Decreased internalisation of erbB1 mutants in lung cancer is linked with a mechanism conferring sensitivity to gefitinib.

A majority of gefitinib (IRESSA)-responsive tumours in non-small cell lung cancer have been found to carry mutations in ErbB1. Previously, it has been observed that internalisation-deficient ErbB1 receptors are strong drivers of oncogenesis. Using a computational model of ErbB1 trafficking and signalling, it is found that a deficiency in ErbB1 internalisation is sufficient to explain the observed signalling phenotype of these gefitinib-responsive ErbB1 mutants in lung cancer cell lines. Experimental tests confirm that gefitinib-sensitive cell lines with and without ErbB1 mutations exhibit markedly slower internalisation rates than gefitinib-insensitive cell lines. Moreover, the computational model demonstrates that reduced ErbB1 internalisation rates are mechanistically linked to upregulated AKT signalling. Experimentally it is confirmed that impaired internalisation of ErbB1 is associated with increased AKT activity, which can be blocked by gefitinib. On the basis of these experimental and computational results, it is surmised that gefitinib sensitivity is a marker of a reliance on AKT signalling for cell survival that may be brought about by impaired ErbB1 internalisation.

Computational modelling of ErbB family phosphorylation dynamics in response to transforming growth factor alpha and heregulin indicates spatial compartmentation of phosphatase activity.

Members of the ErbB receptor family are associated with several cancers and appear to be providing useful targets for pharmacological therapeutics for tumours of the lung and breast. Further improvements of these therapies may be guided by a quantitative, dynamic integrative systems understanding of the complexities of ErbB dimerisation, trafficking and activation, for it is these complexities that render difficult intuiting how perturbations such as drug intervention will affect ErbB signalling activities. Towards this goal, we have developed a computational model implementing commonly accepted principles governing ErbB receptor interaction, trafficking, phosphorylation and dephosphorylation. Using this model, we are able to investigate several hypotheses regarding the compartmental localisation of dephosphorylation. Model results applied to experimental data on ErbB 1, ErbB2 and ErbB3 phosphorylation in H292 human lung carcinoma cells support a hypothesis that key dephosphorylation activity for these receptors occurs largely in an intracellular, endosomal compartment rather than at the cell surface plasma membrane. Thus, the endocytic trafficking-related compartmentalisation of dephosphorylation may define a critical aspect of the ErbB signalling response to ligand.

From vision to action: experiments and models of steering control during driving.

Experienced drivers performed simple steering maneuvers in the absence of continuous visual input. Experiments conducted in a driving simulator assessed drivers' performance of lane corrections during brief visual occlusion and examined the visual cues that guide steering. The dependence of steering behavior on heading, speed, and lateral position at the start of the maneuver was measured. Drivers adjusted steering amplitude with heading and performed the maneuver more rapidly at higher speeds. These dependencies were unaffected by a 1.5-s visual occlusion at the start of the maneuver. Longer occlusions resulted in severe performance degradation. Two steering control models were developed to account for these findings. In the 1st, steering actions were coupled to perceptual variables such as lateral position and heading. In the 2nd, drivers pursued a virtual target in the scene. Both models yielded behavior that closely matches that of human drivers.

Optic flow and the metric of the visual ground plane.

A theory is developed in which the optic flow of an observer translating over the ground plane determines the metric of egocentric visual space. Optic flow is used to operationalize the equality of spatial intervals not unlike physicists use time to compare spatial intervals. The theory predicts empirical matching ratios for collinear, sagittal intervals to within 2% of the mean (eight subjects, standard error also 2%). The theory predicts that frontoparallel intervals on the ground plane will match sagittal intervals if their relative image motions match, which was found empirically. It is suggested that the optic flow metric serves to calibrate static depth cues such as angular elevation and binocular parallax.

Perceived object shape affects the perceived direction of self-movement.

The 'direct-perception' model of heading perception posits that heading is computed directly from optic flow without an intervening structural representation of environmental layout. Here, I give an example in which such a representation is seen to play a role in the interpretation of optic flow. Manipulating the outline of concave objects to give an erroneous percept of convexity caused the perceived direction of heading during a stimulated approach to change as well. Thus, the representation of environmental structure provides the context for using and interpreting image motion.

Chromatic properties of neurons in macaque MT.

We have studied the responses of MT neurons to moving gratings, spatially modulated in luminance and chromaticity. Most MT neurons responded briskly and with high contrast sensitivity to targets whose luminance was modulated, with or without added chromatic contrast. When luminance modulation was removed and only chromatic stimulation was used, the responses of all MT neurons were attenuated. Most were completely unresponsive to stimulation with targets whose modulation fell within a "null" plane in color space; these null planes varied from neuron to neuron, but all lay close to the plane of constant photometric luminance. For about a third of the neurons, there was no color direction in which responses were completely abolished; almost all of these neurons had a definite minimum response for chromatic modulation near the isoluminant plane. MT neurons that responded to isoluminant targets did so inconsistently and with poor contrast sensitivity, so that only intensely modulated targets were effective. Whereas the best thresholds of MT neurons for luminance targets are close to behavioral contrast threshold, the thresholds for isoluminant targets lie considerably above behavioral contrast threshold. Therefore, although some MT neurons do give responses to isoluminant targets, they are unlikely to be the source of the chromatic motion signals revealed behaviorally.

Computing the direction of heading from affine image flow.

Observers moving through a three-dimensional environment can use optic flow to determine their direction of heading. Existing heading algorithms use cartesian flow fields in which image flow is the displacement of image features over time. I explore a heading algorithm that uses affine flow instead. The affine flow at an image feature is its displacement modulo an affine transformation defined by its neighborhood. Modeling the observer's instantaneous motion by a translation and a rotation about an axis through its eye, affine flow is tangent to the translational field lines on the observer's viewing sphere. These field lines form a radial flow field whose center is the direction of heading. The affine flow heading algorithm has characteristics that can be used to determine whether the human visual system relies on it. The algorithm is immune to observer rotation and arbitrary affine transformations of its input images; its accuracy improves with increasing variation in environmental depth; and it cannot recover heading in an environment consisting of a single plane because affine flow vanishes in this case. Translational field lines can also be approximated through differential cartesian motion. I compare the performance of heading algorithms based on affine flow, differential cartesian flow, and least-squares search.