ethenes is studied, a rather simple dependence of nH and pD2 on the nature of alkyl groups symmetrically substituted at C-atoms 1 and 2 can be observed. In terms of the model this implies that ethyl and alpha-branched higher alkyl substituents (nH >> 1) appear to stabilize the homodimer, while methyl and CF3 groups (nH << 1) could lead to a rapid dissociation of the homodimer to the heterodimer. With longer n-alkyl and beta-branched alkyl substitution (nH from 0.66 to 1.3), dimerization itself can be limited or the ligand-homodimer dissociation is only moderately increased. Thus, a strong sterical constraint could exist with respect to the stabilization of the second ligand-receptor bond in the homodimer.

Animals↗

PubMed2005

Effects of Bcl-2 levels on Fas signaling-induced caspase-3 activation: molecular genetic tests of computational model predictions.

Fas-induced apoptosis is a critical process for normal immune system development and function. Although many molecular components in the Fas signaling pathway have been identified, a systematic understanding of how they work together to determine network dynamics and apoptosis itself has remained elusive. To address this, we generated a computational model for interpreting and predicting effects of pathway component properties. The model integrates current information concerning the signaling network downstream of Fas activation, through both type I and type II pathways, until activation of caspase-3. Unknown parameter values in the model were estimated using experimental data obtained from human Jurkat T cells. To elucidate critical signaling network properties, we examined the effects of altering the level of Bcl-2 on the kinetics of caspase-3 activation, using both overexpression and knockdown in the model and experimentally. Overexpression was used to distinguish among alternative hypotheses for inhibitory binding interactions of Bcl-2 with various components in the mitochondrial pathway. In comparing model simulations with experimental results, we find the best agreement when Bcl-2 blocks the release of cytochrome c by binding to both Bax and truncated Bid instead of Bax, truncated Bid, or Bid alone. Moreover, although Bcl-2 overexpression strongly reduces caspase-3 activation, Bcl-2 knockdown has a negligible effect, demonstrating a general model finding that varying the expression levels of signal molecules frequently has asymmetric effects on the outcome. Finally, we demonstrate that the relative dominance of type I vs type II pathways can be switched by varying particular signaling component levels without changing network structure.

Apoptosis↗

PubMed2000

Computational modelling of interleaved first- and second-order motion sequences and translating 3f+4f beat patterns.

Despite detailed psychophysical, neurophysiological and electrophysiological investigation, the number and nature of independent and parallel motion processing mechanisms in the visual cortex remains controversial. Here we use computational modelling to evaluate evidence from two psychophysical studies collectively thought to demonstrate the existence of three separate and independent motion processing channels. We show that the pattern of psychophysical results can largely be accounted for by a single mechanism. The results demonstrate that a low-level luminance based approach can potentially provide a wider account of human motion processing than generally thought possible.

Humans↗

PubMed1998

Computational models of thalamocortical augmenting responses.

Repetitive stimulation of the dorsal thalamus at 7-14 Hz produces an increasing number of spikes at an increasing frequency in neocortical neurons during the first few stimuli. Possible mechanisms underlying these cortical augmenting responses were analyzed with a computer model that included populations of thalamocortical cells, thalamic reticular neurons, up to two layers of cortical pyramidal cells, and cortical inhibitory interneurons. Repetitive thalamic stimulation produced a low-threshold intrathalamic augmentation in the model based on the deinactivation of the low-threshold Ca2+ current in thalamocortical cells, which in turn induced cortical augmenting responses. In the cortical model, augmenting responses were more powerful in the "input" layer compared with those in the "output" layer. Cortical stimulation of the network model produced augmenting responses in cortical neurons in distant cortical areas through corticothalamocortical loops and low-threshold intrathalamic augmentation. Thalamic stimulation was more effective in eliciting augmenting responses than cortical stimulation. Intracortical inhibition had an important influence on the genesis of augmenting responses in cortical neurons: A shift in the balance between intracortical excitation and inhibition toward excitation transformed an augmenting responses to long-lasting paroxysmal discharge. The predictions of the model were compared with in vivo recordings from neurons in cortical area 4 and thalamic ventrolateral nucleus of anesthetized cats. The known intrinsic properties of thalamic cells and thalamocortical interconnections can account for the basic properties of cortical augmenting responses.

