Xenorhabdus griffiniae is a bacterium that lives inside the intestine of the entomopathogenic nematode Steinernema hermaphroditum and partners with the nematode to infect and kill insect larvae in soil. The construction of gene circuits, like reporters, in X. griffiniae would provide tools to study and better understand the symbiotic relationship it has with its host. However, because X. griffiniae is not a model organism, information about gene circuit construction in X. griffiniae is limited. We develop and characterize a DNA part library similar to the CIDAR MoClo extension library for E. coli to allow more efficient construction of genetic circuits in X. griffiniae. TurboRFP expressing strains with different constitutive Anderson promoters and different ribosome binding sites (RBS) were constructed to quantify promoter and RBS strengths in X. griffiniae. Furthermore, two fluorescent proteins sfGFP and sfYFP, as well as the bioluminescent luxCDABE operon were added to the part library and successfully expressed in X. griffiniae. We then used the characterized parts to build and characterize IPTG inducible constructs.
", "doi": "10.1101/2025.06.09.658710", "publisher": "BioRxiv", "publication_date": "2025-06-09" }, { "id": "authors:hb9x2-t0n76", "collection": "authors", "collection_id": "hb9x2-t0n76", "cite_using_url": "https://authors.library.caltech.edu/records/hb9x2-t0n76", "type": "monograph", "title": "Policy Recommendations for the Regulation of Engineered Microbes for Environmental Release", "author": [ { "family_name": "Marken", "given_name": "John P.", "orcid": "0000-0001-9696-088X", "clpid": "Marken-John-P" }, { "family_name": "Maxon", "given_name": "Mary E." }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "Engineered Microbes for Environmental Release (EMERs) are an emerging biotechnology sector that is poised to play a significant role in shaping the global bioeconomy through their ability to address challenges related to climate change, environmental remediation and diagnostics, self-regenerating structural infrastructure, and more. However, the current U.S. regulatory system is not well equipped to efficiently regulate EMERs, leading to a large regulatory burden on EMER developers that may not be commensurate with the level of risk associated with the product. Such burdens impede innovation in the EMER sector. In this report, we identify some of the specific challenges that EMER products face in navigating the federal biotechnology regulatory framework, and present actionable policy recommendations to the federal government, the biotechnology industry, and the wider scientific community about how to address these challenges.
", "doi": "10.57959/bgny-v542", "publisher": "The Linde Center for Science, Society, and Policy, Caltech", "publication_date": "2024-06-28" }, { "id": "authors:0p6md-nzv84", "collection": "authors", "collection_id": "0p6md-nzv84", "cite_using_url": "https://authors.library.caltech.edu/records/0p6md-nzv84", "type": "monograph", "title": "TRILL: Orchestrating Modular Deep-Learning Workflows for Democratized, Scalable Protein Analysis and Engineering", "author": [ { "family_name": "Martinez", "given_name": "Zachary A", "orcid": "0000-0002-7830-3162", "clpid": "Martinez-Zachary-A" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" }, { "family_name": "Thomson", "given_name": "Matt", "orcid": "0000-0003-1021-1234", "clpid": "Thomson-M-W" } ], "abstract": "Deep-learning models have been rapidly adopted by many fields, partly due to the deluge of data humanity has amassed. In particular, the petabases of biological sequencing data enable the unsupervised training of protein language models that learn the “language of life.” However, due to their prohibitive size and complexity, contemporary deep-learning models are often unwieldy, especially for scientists with limited machine learning backgrounds. TRILL (TRaining and Inference using the Language of Life) is a platform for creative protein design and discovery. Leveraging several state-of-the-art models such as ESM-2, DiffDock, and RFDiffusion, TRILL allows researchers to generate novel proteins, predict 3-D structures, extract high-dimensional representations of proteins, functionally classify proteins and more. What sets TRILL apart is its ability to enable complex pipelines by chaining together models and effectively merging the capabilities of different models to achieve a sum greater than its individual parts. Whether using Google Colab with one GPU or a supercomputer with hundreds, TRILL allows scientists to effectively utilize models with millions to billions of parameters by using optimized training strategies such as ZeRO-Offload and distributed data parallel. Therefore, TRILL not only bridges the gap between complex deep-learning models and their practical application in the field of biology, but also simplifies the orchestration of these models into comprehensive workflows, democratizing access to powerful methods. Documentation: https://trill.readthedocs.io/en/latest/home.html.
