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PubMed1994

A computational model of the auditory periphery for speech and hearing research. II. Descending paths.

The auditory model described in Giguère and Woodland [J. Acoust. Soc. Am. 94, 331-342 (1993)] is applied to the simulation of the descending paths to the peripheral ear. An external feedback unit regulates the average firing rate of inner hair cell afferent fibers via a simplified modeling of the dynamics of the acoustic reflex to the middle ear and of the slow efferent innervation of the outer hair cells. The terminal effector of the acoustic reflex system is the stapedial muscle which stiffens the middle ear and reduces vibration of the stapes up to 15 dB below 1000 Hz. The control function of the efferent system is realized by modulating the coupling gain between the inner hair cell cilia and the surrounding subtectoral fluid over a range of 24 dB. The efferent system has the capability to regulate firing rate over selective tonotopic regions of the auditory nerve. It operates at a lower target rate and has a faster response than the acoustic reflex system. The feedback unit leads to dynamic compression of speech cochleograms along both the time and frequency axes.

Computer Simulation↗
PubMed1984

Theoretical analysis of the Farr antibody assay with a computer model: importance of antigen concentration and antibody affinity.

The Farr assay for antibody was analyzed theoretically in order to determine the maximum sensitivity of the assay, the quantitative relationship between actual antibody concentration and antibody estimates by the Farr technique, and the relationship between antibody affinity and the Farr avidity index. Analysis shows that sensitivity is limited by the antigen concentration when large amounts of antigen are used in the assay. Sensitivity at low antigen concentrations is maximal and varies with the affinity of the antibody studied. Antibody titers obtained by the Farr technique using low antigen concentrations vary with antibody affinity as well as antibody concentration. Titers measured at high antigen concentration are less affected by affinity and correlate better with antibody concentration. Antibody measurements expressed as Antigen Binding Capacity reflect antibody concentration only when the antigen concentration used in the assay exceeds a value equal to ten times the reciprocal of the antibody affinity constant. The Farr avidity index correlates with antibody affinity over a narrow affinity range. Different ranges of affinity can be examined by changing the antigen concentrations.

Antibodies↗
PubMed1998

The neural development and organization of letter recognition: evidence from functional neuroimaging, computational modeling, and behavioral studies.

Although much of the brain's functional organization is genetically predetermined, it appears that some noninnate functions can come to depend on dedicated and segregated neural tissue. In this paper, we describe a series of experiments that have investigated the neural development and organization of one such noninnate function: letter recognition. Functional neuroimaging demonstrates that letter and digit recognition depend on different neural substrates in some literate adults. How could the processing of two stimulus categories that are distinguished solely by cultural conventions become segregated in the brain? One possibility is that correlation-based learning in the brain leads to a spatial organization in cortex that reflects the temporal and spatial clustering of letters with letters in the environment. Simulations confirm that environmental co-occurrence does indeed lead to spatial localization in a neural network that uses correlation-based learning. Furthermore, behavioral studies confirm one critical prediction of this co-occurrence hypothesis, namely, that subjects exposed to a visual environment in which letters and digits occur together rather than separately (postal workers who process letters and digits together in Canadian postal codes) do indeed show less behavioral evidence for segregated letter and digit processing.

Adult↗
PubMed1999

Temporal constraints on visual learning: a computational model.

Given a constant stream of perceptual stimuli, how can the underlying invariances associated with a given input be learned? One approach consists of using generic truths about the spatiotemporal structure of the physical world as constraints on the types of quantities learned. The learning methodology employed here embodies one such truth: that perceptually salient properties (such as stereo disparity) tend to vary smoothly over time. Unfortunately, the units of an artificial neural network tend to encode superficial image properties, such as individual grey-level pixel values, which vary rapidly over time. However, if the states of units are constrained to vary slowly, then the network is forced to learn a smoothly varying function of the training data. We implemented this temporal-smoothness constraint in a backpropagation network which learned stereo disparity from random-dot stereograms. Temporal smoothness was formalized with the use of regularization theory by modifying the standard cost function minimised during training of a network. Temporal smoothness was found to be similar to other techniques for improving generalisation, such as early stopping and weight decay. However, in contrast to these, the theoretical underpinnings of temporal smoothing are intimately related to fundamental characteristics of the physical world. Results are discussed in terms of regularization theory and the physically realistic assumptions upon which temporal smoothing is based.

Depth Perception↗
PubMed2005

The coarse-to-fine hypothesis revisited: evidence from neuro-computational modeling.

