Robustness and reproducibility of simple and complex synthetic logic circuit designs using a DBTL loop.

Computational tools addressing various components of design-build-test-learn (DBTL) loops for the construction of synthetic genetic networks exist but do not generally cover the entire DBTL loop. This manuscript introduces an end-to-end sequence of tools that together form a DBTL loop called Design Assemble Round Trip (DART). DART provides rational selection and refinement of genetic parts to construct and test a circuit. Computational support for experimental process, metadata management, standardized data collection and reproducible data analysis is provided via the previously published Round Trip (RT) test-learn loop. The primary focus of this work is on the Design Assemble (DA) part of the tool chain, which improves on previous techniques by screening up to thousands of network topologies for robust performance using a novel robustness score derived from dynamical behavior based on circuit topology only. In addition, novel experimental support software is introduced for the assembly of genetic circuits. A complete design-through-analysis sequence is presented using several OR and NOR circuit designs, with and without structural redundancy, that are implemented in budding yeast. The execution of DART tested the predictions of the design tools, specifically with regard to robust and reproducible performance under different experimental conditions. The data analysis depended on a novel application of machine learning techniques to segment bimodal flow cytometry distributions. Evidence is presented that, in some cases, a more complex build may impart more robustness and reproducibility across experimental conditions. Graphical Abstract.

Experimental guidance for discovering genetic networks through hypothesis reduction on time series.

Large programs of dynamic gene expression, like cell cyles and circadian rhythms, are controlled by a relatively small "core" network of transcription factors and post-translational modifiers, working in concerted mutual regulation. Recent work suggests that system-independent, quantitative features of the dynamics of gene expression can be used to identify core regulators. We introduce an approach of iterative network hypothesis reduction from time-series data in which increasingly complex features of the dynamic expression of individual, pairs, and entire collections of genes are used to infer functional network models that can produce the observed transcriptional program. The culmination of our work is a computational pipeline, Iterative Network Hypothesis Reduction from Temporal Dynamics (Inherent dynamics pipeline), that provides a priority listing of targets for genetic perturbation to experimentally infer network structure. We demonstrate the capability of this integrated computational pipeline on synthetic and yeast cell-cycle data.

Rational design of complex phenotype via network models.

We demonstrate a modeling and computational framework that allows for rapid screening of thousands of potential network designs for particular dynamic behavior. To illustrate this capability we consider the problem of hysteresis, a prerequisite for construction of robust bistable switches and hence a cornerstone for construction of more complex synthetic circuits. We evaluate and rank most three node networks according to their ability to robustly exhibit hysteresis where robustness is measured with respect to parameters over multiple dynamic phenotypes. Focusing on the highest ranked networks, we demonstrate how additional robustness and design constraints can be applied. We compare our results to more traditional methods based on specific parameterization of ordinary differential equation models and demonstrate a strong qualitative match at a small fraction of the computational cost.

Quantitative measure of memory loss in complex spatiotemporal systems.

History dependence of the evolution of complex systems plays an important role in forecasting. The precision of the predictions declines as the memory of the systems is lost. We propose a simple method for assessing the rate of memory loss that can be applied to experimental data observed in any metric space X. This rate indicates how fast the future states become independent of the initial condition. Under certain regularity conditions on the invariant measure of the dynamical system, we prove that our method provides an upper bound on the mixing rate of the system. This rate can be used to infer the longest time scale on which the predictions are still meaningful. We employ our method to analyze the memory loss of a slowly sheared granular system with a small inertial number I. We show that, even if I is kept fixed, the rate of memory loss depends erratically on the shear rate. Our study suggests the presence of bifurcations at which the rate of memory loss increases with the shear rate, while it decreases away from these points. We also find that the rate of memory loss is closely related to the frequency of the sudden transitions of the force network. Moreover, the rate of memory loss is also well correlated with the loss of correlation of shear stress measured at the system scale. Thus, we have established a direct link between the evolution of force networks and the macroscopic properties of the considered system.