", "doi": "10.1101/2023.10.24.563881", "pmcid": "PMC10659302", "issn": "2692-8205", "publisher": "Cold Spring Harbor Laboratory Press", "publication": "bioRxiv", "publication_date": "2023-11-10", "pages": "2023.10.24.563881" }, { "id": "authors:0adck-tpr02", "collection": "authors", "collection_id": "0adck-tpr02", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20230327-442725000.2", "type": "monograph", "title": "Probing metabolism in an E. coli-based cell-free system reveals a trade-off between transcription and translation", "author": [ { "family_name": "Kapasiawala", "given_name": "Manisha", "orcid": "0000-0002-0302-2921", "clpid": "Kapasiawala-Manisha" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "Cell-free transcription-translation (TX-TL) systems have been used for diverse applications, from prototyping gene circuits to providing a platform for the development of synthetic life, but their performance is limited by issues such as batch-to-batch variability, poor predictability, and limited lifetime. These issues stem largely from the fact that cell lysate contains an active and complex metabolism whose effect on TX-TL has remained largely uncharacterized. \n\nMotivated by a minimal model of cell-free metabolism, this work explored the effects of energy molecules, which power TX-TL, and fuel molecules, which regenerate energy by harnessing core metabolism, on anE. coli-based TX-TL system. This work reports a compensatory interaction between TX-TL components Mg\u207a\u00b2 and 3-phosphoglyceric acid (3-PGA, used to regenerate ATP), where if one component's concentration is increased, the other's must likewise be increased to maintain optimal translation. Furthermore, maximum total mRNA and protein production occur in different and opposite concentration regimes of Mg\u207a\u00b2 and 3-PGA. To explore the observed phenomenon, transcription and translation were decoupled. Under translation inhibition, transcriptional output was uniform across Mg\u207a\u00b2 and 3-PGA concentrations, but in a translation-only system, maximum protein production occurred in the previously found optimal regime of Mg\u207a\u00b2 and 3-PGA, suggesting a TX-TL trade-off. Using alternative fuels to regenerate energy, this work found that the trade-off is universal across the different fuel sources, and that a system's position along the trade-off is determined strongly by Mg\u207a\u00b2 and DNA concentrations. In systems where additional energy is supplied and where a fuel source is absent, the trade-off is absent, suggesting the trade-off arises from limitations in the regulation of translation and efficient energy regeneration. This work represents a significant advancement in understanding the effects of fuel and energy metabolism on TX-TL in cell-free systems and lays the foundation for improving TX-TL performance, lifetime, standardization, and prediction.", "doi": "10.1101/2023.03.22.533877", "publication_date": "2023-03-24" }, { "id": "authors:sba98-91065", "collection": "authors", "collection_id": "sba98-91065", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20230316-182856000.69", "type": "monograph", "title": "Addressable and adaptable intercellular communication via DNA messaging", "author": [ { "family_name": "Marken", "given_name": "John P.", "orcid": "0000-0001-9696-088X", "clpid": "Marken-John-P" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "Engineered consortia are a major research focus for synthetic biologists because they can implement sophisticated behaviors inaccessible to single-strain systems. However, this functional capacity is constrained by their constituent strains' ability to engage in complex communication. DNA messaging, by enabling information-rich channel-decoupled communication, is a promising candidate architecture for implementing complex communication. But its major advantage, its messages' dynamic mutability, is still unexplored. We develop a framework for addressable and adaptable DNA messaging that leverages all three of these advantages and implement it in a plasmid conjugation-based communication channel. Our system can bias the transfer of messages to targeted receiver strains by 100-to 1000-fold, and their recipient lists can be dynamically updatedin situto control the flow of information through the population. This work lays the foundation for future developments that further utilize the unique advantages of DNA messaging to engineer previously-inaccessible levels of complexity into biological systems.", "doi": "10.1101/2022.11.17.516988", "publication_date": "2022-11-18" }, { "id": "authors:0x59b-dhz66", "collection": "authors", "collection_id": "0x59b-dhz66", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20221219-234021838", "type": "monograph", "title": "Evaluation Metrics for Object Detection for Autonomous Systems", "author": [ { "family_name": "Badithela", "given_name": "Apurva", "clpid": "Badithela-Apurva" }, { "family_name": "Wongpiromsarn", "given_name": "Tichakorn", "orcid": "0000-0002-3977-122X", "clpid": "Wongpiromsarn-Tichakorn" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "This paper studies the evaluation of learning-based object detection models in conjunction with model-checking of formal specifications defined on an abstract model of an autonomous system and its environment. In particular, we define two metrics -- \\emph{proposition-labeled} and \\emph{class-labeled} confusion matrices -- for evaluating object detection, and we incorporate these metrics to compute the satisfaction probability of system-level safety requirements. While confusion matrices have been effective for comparative evaluation of classification and object detection models, our framework fills two key gaps. First, we relate the performance of object detection to formal requirements