The human perceptual system seems to be driven by a coarse-to-fine integration of visual information. Different results have shown a faster integration of low-spatial frequency compared with high-spatial frequency (HSF) information, starting at early retinal processes. The difference in spatial scale decomposition remains throughout the lateral geniculate nucleus (Hubel & Wiesel, 1977) and V1 (Tootell, Silverman, & De Valois, 1981). During the last decade, a debate has emerged concerning the origin of the coarse-to-fine integration. Is it a constant, perceptually driven integration (Parker et al., 1992 and Parker et al., 1996)? Instead, the flexible use hypothesis suggests that different spatial frequency channels could be enhanced depending on the requirement of the task for high-level cognitive processes like categorization (Oliva and Schyns, 1997 and Schyns and Oliva, 1999). In two connectionist simulations, we have shown that global categorization performance could actually be better performed with HSF information when the amount of information is normalized across the different spatial frequency channels. Those results suggest that high-level requirement alone could not explain the coarse-to-fine bias toward LSF information. A hypothesis is proposed concerning the possible implication of the amount of data provided by different spatial frequency channel that might provide the perceptual bias toward LSF information.

Algorithms↗
PubMed2001

The effect of design variables of condylar total knees on the joint forces in step climbing based on a computer model.

The ability to climb a steep step or rise from a low chair after total knee replacement may be enhanced if the required force in the quadriceps muscle is reduced. This can potentially be achieved if the total knee produces a large lever arm measured from the femoral-tibial contact point to the patellar ligament. A reduced quadriceps force would also reduce the patello-femoral force and the femoral-tibial contact force. The contact point location is likely to be a function of the geometry of the femoral and tibial components in the sagittal plane, including the relative distal and posterior radii of the femoral profile, the location of the bottom-of-the-dish of the tibial surface, the radius of the tibial surface, and the presence or absence of the posterior cruciate ligament. A three-dimensional model of the knee was developed including the quadriceps and various ligaments. In the study, the motion was confined to flexion extension and displacement in the sagittal plane. The quadriceps was assumed to be the only muscle acting. A standard software package (Pro/Mechanica) was used for the analysis. For a femoral component with a smaller distal radius, there was 12% reduction in the quadriceps muscle force and up to 11% reduction in the patello-femoral force from about 100 up to 60 degrees flexion. However, apart from that, there were less than 10% differences in all the forces as a function of all of the design variables studied. This was attributed to the relatively small changes in the lever arm of the patella tendon, since the tendon moves in an anterior-posterior direction along with the femur. An additional factor explaining the results was the change in the anterior-posterior contact point as controlled by the forces in the patella tendon and in the soft tissues. The results imply that for a standard condylar replacement knee, the muscle and contact forces are not greatly affected by the geometrical design variables.

Biomechanical Phenomena↗
PubMed1989

Computer modeling of sheep reproduction: I. An algorithm for quantifying anestrous cycles in ewes.

An algorithm that mathematically describes annual estrous activity in ewes is given. The function fitted as the ordinate is similar to a normal distribution function related to date as the abscissa. The data used were collected from literature on different breeds and from different locations of the world; all studies had been specifically conducted to study estrous activity in ewes in these locations. Parameters estimated in an iterative procedure from the algorithm were length of time during which estrous cycles occurred (SA), a measure of asymmetry (SD), day of mid-estrous (DE), highest incidence of estrus (MX) and lowest incidence of estrus (MN), day of lowest incidence of estrus (DN) and day of mid-anestrous season (DA). Incidence of estrus is defined as the proportion of ewes exhibiting an active estrus. These parameters were estimated for several breeds and locations. The data, as collected, were inadequately cross-classified to allow for unconfounded estimation. However, analyses of fitted parameters that describe the curves gave quantitative results about the influences of breed of sheep, location, latitude and altitude and indicated which parameters were associated with these factors. Breeds differed significantly for SA, DE, MX and DA. Locations differed for DE, MX and DA. Latitude was associated with differences in DE, DN and DA with altitude also associated with differences in DE and DA. There were no significant effects on SD even though breeds differed sizably in SD.

Algorithms↗
PubMed2003

Analysis of interaction between number of implant catheters and dose-volume histograms in prostate high- dose-rate brachytherapy using a computer model.

PURPOSE: In prostate high-dose-rate brachytherapy, to determine before implant, using the standard geometric optimization algorithm, whether there is an optimal number of catheters. MATERIALS AND METHODS: Transrectal ultrasound images of the prostate from 24 patients were transferred into the brachytherapy planning system. Urethra and prostate contours were digitized onto each axial slice of a CT scan, as well as hypothetical locations of the catheters (2/3 of the catheters along the prostate contour, 1/3 around the urethra). Each prostate was implanted with 9, 12, 15, 18, and 21 catheters. Dosimetry was optimized using a geometric optimization algorithm; prescription isodose was chosen so that 95% of planning target volume was covered by the 100% isodose. RESULTS: A significant increase in mean volume of prostate receiving 150% of the dose (V150) when the number of catheters decreased (p < 0.0001). The 9-catheter group significantly differed from each of the other groups; no difference was seen in V150 among the 21-, 18-, and 15-catheter groups. Parallel results were observed for urethra V150 and homogeneity index; there was no difference in conformity index by catheter group. CONCLUSION: V150 increased when fewer catheters were used. There was no significant difference among the 21-, 18-, and 15-catheter groups: the geometric optimization routine probably compensated for the larger distance between dwell positions. Based on the technique described in our study, we conclude that 15 to 21 catheters seem to cover the prostate adequately without creating excess hot spots.