Mapping parameter spaces of biological switches.

Since the seminal 1961 paper of Monod and Jacob, mathematical models of biomolecular circuits have guided our understanding of cell regulation. Model-based exploration of the functional capabilities of any given circuit requires systematic mapping of multidimensional spaces of model parameters. Despite significant advances in computational dynamical systems approaches, this analysis remains a nontrivial task. Here, we use a nonlinear system of ordinary differential equations to model oocyte selection in Drosophila, a robust symmetry-breaking event that relies on autoregulatory localization of oocyte-specification factors. By applying an algorithmic approach that implements symbolic computation and topological methods, we enumerate all phase portraits of stable steady states in the limit when nonlinear regulatory interactions become discrete switches. Leveraging this initial exact partitioning and further using numerical exploration, we locate parameter regions that are dense in purely asymmetric steady states when the nonlinearities are not infinitely sharp, enabling systematic identification of parameter regions that correspond to robust oocyte selection. This framework can be generalized to map the full parameter spaces in a broad class of models involving biological switches.

Contractibility of a persistence map preimage.

This work is motivated by the following question in data-driven study of dynamical systems: given a dynamical system that is observed via time series of persistence diagrams that encode topological features of snapshots of solutions, what conclusions can be drawn about solutions of the original dynamical system? We address this challenge in the context of an N dimensional system of ordinary differential equation defined in R N . To each point in R N (e.g. an initial condition) we associate a persistence diagram. The main result of this paper is that under this association the preimage of every persistence diagram is contractible. As an application we provide conditions under which multiple time series of persistence diagrams can be used to conclude the existence of a fixed point of the differential equation that generates the time series.

Conley Index Approach to Sampled Dynamics.

The topological method for the reconstruction of dynamics from time series [K. Mischaikow et al., Phys. Rev. Lett., 82 (1999), pp. 1144-1147] is reshaped to improve its range of applicability, particularly in the presence of sparse data and strong expansion. The improvement is based on a multivalued map representation of the data. However, unlike the previous approach, it is not required that the representation has a continuous selector. Instead of a selector, a recently developed new version of Conley index theory for multivalued maps [B. Batko, SIAM J. Appl. Dyn. Syst., 16 (2017), pp. 1587-1617; B. Batko and M. Mrozek, SIAM J. Appl. Dyn. Syst., 15 (2016), pp. 1143-1162] is used in computations. The existence of a continuous, single valued generator of the relevant dynamics is guaranteed in the vicinity of the graph of the multivalued map constructed from data. Some numerical examples based on time series derived from the iteration of Hénon-type maps are presented.

A comparison framework for interleaved persistence modules.

We present a generalization of the induced matching theorem of as reported by Bauer and Lesnick (in: Proceedings of the thirtieth annual symposium computational geometry 2014) and use it to prove a generalization of the algebraic stability theorem for ℝ -indexed pointwise finite-dimensional persistence modules. Via numerous examples, we show how the generalized algebraic stability theorem enables the computation of rigorous error bounds in the space of persistence diagrams that go beyond the typical formulation in terms of bottleneck (or log bottleneck) distance.

Global dynamics for switching systems and their extensions by linear differential equations.

Switching systems use piecewise constant nonlinearities to model gene regulatory networks. This choice provides advantages in the analysis of behavior and allows the global description of dynamics in terms of Morse graphs associated to nodes of a parameter graph. The parameter graph captures spatial characteristics of a decomposition of parameter space into domains with identical Morse graphs. However, there are many cellular processes that do not exhibit threshold-like behavior and thus are not well described by a switching system. We consider a class of extensions of switching systems formed by a mixture of switching interactions and chains of variables governed by linear differential equations. We show that the parameter graphs associated to the switching system and any of its extensions are identical. For each parameter graph node, there is an order-preserving map from the Morse graph of the switching system to the Morse graph of any of its extensions. We provide counterexamples that show why possible stronger relationships between the Morse graphs are not valid.

