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PubMed2001

[Computer modeling of joint selection response of MGE patterns and a polygenic system].

Using computer simulation, selection response of three genome patterns--polygenes, mobile genetic elements (MGEs), and labels of identity by origin (LIOs)--were studied. In each generation of selection, variability of each pattern type was described by on UPGMA tree. Stringent positive truncation selection on an additive polygenic trait and recombination between segments of the genetic map were considered. MGEs were classified into three groups: modifiers (enhancers) of the polygenic expression, markers, and independent copies. It was shown that at generations 30 to 40, 95-96% and 70-80% of respectively enforced and non-enforced active polygenic alleles were fixed (2-3% and 16-17% lost). In all generations, Hkn < or = Dkn of the length of the maximal route along the tree. At the same time, modifier MGEs were fixed for 85-88% (lost for 11-12%); marker MGEs, for 60-70 (lost for 21-25%); and independent copies, for 30-40 (lost for 50-60%). The behavior of independent MGE copies was generally consistent with the predictions of the genetic drift theory, modifier MGEs behaved similarly to the modified polygenes, and marker MGEs exhibited intermediate properties. The LIO patterns showed rapid homozygotization: their variability dropped dramatically between generations 10 and 30. In F50, the final consensus pattern of polygenes included 16 out of 18 enforced and 18 out of 21 non-enforced polygenic alleles. The fixation/loss ratios were 16:3 for modifier MGEs, 15:6 for marker MGEs, and 25:28 (with 7 polymorphic) for independent copies. The LIO consensus pattern contained 13 out of 100 original markers, which formed 26 fragments of one to ten map segments in size; 21 fragments contained active polygenic alleles, and 14 of them had also modifier MGEs. Recombinational shuffling of patterns was not completed. In the course of selection, active polygenic alleles take along adjacent segments, including those containing modifier MGEs and markers. These constitute the conservative part of all consensus patterns while the remaining segments are random.

Computer Simulation↗
PubMed1996

Computational models of cortical visual processing.

The visual responses of neurons in the cerebral cortex were first adequately characterized in the 1960s by D. H. Hubel and T. N. Wiesel [(1962) J. Physiol. (London) 160, 106-154; (1968) J. Physiol. (London) 195, 215-243] using qualitative analyses based on simple geometric visual targets. Over the past 30 years, it has become common to consider the properties of these neurons by attempting to make formal descriptions of these transformations they execute on the visual image. Most such models have their roots in linear-systems approaches pioneered in the retina by C. Enroth-Cugell and J. R. Robson [(1966) J. Physiol. (London) 187, 517-552], but it is clear that purely linear models of cortical neurons are inadequate. We present two related models: one designed to account for the responses of simple cells in primary visual cortex (V1) and one designed to account for the responses of pattern direction selective cells in MT (or V5), an extrastriate visual area thought to be involved in the analysis of visual motion. These models share a common structure that operates in the same way on different kinds of input, and instantiate the widely held view that computational strategies are similar throughout the cerebral cortex. Implementations of these models for Macintosh microcomputers are available and can be used to explore the models' properties.

Computer Simulation↗
PubMed1995

Structural basis of the phospholipid acyltransferase enzyme substrate specificity: a computer modeling study of the phospholipid acceptor molecule.

The activity of the 1-acyl-sn-glycero-3-phosphocholine acyltransferase enzyme (E.C. 2.3.1.??) was measured with three radically different acceptor substrates: 1-palmitoyl-sn-glycero-3-phosphocholine (P-sn-G3PC), 1-palmitoyl-sn-glycero-2-phosphocholine (P-sn-G2PC), and 1-hexadecyl-sn-glycero-3-phosphocholine (He-sn-G3PC). It was found that the enzyme had similar activity with P-sn-G3PC, the natural acceptor substrate, and with P-sn-G2PC. The enzyme showed no detectable activity toward He-sn-G3PC. These results are much different than would be expected from simple examination of the structures. Computer-assisted molecular modeling was done to study the geometrical configurations and to focus upon the similarities and differences of the three substrate acceptor molecules. Three bond distances were selected as important for enzyme recognition: the distance between the oxygen of the acceptor hydroxyl group and 1) the phosphorus; 2) the nitrogen; and 3) the oxygen bridge to the hydrocarbon chain. There were striking similarities for the bond distances of two of the three acceptor substrates, P-sn-G3PC and P-sn-G2PC. These were the two molecules that were shown to have activity with the enzyme. The bond distances found for the enzymically inactive acceptor substrate, He-sn-G3PC, differed significantly from P-sn-G3PC and P-sn-G2PC. Therefore, this latter molecule probably does not fit into the active site of the enzyme. The modeling data are also consistent with the experimental observation that He-sn-G3PC is not an inhibitor.

Acyltransferases↗
PubMedDate not supplied

Computational modeling of orientation tuning dynamics in monkey primary visual cortex.