Algorithms↗
PubMed2000

Melting of cross-linked DNA IV. Methods for computer modeling of total influence on DNA melting of monofunctional adducts, intrastrand and interstrand cross-links formed by molecules of an antitumor drug.

A theoretical method is developed for calculation of melting curves of covalent complexes of DNA with antitumor drugs. The method takes into account all the types of chemical modifications of the double helix caused by platinum compounds and DNA alkylating agents: 1) monofunctional adducts bound to one nucleotide; 2) intrastrand cross-links which appear due to bidentate binding of a drug molecule to two nucleotides that are included into the same DNA strand; 3) interstrand cross-links caused by bidentate binding of a molecule to two nucleotides of different strands. The developed calculation method takes into account the following double helix alterations at sites of chemical modifications: 1) a change in stability of chemically modified base pairs and neighboring ones, that is caused by all the types of chemical modifications; 2) a change in the energy of boundaries between helical and melted regions at sites of chemical modification (local alteration of the factor of cooperativity of DNA melting), that is caused by all the types of chemical modifications, too; 3) a change in the loop entropy factor of melted regions that include interstrand cross-links; 4) the prohibition of divergence of DNA strands in completely melted DNA molecules, which is caused by interstrand cross-links only. General equations are derived, and three calculation methods are proposed to calculate DNA melting curves and the parameters that characterize the helix-coil transition.

Algorithms↗
PubMed2005

Increased aortic wall stress in aortic insufficiency: clinical data and computer model.

OBJECTIVE: The study was aimed at determining which cardiac pathologies are associated with increased longitudinal stress in the aorta and therefore may be responsible for the intimal transverse tears seen in aortic dissections. METHODS: Aortic root contrast injections were analyzed in 90 cardiac patients to measure the downward motion of the annulus during a cardiac cycle. A finite element model of the pressurized aortic root, arch and supra-aortic vessels was created to assess the influence of the aortic root motion on the aortic wall stress. RESULTS: The axial displacement of the aortic root ranged from 0 to 14 mm. A multivariate analysis showed that aortic insufficiency (AI) grade, hypokinesis of the left ventricle (HKI), and myocardial hypertrophy (HTR) were 3 independent variables which correlated with the axial displacement of the aortic root (DISP), such that ARM (mm)=5.379 (P<0.0001) +1.186 x AI grade (P=0.0016) - 1.611 x HKI (P=0.0078) - 1.399 x HTR (P=0.0355) with R2=0.23. The major finding of the stress analysis was that in the ascending aorta, at approximately 2 cm above the sino-tubular junction, the longitudinal stress due to aortic root motion was 32% higher in patients with AI than in patients without AI, thereby increasing the risk of transverse intimal rupture. CONCLUSIONS: Cardiac patients with AI are likely to experience enhanced longitudinal stress in the ascending aorta due to increased aortic root motion. Thus, these patients should be targeted and their aortic root movement monitored because it may be an important risk factor for aortic dissection.

Adult↗
PubMed1997

Computational modelling of low-energy electron-induced DNA damage by early physical and chemical events.

Modelling and calculations are presented as a first step towards mechanistic interpretation and prediction of radiation effects based on the spectrum of initial DNA damage produced by low energy electrons (100 eV-4.5 keV) that can be compared with experimental information. Relative yields of single and clustered strand breaks are presented in terms of complexity and source of damage, either by direct energy deposition or by reaction of OH radicals, and dependence on the activation probability of OH radicals and the amount of energy required to give a single strand break (ssb). Data show that the majority of interactions in DNA do not lead to damage in the form of strand breaks and when they do occur, they are most frequently simple ssb. However, for double-strand breaks (dsb), a high proportion (approximately 30%) are of more complex forms, even without considering additional complexity from base damage. The greater contribution is from direct interactions in the DNA but reactions of OH radicals add substantially to this, both in terms of the total number of breaks and in increasing the complexity within a cluster. It has been shown that the lengths of damaged segments of DNA from individual electron tracks tend to be short, indicating that consequent deletion length (simply by loss of a fragment between nearby dsb) would be short, very seldom exceeding a few tens of base pairs.

Computer Simulation↗
PubMed1990

Computer modeling studies of ribonuclease T1-guanosine monophosphate complexes.