DSGRN: Examining the Dynamics of Families of Logical Models.

We present a computational tool DSGRN for exploring the dynamics of a network by computing summaries of the dynamics of switching models compatible with the network across all parameters. The network can arise directly from a biological problem, or indirectly as the interaction graph of a Boolean model. This tool computes a finite decomposition of parameter space such that for each region, the state transition graph that describes the coarse dynamical behavior of a network is the same. Each of these parameter regions corresponds to a different logical description of the network dynamics. The comparison of dynamics across parameters with experimental data allows the rejection of parameter regimes or entire networks as viable models for representing the underlying regulatory mechanisms. This in turn allows a search through the space of perturbations of a given network for networks that robustly fit the data. These are the first steps toward discovering a network that optimally matches the observed dynamics by searching through the space of networks.

Characterizing granular networks using topological metrics.

We carry out a direct comparison of experimental and numerical realizations of the exact same granular system as it undergoes shear jamming. We adjust the numerical methods used to optimally represent the experimental settings and outcomes up to microscopic contact force dynamics. Measures presented here range from microscopic through mesoscopic to systemwide characteristics of the system. Topological properties of the mesoscopic force networks provide a key link between microscales and macroscales. We report two main findings: (1) The number of particles in the packing that have at least two contacts is a good predictor for the mechanical state of the system, regardless of strain history and packing density. All measures explored in both experiments and numerics, including stress-tensor-derived measures and contact numbers depend in a universal manner on the fraction of nonrattler particles, f_{NR}. (2) The force network topology also tends to show this universality, yet the shape of the master curve depends much more on the details of the numerical simulations. In particular we show that adding force noise to the numerical data set can significantly alter the topological features in the data. We conclude that both f_{NR} and topological metrics are useful measures to consider when quantifying the state of a granular system.

Identifying robust hysteresis in networks.

We present a new modeling and computational tool that computes rigorous summaries of network dynamics over large sets of parameter values. These summaries, organized in a database, can be searched for observed dynamics, e.g., bistability and hysteresis, to discover parameter regimes over which they are supported. We illustrate our approach on several networks underlying the restriction point of the cell cycle in humans and yeast. We rank networks by how robustly they support hysteresis, which is the observed phenotype. We find that the best 6-node human network and the yeast network share similar topology and robustness of hysteresis, in spite of having no homology between the corresponding nodes of the network. Our approach provides a new tool linking network structure and dynamics.

Model Rejection and Parameter Reduction via Time Series.

We show how a graph algorithm for finding matching labeled paths in pairs of labeled directed graphs can be used to perform model invalidation for a class of dynamical systems including regulatory network models of relevance to systems biology. In particular, given a partial order of events describing local minima and local maxima of observed quantities from experimental time series data, we produce a labeled directed graph we call the pattern graph for which every path from root to leaf corresponds to a plausible sequence of events. We then consider the regulatory network model, which can itself be rendered into a labeled directed graph we call the search graph via techniques previously developed in computational dynamics. Labels on the pattern graph correspond to experimentally observed events, while labels on the search graph correspond to mathematical facts about the model. We give a theoretical guarantee that failing to find a match invalidates the model. As an application we consider gene regulatory models for the yeast S. cerevisiae.

Combinatorial representation of parameter space for switching networks.

