Survival and proliferation of immature B lymphocytes requires expression and tonic signaling of the pre-B cell receptor (pre-BCR). This low level, ligand-independent signaling is likely achieved through frequent, but short-lived, homo interactions. Tonic signaling is also central in the pathology of precursor B acute lymphoblastic leukemia (B-ALL). In order to understand how repeated, transient events can lead to sustained signaling and to assess the impact of receptor accumulation induced by the membrane landscape, we developed a spatial stochastic model of receptor aggregation and downstream signaling events. Our rule- and agent-based model builds on previous mature BCR signaling models and incorporates novel parameters derived from single particle tracking of pre-BCR on surfaces of two different B-ALL cell lines, 697 and Nalm6. Live cell tracking of receptors on the two cell lines revealed characteristic differences in their dimer dissociation rates and diffusion coefficients. We report here that these differences affect pre-BCR aggregation and consequent signal initiation events. Receptors on Nalm6 cells, which have a lower off-rate and lower diffusion coefficient, more frequently form higher order oligomers than pre-BCR on 697 cells, resulting in higher levels of downstream phosphorylation in the Nalm6 cell line.

True steady states are a rare occurrence in living organisms, yet their knowledge is essential for quasi-steady-state approximations, multistability analysis, and other important tools in the investigation of chemical reaction networks (CRN) used to describe molecular processes on the cellular level. Here, we present an approach that can provide closed form steady-state solutions to complex systems, resulting from CRN with binary reactions and mass-action rate laws. We map the nonlinear algebraic problem of finding steady states onto a linear problem in a higher-dimensional space. We show that the linearized version of the steady-state equations obeys the linear conservation laws of the original CRN. We identify two classes of problems for which complete, minimally parameterized solutions may be obtained using only the machinery of linear systems and a judicious choice of the variables used as free parameters. We exemplify our method, providing explicit formulae, on CRN describing signal initiation of two important types of RTK receptor-ligand systems, VEGF and EGF-ErbB1.

We present a scalable approach to optimizing robot control policies for a target collective behavior in a spatially inhomogeneous robotic swarm. The approach can incorporate robot feedback to maintain system performance in an unknown environmental flow field. We consider systems in which the robots follow both deterministic and random motion and transition stochastically between tasks. Our methodology is based on an abstraction of the swarm to a macroscopic continuous model, whose dimensionality is independent of the population size, that describes the expected time evolution of swarm subpopulations over a discretization of the environment. We incorporate this model into a stochastic optimization method and map the optimized model parameters onto the robot motion and task transition control policies to achieve a desired global objective. We illustrate our methodology with a scenario in which the behaviors of a swarm of robotic bees are optimized for both uniform and nonuniform pollination of a blueberry field, including in the presence of an unknown wind.

We present an investigation of specialization when considering the execution of collaborative tasks by a robot swarm. Specifically, we consider the stick-pulling problem first proposed by Martinoli et al. [1], [2] and develop a macroscopic analytical model for the swarm executing a set of tasks that require the collaboration of two robots. We show, for constant external conditions, maximum productivity can be achieved by a single species swarm with carefully chosen operational parameters. While the same applies for a two species swarm, we show how specialization is a strategy best employed for changing external conditions.

We present a scalable approach to dynamically allocating a swarm of homogeneous robots to multiple tasks, which are to be performed in parallel, following a desired distribution. We employ a decentralized strategy that requires no communication among robots. It is based on the development of a continuous abstraction of the swarm obtained by modeling population fractions and defining the task allocation problem as the selection of rates of robot ingress and egress to and from each task. These rates are used to determine probabilities that define stochastic control policies for individual robots, which, in turn, produce the desired collective behavior. We address the problem of computing rates to achieve fast redistribution of the swarm subject to constraint(s) on switching between tasks at equilibrium. We present several formulations of this optimization problem that vary in the precedence constraints between tasks and in their dependence on the initial robot distribution. We use each formulation to optimize the rates for a scenario with four tasks and compare the resulting control policies using a simulation in which 250 robots redistribute themselves among four buildings to survey the perimeters.

We present a methodology for characterizing and synthesizing swarm behaviors using both a macroscopic model that represents a swarm as a continuum and a microscopic model that represents individual robots. We develop a systematic approach for synthesizing behaviors at the macroscopic level that can be realized on individual robots at the microscopic level. Our methodology is inspired by a dynamical model of ant house hunting [1], a decentralized process in which a colony attempts to emigrate to the best site among several alternatives. The model is hybrid because the colony switches between different sets of behaviors, or modes, during this process. At the macroscopic level, we are able to synthesize controllers that result in the deployment of a robotic swarm in a predefined ratio between distinct sites. We then derive hybrid controllers for individual robots using only local interactions and no communication that respect the specifications of the global continuous behavior. Our simulations demonstrate that our synthesis procedure yields a correct microscopic model from the macroscopic description with guarantees on performance at both levels

We present an approach for the dynamic assignment and reassignment of a large team of homogeneous robotic agents to multiple locations with applications to search and rescue, reconnaissance and exploration missions. Our work is inspired by experimental studies of ant house hunting and empirical models that predict the behavior of the colony that is faced with a choice between multiple candidate nests. We design stochastic control policies that enable the team of agents to distribute themselves between multiple candidate sites in a specified ratio. Additionally, we present an extension to our model to enable fast convergence via switching behaviors based on quorum sensing. The stability and convergence properties of these control policies are analyzed and simulation results are presented.

MOTIVATION: A phenotype mechanism is classically derived through the study of a set of mutants and comparison of their biochemical capabilities. One method of comparing mutant capabilities is to characterize producible and knocked out metabolites. However such an effect is difficult to manually assess, especially for a large biochemical network and a complex media. Current algorithmic approaches towards analyzing metabolic networks either do not address this specific property or are computationally infeasible on the genome-scale. RESULTS: We have developed a novel genome-scale computational approach that identifies the full set of biochemical species that are knocked out from the metabolome following a gene deletion. Results from this approach are combined with data from in vivo mutant screens to examine the essentiality of metabolite production for a phenotype. This approach can also be a useful tool for metabolic network annotation validation and refinement in newly sequenced organisms. Combining an in silico genome-scale model of Escherichia coli metabolism with in vivo survival data, we uncover possible essential roles for several cell membranes, cell walls, and quinone species. We also identify specific biomass components whose production appears to be non-essential for survival, contrary to the assumptions of previous models. AVAILABILITY: Programs are available upon request from the authors in the form of Matlab script files. SUPPLEMENTARY INFORMATION: http://www.cis.upenn.edu/biocomp/manuscripts/bioinformatics_bti245/supp-info.html.