Andrew Philippides

The role of differential VE-cadherin dynamics in cell rearrangement during angiogenesis

Endothelial cells show surprising cell rearrangement behaviour during angiogenic sprouting; however, the underlying mechanisms and functional importance remain unclear. By combining computational modelling with experimentation, we identify that Notch/VEGFR-regulated differential dynamics of VE-cadherin junctions drive functional endothelial cell rearrangements during sprouting. We propose that continual flux in Notch signalling levels in individual cells results in differential VE-cadherin turnover and junctional-cortex protrusions, which powers differential cell movement. In cultured endothelial cells, Notch signalling quantitatively reduced junctional VE-cadherin mobility. In simulations, only differential adhesion dynamics generated long-range position changes, required for tip cell competition and stalk cell intercalation. Simulation and quantitative image analysis on VE-cadherin junctional patterning in vivo identified that differential VE-cadherin mobility is lost under pathological high VEGF conditions, in retinopathy and tumour vessels. Our results provide a mechanistic concept for how cells rearrange during normal sprouting and how rearrangement switches to generate abnormal vessels in pathologies.

A model of ant route navigation driven by scene familiarity

In this paper we propose a model of visually guided route navigation in ants that captures the known properties of real behaviour whilst retaining mechanistic simplicity and thus biological plausibility. For an ant, the coupling of movement and viewing direction means that a familiar view specifies a familiar direction of movement. Since the views experienced along a habitual route will be more familiar, route navigation can be re-cast as a search for familiar views. This search can be performed with a simple scanning routine, a behaviour that ants have been observed to perform. We test this proposed route navigation strategy in simulation, by learning a series of routes through visually cluttered environments consisting of objects that are only distinguishable as silhouettes against the sky. In the first instance we determine view familiarity by exhaustive comparison with the set of views experienced during training. In further experiments we train an artificial neural network to perform familiarity discrimination using the training views. Our results indicate that, not only is the approach successful, but also that the routes that are learnt show many of the characteristics of the routes of desert ants. As such, we believe the model represents the only detailed and complete model of insect route guidance to date. What is more, the model provides a general demonstration that visually guided routes can be produced with parsimonious mechanisms that do not specify when or what to learn, nor separate routes into sequences of waypoints.

Animal Cognition: Multi-modal Interactions in Ant Learning

A recent study shows that desert ants use a precise behaviour, based on the internal cues of path integration, to facilitate the learning of visual landmark information. This raises fascinating questions about how insects encode familiar terrain.

Holistic visual encoding of ant-like routes: Navigation without waypoints

It is known that ants learn long visually guided routes through complex terrain. However, the mechanisms by which visual information is first learned and then used to control a route direction are not well understood. In this article, we propose a parsimonious mechanism for visually guided route following. We investigate whether a simple approach, involving scanning the environment and moving in the direction that appears most familiar, can provide a model of visually guided route learning in ants. We implement view familiarity as a means of navigation by training a classifier to determine whether a given view is part of a route and using the confidence in this classification as a proxy for familiarity. Through the coupling of movement and viewing direction, a familiar view specifies a familiar direction of viewing and thus a familiar movement to make. We show the feasibility of our approach as a model of ant-like route acquisition by learning a series of nontrivial routes through an indoor environment using a large gantry robot equipped with a panoramic camera.

Modeling Cooperative Volume Signaling in a Plexus of Nitric Oxide Synthase-Expressing Neurons

In vertebrate and invertebrate brains, nitric oxide (NO) synthase (NOS) is frequently expressed in extensive meshworks (plexuses) of exceedingly fine fibers. In this paper, we investigate the functional implications of this morphology by modeling NO diffusion in fiber systems of varying fineness and dispersal. Because size severely limits the signaling ability of an NO-producing fiber, the predominance of fine fibers seems paradoxical. Our modeling reveals, however, that cooperation between many fibers of low individual efficacy can generate an extensive and strong volume signal. Importantly, the signal produced by such a system of cooperating dispersed fibers is significantly more homogeneous in both space and time than that produced by fewer larger sources. Signals generated by plexuses of fine fibers are also better centered on the active region and less dependent on their particular branching morphology. We conclude that an ultrafine plexus is configured to target a volume of the brain with a homogeneous volume signal. Moreover, by translating only persistent regional activity into an effective NO volume signal, dispersed sources integrate neural activity over both space and time. In the mammalian cerebral cortex, for example, the NOS plexus would preferentially translate persistent regional increases in neural activity into a signal that targets blood vessels residing in the same region of the cortex, resulting in an increased regional blood flow. We propose that the fineness-dependent properties of volume signals may in part account for the presence of similar NOS plexus morphologies in distantly related animals.