We describe the theoretical and computational framework for the Dynamic Signatures for Genetic Regulatory Network ( DSGRN) database. The motivation stems from urgent need to understand the global dynamics of biologically relevant signal transduction/gene regulatory networks that have at least 5 to 10 nodes, involve multiple interactions, and decades of parameters. The input to the database computations is a regulatory network, i.e. a directed graph with edges indicating up or down regulation. A computational model based on switching networks is generated from the regulatory network. The phase space dimension of this model equals the number of nodes and the associated parameter space consists of one parameter for each node (a decay rate), and three parameters for each edge (low level of expression, high level of expression, and threshold at which expression levels change). Since the nonlinearities of switching systems are piece-wise constant, there is a natural decomposition of phase space into cells from which the dynamics can be described combinatorially in terms of a state transition graph. This in turn leads to a compact representation of the global dynamics called an annotated Morse graph that identifies recurrent and nonrecurrent dynamics. The focus of this paper is on the construction of a natural computable finite decomposition of parameter space into domains where the annotated Morse graph description of dynamics is constant. We use this decomposition to construct an SQL database that can be effectively searched for dynamical signatures such as bistability, stable or unstable oscillations, and stable equilibria. We include two simple 3-node networks to provide small explicit examples of the type of information stored in the DSGRN database. To demonstrate the computational capabilities of this system we consider a simple network associated with p53 that involves 5 nodes and a 29-dimensional parameter space.

Topological data analysis of contagion maps for examining spreading processes on networks.

Social and biological contagions are influenced by the spatial embeddedness of networks. Historically, many epidemics spread as a wave across part of the Earth's surface; however, in modern contagions long-range edges-for example, due to airline transportation or communication media-allow clusters of a contagion to appear in distant locations. Here we study the spread of contagions on networks through a methodology grounded in topological data analysis and nonlinear dimension reduction. We construct 'contagion maps' that use multiple contagions on a network to map the nodes as a point cloud. By analysing the topology, geometry and dimensionality of manifold structure in such point clouds, we reveal insights to aid in the modelling, forecast and control of spreading processes. Our approach highlights contagion maps also as a viable tool for inferring low-dimensional structure in networks.

Evolution of force networks in dense particulate media.

We discuss sets of measures with the goal of describing dynamical properties of force networks in dense particulate systems. The presented approach is based on persistent homology and allows for extracting precise, quantitative measures that describe the evolution of geometric features of the interparticle forces, without necessarily considering the details related to individual contacts between particles. The networks considered emerge from discrete element simulations of two-dimensional particulate systems consisting of compressible frictional circular disks. We quantify the evolution of the networks for slowly compressed systems undergoing jamming transition. The main findings include uncovering significant but localized changes of force networks for unjammed systems, global (systemwide) changes as the systems evolve through jamming, to be followed by significantly less dramatic evolution for the jammed states. We consider both connected components, related in a loose sense to force chains, and loops and find that both measures provide a significant insight into the evolution of force networks. In addition to normal, we consider also tangential forces between the particles and find that they evolve in the consistent manner. Consideration of both frictional and frictionless systems leads us to the conclusion that friction plays a significant role in determining the dynamical properties of the considered networks. We find that the proposed approach describes the considered networks in a precise yet tractable manner, making it possible to identify features which could be difficult or impossible to describe using other approaches.

Combinatorial-topological framework for the analysis of global dynamics.

We discuss an algorithmic framework based on efficient graph algorithms and algebraic-topological computational tools. The framework is aimed at automatic computation of a database of global dynamics of a given m-parameter semidynamical system with discrete time on a bounded subset of the n-dimensional phase space. We introduce the mathematical background, which is based upon Conley's topological approach to dynamics, describe the algorithms for the analysis of the dynamics using rectangular grids both in phase space and parameter space, and show two sample applications.

Extensive scaling from computational homology and Karhunen-Loève decomposition analysis of Rayleigh-Bénard convection experiments.

Spatiotemporally chaotic dynamics in laboratory experiments on convection are characterized using a new dimension, D(CH), determined from computational homology. Over a large range of system sizes, D(CH) scales in the same manner as D(KLD), a dimension determined from experimental data using Karhuenen-Loéve decomposition. Moreover, finite-size effects (the presence of boundaries in the experiment) lead to deviations from scaling that are similar for both D(CH) and D(KLD). In the absence of symmetry, D(CH) can be determined more rapidly than D(KLD).