In the primate visual pathway, orientation tuning of neurons is first observed in the primary visual cortex. The LGN cells that comprise the thalamic input to V1 are not orientation tuned, but some V1 neurons are quite selective. Two main classes of theoretical models have been offered to explain orientation selectivity: feedforward models, in which inputs from spatially aligned LGN cells are summed together by one cortical neuron; and feedback models, in which an initial weak orientation bias due to convergent LGN input is sharpened and amplified by intracortical feedback. Recent data on the dynamics of orientation tuning, obtained by a cross-correlation technique, may help to distinguish between these classes of models. To test this possibility, we simulated the measurement of orientation tuning dynamics on various receptive field models, including a simple Hubel-Wiesel type feedforward model: a linear spatiotemporal filter followed by an integrate-and-fire spike generator. The computational study reveals that simple feedforward models may account for some aspects of the experimental data but fail to explain many salient features of orientation tuning dynamics in V1 cells. A simple feedback model of interacting cells is also considered. This model is successful in explaining the appearance of Mexican-hat orientation profiles, but other features of the data continue to be unexplained.

Action Potentials↗
PubMed2001

A computational model of postoperative knee kinematics.

A mathematical model for studying the passive kinematics of total knee prostheses can be useful in computer-aided planning and guidance of total joint replacement. If the insertion location and neutral length of knee ligaments is known, the passive kinematics of the knee can be calculated by minimizing the strain energy stored in the ligaments at any angular configuration of the knee. Insertions may be found intraoperatively, or may come from preoperative 3D medical images. The model considered here takes into consideration the geometry of the prosthesis and patient-specific information. This model can be used to study the kinematics of the knee joint of a patient after total joint replacement. The model may be useful in preoperative planning, computer-aided intraoperative guidance, and the design of new prosthetic joints.

Arthroplasty, Replacement, Knee↗
PubMed2001

Interactions between frontal cortex and basal ganglia in working memory: a computational model.

The frontal cortex and the basal ganglia interact via a relatively well understood and elaborate system of interconnections. In the context of motor function, these interconnections can be understood as disinhibiting, or "releasing the brakes," on frontal motor action plans: The basal ganglia detect appropriate contexts for performing motor actions and enable the frontal cortex to execute such actions at the appropriate time. We build on this idea in the domain of working memory through the use of computational neural network models of this circuit. In our model, the frontal cortex exhibits robust active maintenance, whereas the basal ganglia contribute a selective, dynamic gating function that enables frontal memory representations to be rapidly updated in a task-relevant manner. We apply the model to a novel version of the continuous performance task that requires subroutine-like selective working memory updating and compare and contrast our model with other existing models and theories of frontal-cortex-basal-ganglia interactions.

Basal Ganglia↗
PubMed2002

Computational model of the fluid dynamics of a cannula inserted in a vessel: incidence of the presence of side holes in blood flow.

Vascular access methods, performed by the insertion of cannulae into vessels, may disturb the physiological flow of blood, giving rise to non-physiological pressure variations and shear stresses. To date, the hydrodynamic behaviour of the cannulae has been evaluated comparing their pressure loss-flow rate relationships, as obtained from in vitro experiments using a monodimensional approach; this methodology neither furnish information about the local fluid dynamics nor the established flow field in specific clinical work conditions. Since the shear stress is a critical factor in the design of artificial circulatory devices, more knowledge should be necessary about the local values assumed by the haemodynamic parameters during cannulation. An alternative way to investigate the fluid dynamic as accurately as possible is given by numeric studies. A 3D model of cannula concentrically placed in a rigid wall vessel is presented, with the finite element methodology used to numerically simulate the steady-state flow field in two different venous cannulation case studies, with two cannulae having a central hole and two or four side holes, respectively, with the same boundary conditions. Lower velocity and shear stress peak values have been computed for the model with four side holes upstream of the central hole, in the region of the cannula where the inlet flows meet and towards cannula's outlet, due to the increased flow symmetry and inlet area with respect to the model with two side holes. Starting from the investigation of different cannula designs, numerically assessing the local fluid dynamics, indications can be drawn to support both the design phase and the device optimal clinical use, in order to limit risks of biomechanical origin. Thus the presence of four side holes implied, as a consequence of the greater inlet area and of the increased symmetry, a less disturbed blood flow, together with reduced shear stress values. Furthermore, results show that the numerical simulations furnished useful informations on the interaction between vessel and cannula, e.g. on the fluid dynamics establishing in the free luminal space left, in the vessel, by the inserted cannula.

Blood Flow Velocity↗
PubMed2006

Computer modeling demonstrates that electrostatic attraction of nucleosomal DNA is mediated by histone tails.

We conducted molecular dynamics computer simulations of charged histone tail-DNA interactions in systems mimicking nucleosome core particles (NCP) . In a coarse-grained model, the NCP is modeled as a negatively charged spherical particle with flexible polycationic histone tails attached to it in a dielectric continuum with explicit mobile counterions and added salt. The size, charge, and distribution of the tails relative to the core were built to mimick real NCP. In this way, we incorporate attractive ion-ion correlation effects due to fluctuations in the ion cloud and the attractive entropic and energetic tail-bridging effects. In agreement with experimental data, increase of monovalent salt content from salt-free to physiological concentration leads to the formation of NCP aggregates; likewise, in the presence of MgCl2, the NCPs form condensed systems via histone-tail bridging and accumulation of counterions. More detailed mechanisms of the histone tail-DNA interactions and dynamics have been obtained from all-atom molecular dynamics simulations (including water), comprising three DNA 22-mers and 14 short fragments of the H4 histone tail (amino acids 5-12) carrying three positive charges on lysine+ interacting with DNA. We found correlation of the DNA-DNA distance with the presence and association of the histone tail between the DNA molecules.

Binding Sites↗