Animals↗

PubMed2005

A computational model of parallel navigation systems in rodents.

Several studies in rats support the idea of multiple neural systems competing to select the best action for reaching a goal or food location. Locale navigation strategies, necessary for reaching invisible goals, seem to be mediated by the hippocampus and the ventral and dorsomedial striatum whereas taxon strategies, applied for approaching goals in the visual field, are believed to involve the dorsolateral striatum. A computational model of action selection is presented, in which different experts, implementing locale and taxon strategies, compete in order to select the appropriate behavior for the current task. The model was tested in a simulated robot using an experimental paradigm that dissociates the use of cue and spatial information.

Animals↗

PubMedDate not supplied

Recognition of cyclooxygenase-2 (COX-2) active site by NSAIDs: a computer modelling study.

The energetics and models of COX-2 complexed with nonsteroidal anti-inflammatory drugs (NSAIDs) having different degrees of selectivity for two isoforms of COX (COX-2 and COX-1) have been studied using computer modelling approach. The models are obtained for complexes of NS398 (NS), a selective COX-2 inhibitor; indoprofen (Ind), a non-selective inhibitor; di-tert-butylbenzofurans (DHDMBFs) with substituents at the 5th position: CONH(CH2)2OMe (BF1), CONH-c-Pr (BF2), 3-methylene-gamma-butyrolactonyl (BF3) and oxicams namely, meloxicam (Mel), piroxicam (Pir) and tenoxicam (Ten). These were optimized using molecular mechanics (MM) and molecular dynamics (MD) techniques. The binding energies and structures were compared with pharmacological parameters and available results with COX-1. In case of NS a larger difference in the binding energies between COX-2 and COX-1 was noticed as compared to that of Ind. It also had stronger interaction with His90 and Tyr355 which is considered important for COX-2 selectivity. There was a difference in the compactness at the channel entrance between COX-2 selective and non-selective ligands. Models with DHDMBFs and oxicams showed a similar correlation. The results were used to design a peptide inhibitor, Tyr-Arg-Cys-Ala-delta Phe-Cys (Pept) which could fit better in the COX-2 cavity. As per our MD simulation results this peptide inhibitor showed both higher activity and COX-2 selectivity.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2006

Shock-induced changes of Ca(i)2+ and Vm in myocyte cultures and computer model: Dependence on the timing of shock application.

OBJECTIVES: Responses of Ca(i)2+ to electrical shocks are believed to be important in defibrillation but measurements of shock-induced Ca(i)2+ changes during different phases of the action potential (AP) are lacking. The effects of shocks on Ca(i)2+ and Vm were investigated in geometrically defined cell cultures and in a computer model. METHODS: Uniform-field shocks (E = 10.4+/-0.9 V/cm) were applied 15-300 ms after AP upstroke in strands of cultured neonatal rat myocytes. Optical mapping was used to measure shock-induced Ca(i)2+ and Vm changes. A rat ionic model was used to elucidate ionic mechanisms of Ca(i)2+ responses. RESULTS: In experiments and simulations, shocks applied with short delays (15-40 ms) caused a transient decrease of Ca(i)2+ at sites of both DeltaV(+)m and DeltaV(-)m. Simulations indicated that the Ca(i)2+ decrease at DeltaV(+)m sites was caused by reversed outward flow of L-type Ca2+ current (I(CaL)), while the Ca(i)2+ decrease at DeltaV(-)m sites was due to the NaCa exchanger (NCX). At intermediate delays (40-150 ms), shocks caused a Ca(i)2+ decrease at sites of DeltaV(-)m and an increase at sites of DeltaV(+)m. Simulations indicated that the Ca(i)2+ increase at DeltaV(+)m sites was caused by transient reactivation of I(CaL) combined with a reverse-mode operation of NCX. Shocks applied at long delays (150-300 ms) caused a Ca(i)2+ increase at DeltaV(+)m and no change at DeltaV(-)m sites. CONCLUSION: Effects of shocks on Ca(i)2+ depend on the timing of shock application. Shocks applied during the early AP cause a transient Ca(i)2+ decrease, while later in AP shocks induce a Ca(i)2+ increase at sites of DeltaV(+)m. Shock-induced Ca(i)2+ changes in different AP phases are primarily determined by combination of I(CaL) and NCX.

Action Potentials↗