defined over downstream high-level planning tasks. In particular, we provide empirical results that show that the choice of a good object detection algorithm, with respect to formal requirements on the overall system, significantly depends on the downstream planning and control design. Secondly, unlike the traditional confusion matrix, our metrics account for variations in performance with respect to the distance between the ego and the object being detected. We demonstrate this framework on a car-pedestrian example by computing the satisfaction probabilities for safety requirements formalized in Linear Temporal Logic (LTL).", "doi": "10.48550/arXiv.2210.10298", "publisher": "arXiv", "publication_date": "2022-10-19" }, { "id": "authors:pnp9k-akm20", "collection": "authors", "collection_id": "pnp9k-akm20", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20221219-234102223", "type": "monograph", "title": "Synthesizing Reactive Test Environments for Autonomous Systems: Testing Reach-Avoid Specifications with Multi-Commodity Flows", "author": [ { "family_name": "Badithela", "given_name": "Apurva", "clpid": "Badithela-Apurva" }, { "family_name": "Graebener", "given_name": "Josefine B.", "clpid": "Graebener-Josefine-B" }, { "family_name": "Ubellacker", "given_name": "Wyatt", "orcid": "0000-0002-4732-6185", "clpid": "Ubellacker-Wyatt-L" }, { "family_name": "Mazumdar", "given_name": "Eric V.", "orcid": "0000-0002-1815-269X", "clpid": "Mazumdar-Eric" }, { "family_name": "Ames", "given_name": "Aaron D.", "orcid": "0000-0003-0848-3177", "clpid": "Ames-A-D" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "We study automated test generation for verifying discrete decision-making modules in autonomous systems. We utilize linear temporal logic to encode the requirements on the system under test in the system specification and the behavior that we want to observe during the test is given as the test specification which is unknown to the system. First, we use the specifications and their corresponding non-deterministic B\u00fcchi automata to generate the specification product automaton. Second, a virtual product graph representing the high-level interaction between the system and the test environment is constructed modeling the product automaton encoding the system, the test environment, and specifications. The main result of this paper is an optimization problem, framed as a multi-commodity network flow problem, that solves for constraints on the virtual product graph which can then be projected to the test environment. Therefore, the result of the optimization problem is reactive test synthesis that ensures that the system meets the test specifications along with satisfying the system specifications. This framework is illustrated in simulation on grid world examples, and demonstrated on hardware with the Unitree A1 quadruped, wherein dynamic locomotion behaviors are verified in the context of reactive test environments.", "doi": "10.48550/arXiv.2210.10304", "publisher": "arXiv", "publication_date": "2022-10-19" }, { "id": "authors:4cc39-qh396", "collection": "authors", "collection_id": "4cc39-qh396", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20230322-366884000.3", "type": "monograph", "title": "Characterization of Integrase and Excisionase Activity in Cell-free Protein Expression System Using a Modeling and Analysis Pipeline", "author": [ { "family_name": "Pandey", "given_name": "Ayush", "orcid": "0000-0003-3590-4459", "clpid": "Pandey-Ayush" }, { "family_name": "Rodriguez", "given_name": "Makena L.", "clpid": "Rodriguez-Makena-L" }, { "family_name": "Poole", "given_name": "William", "orcid": "0000-0002-2958-6776", "clpid": "Poole-William" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "We present a full-stack modeling, analysis, and parameter identification pipeline to guide the modeling and design of biological systems starting from specifications to circuit implementations and parameterizations. We demonstrate this pipeline by characterizing the integrase and excisionase activity in cell-free protein expression system. We build on existing Python tools \u2014 BioCRNpyler, AutoReduce, and Bioscrape \u2014 to create this pipeline. For enzyme-mediated DNA recombination in cell-free system, we create detailed chemical reaction network models from simple high-level descriptions of the biological circuits and their context using BioCRNpyler. We use Bioscrape to show that the output of the detailed model is sensitive to many parameters. However, parameter identification is infeasible for this high-dimensional model, hence, we use AutoReduce to automatically obtain reduced models that have fewer parameters. This results in a hierarchy of reduced models under different assumptions to finally arrive at a minimal ODE model for each circuit. Then, we run sensitivity analysis-guided Bayesian inference using Bioscrape for each circuit to identify the model parameters. This process allows us to quantify integrase and excisionase activity in cell extracts enabling complex-circuit designs that depend on accurate control over protein expression levels through DNA recombination. The automated pipeline presented in this paper opens up a new approach to complex circuit design, modeling, reduction, and parameterization.", "doi": "10.1101/2022.10.05.511053", "publication_date": "2022-10-07" }, { "id": "authors:c4ba7-6zp34", "collection": "authors", "collection_id": "c4ba7-6zp34", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20221219-234018464", "type": "monograph", "title": "OUTformation: Distributed Data-Gathering with Feedback under Unknown Environment and Communication Delay Constraints", "author": [ { "family_name": "Han", "given_name": "SooJean", "orcid": "0000-0003-1195-6465", "clpid": "Han-SooJean" }, { "family_name": "Effros", "given_name": "Michelle", "orcid": "0000-0003-3757-0675", "clpid": "Effros-M" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "Towards the informed design of large-scale distributed data-gathering architectures under real-world assumptions such as nonzero communication delays and unknown environment dynamics, this paper considers the effects of allowing feedback communication from the central processor to external sensors. Using simple but representative state-estimation examples, we investigate fundamental tradeoffs between the mean-squared error (MSE) of the central processor's estimate of the environment state, and the total power expenditure per sensor under more conventional architectures without feedback (INformation) versus those with broadcast feedback (OUTformation). The primary advantage of enabling feedback is that each sensor's understanding of the central processor's estimate improves, which enables each sensor to determine when and what parts of its current observations to transmit. We use theory to demonstrate conditions in which OUTformation maintains the same MSE as INformation with less power expended on average, and conditions in which OUTformation obtains less MSE than INformation at additional power cost. These performance tradeoffs are also considered under settings where environments undergo less variation, and sensors implement random backoff times to prevent transmission collisions. Our results are supported via numerical studies, which show that the properties derived in theory still hold even when some of the simplifying assumptions are removed.", "doi": "10.48550/arXiv.2208.06395", "publisher": "arXiv", "publication_date": "2022-08-12" }, { "id": "authors:k02tb-zyr67", "collection": "authors", "collection_id": "k02tb-zyr67", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20220412-265499000", "type": "monograph", "title": "From Specification to Implementation: Assume-Guarantee Contracts for Synthetic Biology", "author": [ { "family_name": "Pandey", "given_name": "Ayush", "orcid": "0000-0003-3590-4459", "clpid": "Pandey-Ayush" }, { "family_name": "Incer", "given_name": "Inigo", "clpid": "Incer-Inigo" }, { "family_name": "Sangiovanni-Vincentelli", "given_name": "Alberto", "orcid": "0000-0003-1298-8389", "clpid": "Sangiovanni-Vincentelli-Alberto-L" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "We provide a new perspective on using formal methods to model specifications and synthesize implementations for the design of biological circuits. In synthetic biology, design objectives are rarely described formally. We present an assume-guarantee contract framework to describe biological circuit design objectives as formal specifications. In our approach, these formal specifications are implemented by circuits modeled by ordinary differential equations, yielding a design framework that can be used to design complex synthetic biological circuits at scale. We describe our approach using the design of a biological AND gate as a motivating, running example.", "doi": "10.1101/2022.04.08.487709", "publication_date": "2022-04-11" }, { "id": "authors:wdsfr-e5e61", "collection": "authors", "collection_id": "wdsfr-e5e61", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20220224-200901027", "type": "monograph", "title": "Robust Safe Control Synthesis with Disturbance Observer-Based Control Barrier Functions", "author": [ { "family_name": "Da\u015f", "given_name": "Ersin", "orcid": "0000-0003-1291-3803", "clpid": "Da\u015f-Ersin" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "In a complex real-time operating environment, external disturbances and uncertainties adversely affect the safety, stability, and performance of dynamical systems. This paper presents a robust stabilizing safety-critical controller synthesis framework with control Lyapunov functions (CLFs) and control barrier functions (CBFs) in the presence of disturbance. A high-gain input observer method is adapted to estimate the time-varying unmodelled dynamics of the CBF with an error bound using the first-order time derivative of the CBF. This approach leads to an easily tunable low order disturbance estimator structure with a design parameter as it utilizes only the CBF constraint. The estimated unknown input and associated error bound are used to ensure robust safety and exponential stability by formulating a CLF-CBF quadratic program. The proposed method is applicable to both relative degree one and higher relative degree CBF constraints. The efficacy of the proposed approach is demonstrated using a numerical simulations of an adaptive cruise control system and a Segway platform with an external disturbance.", "doi": "10.48550/arXiv.2201.05758", "publisher": "arXiv", "publication_date": "2022-01-15" }, { "id": "authors:8w47y-2x462", "collection": "authors", "collection_id": "8w47y-2x462", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20210929-174530596", "type": "monograph", "title": "How to model DNA replication in stochastic models of synthetic gene circuits (and why)", "author": [ { "family_name": "Clamons", "given_name": "Samuel E.", "orcid": "0000-0002-7993-2278", "clpid": "Clamons-Samuel-E" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "Biocircuit modeling sometimes requires explicit tracking of a self-replicating DNA species. The most obvious, straightforward way to model a replicating DNA is structurally unstable and leads to pathological model behavior. We describe a simple, stable replication mechanism with good model behavior and show how to derive it from a mechanistic model of ColE1 replication.", "doi": "10.1101/2021.09.26.461880", "publisher": "Cold Spring Harbor Laboratory", "publication_date": "2021-09-27" }, { "id": "authors:44ahy-m7y19", "collection": "authors", "collection_id": "44ahy-m7y19", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20210914-194152756", "type": "monograph", "title": "Layered Feedback Control Overcomes Performance Trade-off in Synthetic Biomolecular Networks", "author": [ { "family_name": "Hu", "given_name": "Chelsea Y.", "orcid": "0000-0002-2211-1778", "clpid": "Hu-Chelsea-Y" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "Layered feedback is an optimization strategy in feedback control designs widely used in electrical and mechanical engineering. Layered control theory suggests that the performance of controllers is bound by the universal robustness-efficiency tradeoff limit, which could be overcome by layering two or more feedbacks together. In natural biological networks, genes are often regulated with redundancy and layering to adapt to environmental perturbations. Control theory hypothesizes that this layering architecture is also adopted by nature to overcome this performance trade-off. In this work, we validated this property of layered control with a synthetic network in living E. coli cells. We performed system analysis on a node-based design to confirm the tradeoff properties before proceeding to simulations with an effective mechanistic model, which guided us to the best performing design to engineer in cells. Finally, we interrogated its system dynamics experimentally with eight sets of perturbations on chemical signals, nutrient abundance, and growth temperature. For all cases, we consistently observed that the layered control overcomes the robustness-efficiency trade-off limit. This work experimentally confirmed that layered control could be adopted in synthetic biomolecular networks as a performance optimization strategy. It also provided insights in understanding genetic feedback control architectures in nature.", "doi": "10.1101/2021.09.12.459953", "publication_date": "2021-09-14" }, { "id": "authors:gcqax-8a355", "collection": "authors", "collection_id": "gcqax-8a355", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20220224-200812106", "type": "monograph", "title": "Risk-Averse Decision Making Under Uncertainty", "author": [ { "family_name": "Ahmadi", "given_name": "Mohamadreza", "orcid": "0000-0003-1447-3012", "clpid": "Ahmadi-Mohamadreza" }, { "family_name": "Rosolia", "given_name": "Ugo", "orcid": "0000-0002-1682-0551", "clpid": "Rosolia-Ugo" }, { "family_name": "Ingham", "given_name": "Michel D.", "orcid": "0000-0001-5893-543X", "clpid": "Ingham-Michel-D" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" }, { "family_name": "Ames", "given_name": "Aaron D.", "orcid": "0000-0003-0848-3177", "clpid": "Ames-A-D" } ], "abstract": "A large class of decision making under uncertainty problems can be described via Markov decision processes (MDPs) or partially observable MDPs (POMDPs), with application to artificial intelligence and operations research, among others. Traditionally, policy synthesis techniques are proposed such that a total expected cost or reward is minimized or maximized. However, optimality in the total expected cost sense is only reasonable if system behavior in the large number of runs is of interest, which has limited the use of such policies in practical mission-critical scenarios, wherein large deviations from the expected behavior may lead to mission failure. In this paper, we consider the problem of designing policies for MDPs and POMDPs with objectives and constraints in terms of dynamic coherent risk measures, which we refer to as the constrained risk-averse problem. For MDPs, we reformulate the problem into a infsup problem via the Lagrangian framework and propose an optimization-based method to synthesize Markovian policies. For MDPs, we demonstrate that the formulated optimization problems are in the form of difference convex programs (DCPs) and can be solved by the disciplined convex-concave programming (DCCP) framework. We show that these results generalize linear programs for constrained MDPs with total discounted expected costs and constraints. For POMDPs, we show that, if the coherent risk measures can be defined as a Markov risk transition mapping, an infinite-dimensional optimization can be used to design Markovian belief-based policies. For stochastic finite-state controllers (FSCs), we show that the latter optimization simplifies to a (finite-dimensional) DCP and can be solved by the DCCP framework. We incorporate these DCPs in a policy iteration algorithm to design risk-averse FSCs for POMDPs.", "doi": "10.48550/arXiv.2109.04082", "publisher": "arXiv", "publication_date": "2021-09-09" }, { "id": "authors:xjphx-6tc71", "collection": "authors", "collection_id": "xjphx-6tc71", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20220224-200808616", "type": "monograph", "title": "Synthesis