Linked Local Navigation for Visual Route Guidance

Insects are able to navigate reliably between food and nest using only visual information. This behavior has inspired many models of visual landmark guidance, some of which have been tested on autonomous robots. The majority of these models work by comparing the agents current view with a view of the world stored when the agent was at the goal. The region from which agents can successfully reach home is therefore limited to the goals visual locale, that is, the area around the goal where the visual scene is not radically different to the goal position. Ants are known to navigate over large distances using visually guided routes consisting of a series of visual memories. Taking inspiration from such route navigation, we propose a framework for linking together local navigation methods. We implement this framework on a robotic platform and test it in a series of environments in which local navigation methods fail. Finally, we show that the framework is robust to environments of varying complexity.

From Mindless Masses to Small Groups: Conceptualizing Collective Behavior in Crowd Modeling

Computer simulations are increasingly used to monitor and predict behavior at large crowd events, such as mass gatherings, festivals and evacuations. We critically examine the crowd modeling literature and call for future simulations of crowd behavior to be based more closely on findings from current social psychological research. A systematic review was conducted on the crowd modeling literature (N = 140 articles) to identify the assumptions about crowd behavior that modelers use in their simulations. Articles were coded according to the way in which crowd structure was modeled. It was found that 2 broad types are used: mass approaches and small group approaches. However, neither the mass nor the small group approaches can accurately simulate the large collective behavior that has been found in extensive empirical research on crowd events. We argue that to model crowd behavior realistically, simulations must use methods which allow crowd members to identify with each other, as suggested by self-categorization theory.

Snapshots in ants? New interpretations of paradigmatic experiments

SUMMARY Ants can use visual information to guide long idiosyncratic routes and accurately pinpoint locations in complex natural environments. It has often been assumed that the world knowledge of these foragers consists of multiple discrete views that are retrieved sequentially for breaking routes into sections controlling approaches to a goal. Here we challenge this idea using a model of visual navigation that does not store and use discrete views to replicate the results from paradigmatic experiments that have been taken as evidence that ants navigate using such discrete snapshots. Instead of sequentially retrieving views, the proposed architecture gathers information from all experienced views into a single memory network, and uses this network all along the route to determine the most familiar heading at a given location. This algorithm is consistent with the navigation of ants in both laboratory and natural environments, and provides a parsimonious solution to deal with visual information from multiple locations.

VEGFR2 pY949 signalling regulates adherens junction integrity and metastatic spread

The specific role of VEGFA-induced permeability and vascular leakage in physiology and pathology has remained unclear. Here we show that VEGFA-induced vascular leakage depends on signalling initiated via the VEGFR2 phosphosite Y949, regulating dynamic c-Src and VE-cadherin phosphorylation. Abolished Y949 signalling in the mouse mutant Vegfr2Y949F/Y949F leads to VEGFA-resistant endothelial adherens junctions and a block in molecular extravasation. Vessels in Vegfr2Y949F/Y949F mice remain sensitive to inflammatory cytokines, and vascular morphology, blood pressure and flow parameters are normal. Tumour-bearing Vegfr2Y949F/Y949F mice display reduced vascular leakage and oedema, improved response to chemotherapy and, importantly, reduced metastatic spread. The inflammatory infiltration in the tumour micro-environment is unaffected. Blocking VEGFA-induced disassembly of endothelial junctions, thereby suppressing tumour oedema and metastatic spread, may be preferable to full vascular suppression in the treatment of certain cancer forms.

Visual scanning behaviours and their role in the navigation of the Australian desert ant Melophorus bagoti

Ants are excellent navigators, using a combination of innate strategies and learnt information to guide habitual routes. The mechanisms underlying this behaviour are little understood though one avenue of investigation is to explore how innate sensori-motor routines are used to accomplish route navigation. For instance, Australian desert ant foragers are occasionally observed to cease translation and rotate on the spot. Here, we investigate this behaviour using high-speed videography and computational analysis. We find that scanning behaviour is saccadic with pauses separated by fast rotations. Further, we have identified four situations where scanning is typically displayed: (1) by naïve ants on their first departure from the nest; (2) by experienced ants departing from the nest for their first foraging trip of the day; (3) by experienced ants when the familiar visual surround was experimentally modified, in which case frequency and duration of scans were proportional to the degree of modification; (4) when the information from visual cues is at odds with the direction indicated by the ant’s path integration system. Taken together, we see a general relationship between scanning behaviours and periods of uncertainty.