The three-dimensional structures of ribonuclease (RNase) T1 complexes with the inhibitors 2'-guanylic acid (2'-GMP), 3'-guanylic acid (3'-GMP), and 5'-guanylic acid (5'-GMP) were predicted by energy minimization studies. It is shown that these inhibitors can bind to RNase T1 in either of the ribose puckered conformations (C2'-endo and C3'-endo) in solid state and exist in significant amounts in both forms in solution. These studies are in agreement with the x-ray crystallographic studies of the 2'-GMP-Lys25-RNase T1 complex, where the inhibitor binds in C2'-endo puckered conformation. These results are also in good agreement with the available 1H-nmr results of Inagaki et al. [(1985) Biochemistry 24, 1013-1020], but differ from their conclusions where the authors favor only the C3'-endo ribose conformation for all the three inhibitors. The calculations explain the apparent discrepancies in the conclusions drawn by x-ray crystallographic and spectroscopic studies. An extensive hydrogen-bonding scheme was predicted in all the three complexes. The hydrogen-bonding scheme predicted for the 2'-GMP (C2'-endo)-RNase T1 complex agrees well with those reported from x-ray crystallographic studies. In all three complexes the base and the phosphate bind in nearly identical sites independent of the position of the phosphate or the ribose pucker. The glycosyl torsion angle favors a value in the +syn range in the 2'-GMP (C2'-endo)-RNase T1, 3'-GMP (C2'-endo)-RNase T1, and 3'-GMP (C3'-endo)-RNase T1 complexes; in the high-syn range in the 2'-GMP (C3'-endo)-RNase T1 complex; and in the -syn range in the 5'-GMP (C2'-endo)-RNase T1 and 5'-GMP (C3'-endo)-RNase T1 complexes. These results are in agreement with experimental studies showing that the inhibitory power decreases in the order 2'-GMP greater than 3'-GMP greater than 5'-GMP, and they also explain the high pKa value observed for Glu58 in the 2'-GMP-RNase T1 complex.

Computer Simulation↗
PubMed2000

Supramolecular assemblies of quaternary ammonium cations and halide anions in the gas phase: ESMS-FTICR data and computer modelling

Supramolecular aggregates of tetraalkylammonium halides (R4NX) are formed by electrospray out of acetonitrile solution. Mass spectrometry reveals 88 charged aggregates for R= Me, Et, Bu; X= Br, I, ranging up to [(Bu4N)39Br42]3- in size. With the objective of improving calculations of intermolecular energies for supramolecular aggregates of ions, calibrated semi-empirical potentials for inter-ion interactions have been developed and applied to these aggregates. The accuracy of the calculated energies is supported by the measured collisional dissociation energy of (Et4N+)4 (I-)5. Energy optimisations indicate that the probable structures have the halide ions dispersed in a matrix of cations, which, for Bu4N+, can be mutually attractive. The aggregates are structurally fluid, with multiple structures separated by 4-8 kJmol(-1). The energy calculations are entirely consistent with the observed formation of large aggregates, and of multiply charged anions. It is estimated that the cohesive energies of supramolecular assemblies of ions such as these reach about 40 kJmol(-1) per constituent ion.

Journal Article↗
PubMed2006

Computational model for the IGF-II/IGF2r complex that is predictive of mutational and surface plasmon resonance data.

Insulin-like growth factors (IGFs) are key regulators of cell proliferation, differentiation, and transformation, and are thus pivotal in cancer, especially breast, prostate, and colon neoplasm. Their potent mitogenic and anti-apoptotic actions depend primarily on their availability to bind to the signaling IGF cell surface receptors. One mechanism by which IGF-II availability is thought to be modulated is by binding to the nonsignaling IGF-II receptor (IGF2R). This binding is essentially mediated by domain 11 in the multidomain IGF2R extracellular region. The crystal structure of domain 11 of the human IGF-II receptor (IGF2R-d11) has identified a putative IGF-II binding site, and a nuclear magnetic resonance (NMR) solution structure for the IGF-II ligand has also been characterized. These structures have now been used to model in silico the protein-protein interaction between IGF-II and IGF2R-d11 using the program 3D-Dock. Because the IGF-II data comprise an ensemble of 20 structures, all of which satisfy the NMR constraints, the docking procedure was applied to each member of the ensemble. Only those models in which residue Ile1572 of IGF2R-d11, known to be essential for the binding of IGF-II, was at the interface were considered further. These plausible complexes were then critically assessed using an array of analysis techniques including consideration of additional mutagenesis data. One model was strongly supported by these analyses and is discussed here in detail. Furthermore, we demonstrate in vitro experimental support for this model by studying the binding of chimeras of IGF-I and IGF-II to IGF2R fragments.

Binding Sites↗