of Static Test Environments for Observing Sequence-like Behaviors in Autonomous Systems", "author": [ { "family_name": "Badithela", "given_name": "Apurva", "clpid": "Badithela-Apurva" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "In this paper, we investigate formal test-case generation for high-level mission objectives, specifically reachability, of autonomous systems. We use Kripke structures to represent the high-level decision-making of the agent under test and the abstraction of the test environment. First, we define the notion of a test specification, focusing on a fragment of linear temporal logic represented by sequence temporal logic formulas. Second, we formulate the problem of test graph synthesis to find a test configuration for which the agent must satisfy the test specification to satisfy its mission objectives. We an algorithm, based on network flows, for synthesizing a test graph by restricting transitions, represented by edge deletions, on the original graph induced by the Kripke structures. The algorithm synthesizes the test graph iteratively using an integer linear program. We prove completeness for our algorithm, and we show that the edge deletions in each iteration maintain feasibility of the integer linear program in the subsequent iteration. We formalize the notion of a minimally constrained test graph in terms of maximum flow, and prove the synthesized test graph to be minimally constrained. We demonstrate our algorithm on a simple graph and on gridworlds.", "doi": "10.48550/arXiv.2108.05911", "publisher": "arXiv", "publication_date": "2021-08-12" }, { "id": "authors:6nghw-ett12", "collection": "authors", "collection_id": "6nghw-ett12", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20210506-075939102", "type": "monograph", "title": "A Method for Cost-Effective and Rapid Characterization of Genetic Parts", "author": [ { "family_name": "McManus", "given_name": "John B.", "clpid": "McManus-John-B" }, { "family_name": "Bernhards", "given_name": "Casey B.", "clpid": "Bernhards-Casey-B" }, { "family_name": "Sharpes", "given_name": "Caitlin E.", "clpid": "Sharpes-Caitlin-E" }, { "family_name": "Garcia", "given_name": "David C.", "clpid": "Garcia-David-C" }, { "family_name": "Cole", "given_name": "Stephanie D.", "clpid": "Cole-Stephanie-D" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" }, { "family_name": "Emanuel", "given_name": "Peter A.", "orcid": "0000-0001-5475-7349", "clpid": "Emanuel-Peter-A" }, { "family_name": "Lux", "given_name": "Matthew W.", "orcid": "0000-0002-2773-742X", "clpid": "Lux-Matthew-W" } ], "abstract": "Characterizing and cataloging genetic parts are critical to the design of useful genetic circuits. Having well-characterized parts allows for the fine-tuning of genetic circuits, such that their function results in predictable outcomes. With the growth of synthetic biology as a field, there has been an explosion of genetic circuits that have been implemented in microbes to execute functions pertaining to sensing, metabolic alteration, and cellular computing. Here, we show a cost-effective and rapid method for characterizing genetic parts. Our method utilizes cell-free lysate, prepared in-house, as a medium to evaluate parts via the expression of a reporter protein. Template DNA is prepared by PCR-amplification using inexpensive primers to add variant parts to the reporter gene, and the template is added to the reaction as linear DNA without cloning. Parts that can be added in this way include promoters, operators, ribosome binding sites, insulators, and terminators. This approach, combined with the incorporation of an acoustic liquid handler and 384-well plates, allows the user to carry out high-throughput evaluations of genetic parts in a single day. By comparison, cell-based screening approaches require time-consuming cloning and have longer testing times due to overnight culture and culture density normalization steps. Further, working in cell-free lysate allows the user to exact tighter control over the expression conditions through the addition of exogenous components, or by titrating DNA concentrations rather than relying on limited plasmid copy numbers. Because this method retains a cell-like environment, the function of the genetic part will typically mimic its function in whole cells.", "doi": "10.1101/2021.04.30.440836", "publication_date": "2021-05-01" }, { "id": "authors:xgt8b-ptj74", "collection": "authors", "collection_id": "xgt8b-ptj74", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20210511-092411322", "type": "monograph", "title": "Failure-Tolerant Contract-Based Design of an Automated Valet Parking System using a Directive-Response Architecture", "author": [ { "family_name": "Graebener", "given_name": "Josefine B.", "clpid": "Graebener-Josefine-B" }, { "family_name": "Phan-Minh", "given_name": "Tung", "clpid": "Phan-Minh-Tung" }, { "family_name": "Yan", "given_name": "Jiaqi", "clpid": "Yan-Jiaqi" }, { "family_name": "Zhao", "given_name": "Qiming", "clpid": "Zhao-Qiming" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "Increased complexity in cyber-physical systems calls for modular system design methodologies that guarantee correct and reliable behavior, both in normal operations and in the presence of failures. This paper aims to extend the contract-based design approach using a