Role of feedback and dynamics in a gene regulatory network

Cells exhibit a diverse repertoire of dynamic behaviors. These dynamic functions are implemented by circuits of interacting biomolecules. Although these regulatory networks function deterministically by executing specific programs in response to extracellular signals, molecular interactions are inherently governed by stochastic fluctuations. This molecular noise can manifest as cell-to-cell phenotypic heterogeneity in a well-mixed environment. Single-cell variability may seem like a design flaw but the coexistence of diverse phenotypes in an isogenic population of cells can also serve a biological function by increasing the probability of survival of individual cells upon an abrupt change in environmental conditions. Decades of extensive molecular and biochemical characterization have revealed the connectivity and mechanisms that constitute regulatory networks. We are now confronted with the challenge of integrating this information to link the structure of these circuits to systems-level properties such as cellular decision making. To investigate cellular decision-making, we used the well studied galactose gene-regulatory network in \textit{Saccharomyces cerevisiae}. We analyzed the mechanism and dynamics of the coexistence of two stable on and off states for pathway activity. We demonstrate that this bimodality in the pathway activity originates from two positive feedback loops that trigger bistability in the network. By measuring the dynamics of single-cells in a mixed sugar environment, we observe that the bimodality in gene expression is a transient phenomenon. Our experiments indicate that early pathway activation in a cohort of cells prior to galactose metabolism can accelerate galactose consumption and provide a transient increase in growth rate. Together these results provide important insights into strategies implemented by cells that may have been evolutionary advantageous in competitive environments.

Neural network design for switching network control

A neural network is a highly interconnected set of simple processors. The many connections allow information to travel rapidly through the network, and due to their simplicity, many processors in one network are feasible. Together these properties imply that we can build efficient massively parallel machines using neural networks. The primary problem is how do we specify the interconnections in a neural network. The various approaches developed so far such as outer product, learning algorithm, or energy function suffer from the following deficiencies: long training/ specification times; not guaranteed to work on all inputs; requires full connectivity.

Alternatively we discuss methods of using the topology and constraints of the problems themselves to design the topology and connections of the neural solution. We define several useful circuits-generalizations of the Winner-Take-All circuitthat allows us to incorporate constraints using feedback in a controlled manner. These circuits are proven to be stable, and to only converge on valid states. We use the Hopfield electronic model since this is close to an actual implementation. We also discuss methods for incorporating these circuits into larger systems, neural and nonneural. By exploiting regularities in our definition, we can construct efficient networks. To demonstrate the methods, we look to three problems from communications. We first discuss two applications to problems from circuit switching; finding routes in large multistage switches, and the call rearrangement problem. These show both, how we can use many neurons to build massively parallel machines, and how the Winner-Take-All circuits can simplify our designs.

Next we develop a solution to the contention arbitration problem of high-speed packet switches. We define a useful class of switching networks and then design a neural network to solve the contention arbitration problem for this class. Various aspects of the neural network/switch system are analyzed to measure the queueing performance of this method. Using the basic design, a feasible architecture for a large (1024-input) ATM packet switch is presented. Using the massive parallelism of neural networks, we can consider algorithms that were previously computationally unattainable. These now viable algorithms lead us to new perspectives on switch design.