directive-response architecture to enable reactivity to failure scenarios. The architecture is demonstrated on a modular automated valet parking (AVP) system. The contracts for the different components in the AVP system are explicitly defined, implemented, and validated against a Python implementation.", "doi": "10.48550/arXiv.2103.12919", "publisher": "arXiv", "publication_date": "2021-03-24" }, { "id": "authors:2j3nq-z6s90", "collection": "authors", "collection_id": "2j3nq-z6s90", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20201221-102922403", "type": "monograph", "title": "Analysis of Circuits for Dosage Control in Microbial Populations", "author": [ { "family_name": "Walton", "given_name": "Sophie J.", "orcid": "0000-0003-1320-1525", "clpid": "Walton-Sophie-J" }, { "family_name": "Clamons", "given_name": "Samuel E.", "orcid": "0000-0002-7993-2278", "clpid": "Clamons-Samuel-E" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "Designing genetic circuits to control the behaviors of microbial populations is an ongoing challenge in synthetic biology. Here we analyze circuits which implement dosage control by controlling levels of a global signal in a microbial population in face of varying cell density, growth rate, and environmental dilution. We utilize the Lux quorum sensing system to implement dosage control circuits, and we analyze the dynamics of circuits using both simplified analytical analysis and in silico simulations. We demonstrate that strong negative feedback through inhibiting LuxI synthase expression along with AiiA degradase activity results in circuits with fast response times and robustness to cell density and dilution rate. We find that degradase activity yields robustness to variations in population density for large population sizes, while negative feedback to synthase production decreases sensitivity to dilution rates.", "doi": "10.1101/2020.12.18.423556", "publication_date": "2020-12-20" }, { "id": "authors:rhcjt-68j20", "collection": "authors", "collection_id": "rhcjt-68j20", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20210120-165255737", "type": "monograph", "title": "Rules of the Road: Towards Safety and Liveness Guarantees for Autonomous Vehicles", "author": [ { "family_name": "Cai", "given_name": "Karena X.", "clpid": "Cai-Karena-X" }, { "family_name": "Phan-Minh", "given_name": "Tung", "clpid": "Phan-Minh-Tung" }, { "family_name": "Chung", "given_name": "Soon-Jo", "orcid": "0000-0002-6657-3907", "clpid": "Chung-Soon-Jo" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "The ability to guarantee safety and progress for all vehicles is vital to the success of the autonomous vehicle industry. We present a framework for the distributed control of autonomous vehicles that is safe and guarantees progress for all agents. In this paper, we first introduce a new game paradigm which we term the quasi-simultaneous discrete-time game. We then define an Agent Protocol agents must use to make decisions in this quasi-simultaneous discrete-time game setting. According to the protocol, agents first select an intended action and then each agent determines whether it can take its intended action or not, given its proposed intention and the intentions of nearby agents. The protocol so defined will ensure safety under all traffic conditions and liveness for all agents under \"sparse\" traffic conditions. These guarantees, however, are predicated on the premise that all agents are operating with the aforementioned protocol. We provide proofs of correctness of the protocol and validate our results in simulation.", "doi": "10.48550/arXiv.2011.14148", "publisher": "arXiv", "publication_date": "2020-11-28" }, { "id": "authors:btga8-n4d36", "collection": "authors", "collection_id": "btga8-n4d36", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20201207-130405486", "type": "monograph", "title": "A two-state ribosome and protein model can robustly capture the chemical reaction dynamics of gene expression", "author": [ { "family_name": "Pandey", "given_name": "Ayush", "orcid": "0000-0003-3590-4459", "clpid": "Pandey-Ayush" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "We derive phenomenological models of gene expression from a mechanistic description of chemical reactions using an automated model reduction method. Using this method, we get analytical descriptions and computational performance guarantees to compare the reduced dynamics with the full models. We develop a new two-state model with the dynamics of the available free ribosomes in the system and the protein concentration. We show that this new two-state model captures the detailed mass-action kinetics of the chemical reaction network under various biologically plausible conditions on model parameters. On comparing the performance of this model with the commonly used mRNA transcript-protein dynamical model for gene expression, we analytically show that the free ribosome and protein model has superior error and robustness performance.", "doi": "10.1101/2020.11.25.399287", "publication_date": "2020-11-26" }, { "id": "authors:e7x24-c2p56", "collection": "authors", "collection_id": "e7x24-c2p56", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20201111-100159834", "type": "monograph", "title": "Engineering Logical Inflammation Sensing Circuit for Modulating Gut Conditions", "author": [ { "family_name": "Merk", "given_name": "Liana N.", "clpid": "Merk-L-N" }, { "family_name": "Shur", "given_name": "Andrey S.", "clpid": "Shur-Andrey-S" }, { "family_name": "Pandey", "given_name": "Ayush", "orcid": "0000-0003-3590-4459", "clpid": "Pandey-Ayush" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" }, { "family_name": "Green", "given_name": "Leopold N.", "orcid": "0000-0001-5479-6970", "clpid": "Green-L-N" } ], "abstract": "The mammalian gut contains trillions of microbes that interact with host cells and monitor changes in the environment. Opportunistic pathogens exploit environmental conditions to stimulate their growth and virulence, leading to a resurgence of chronic disorders such as inflammatory bowel disease (IBD). Current therapies are effective in less than 30% of patients due to the lack of adherence to prescription schedules and overall, off-target effects. Smart microbial therapeutics can be engineered to colonize the gut, providing in situ surveillance and conditional disease modulation. However, many current engineered microbes can only respond to single gut environmental factors, limiting their effectiveness. In this work, we implement the previously characterized split activator AND logic gate in the probiotic E. coli strain Nissle 1917. Our system can respond to two input signals: the inflammatory biomarker tetrathionate and a second input signal, IPTG. We report 4-6 fold induction with minimal leak when both signals are present. We model the dynamics of the AND gate using chemical reaction networks, and by tuning parameters in silico, we identified perturbations that affect our circuit's selectivity. We anticipate that our results will prove useful for designing living therapeutics for spatial targeting and signal processing in complex environments.", "doi": "10.1101/2020.11.10.377085", "publication_date": "2020-11-11" }, { "id": "authors:48cq5-sqj38", "collection": "authors", "collection_id": "48cq5-sqj38", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20210120-165252232", "type": "monograph", "title": "Reactive motion planning with probabilistic safety guarantees", "author": [ { "family_name": "Chen", "given_name": "Yuxiao", "orcid": "0000-0001-5276-7156", "clpid": "Chen-Yuxiao" }, { "family_name": "Rosolia", "given_name": "Ugo", "orcid": "0000-0002-1682-0551", "clpid": "Rosolia-Ugo" }, { "family_name": "Fan", "given_name": "Chuchu", "clpid": "Fan-Chuchu" }, { "family_name": "Ames", "given_name": "Aaron D.", "orcid": "0000-0003-0848-3177", "clpid": "Ames-A-D" }, { "family_name": "Murray", "given_name": "Richard", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "Motion planning in environments with multiple agents is critical to many important autonomous applications such as autonomous vehicles and assistive robots. This paper considers the problem of motion planning, where the controlled agent shares the environment with multiple uncontrolled agents. First, a predictive model of the uncontrolled agents is trained to predict all possible trajectories within a short horizon based on the scenario. The prediction is then fed to a motion planning module based on model predictive control. We proved generalization bound for the predictive model using three different methods, post-bloating, support vector machine (SVM), and conformal analysis, all capable of generating stochastic guarantees of the correctness of the predictor. The proposed approach is demonstrated in simulation in a scenario emulating autonomous highway driving.", "doi": "10.48550/arXiv.2011.03590", "publisher": "arXiv", "publication_date": "2020-11-06" }, { "id": "authors:p9w5c-8nc27", "collection": "authors", "collection_id": "p9w5c-8nc27", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200327-083242603", "type": "monograph", "title": "Layered Feedback Control Improves Robust Functionality across Heterogeneous Cell Populations", "author": [ { "family_name": "Ren", "given_name": "Xinying", "clpid": "Ren-Xinying" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "Realizing homeostatic control of metabolites or proteins is one of the key goals of synthetic circuits. However, if control is only implemented internally in individual cells, cell-cell heterogeneity may break the homeostasis on populationlevel since cells do not contribute equally to the production or regulation. New control structures are needed to achieve robust functionality in heterogeneous cell populations. Quorum sensing(QS) serves as a collective mechanism by releasing and sensing small and diffusible signaling molecules for group decision-making. We propose a layered feedback control structure that includes a global controller using quorum sensing and a local controller via internal signal-receptor systems. We demonstrate with modeling and simulation that the global controller drives contributing cells to compensate for disturbances while the local controller governs the fail-mode performance in non-contributing cells. The layered controller can tolerate a higher portion of non-contributing cells or longer generations of mutant cells while maintaining metabolites or proteins level within a small error range, compared with only internal feedback control. We further discuss the potential of such layered structures in robust control of cell population size,population fraction and other population-dependent functions.", "doi": "10.1101/2020.03.24.006528", "publication_date": "2020-03-25" }, { "id": "authors:f818a-vce67", "collection": "authors", "collection_id": "f818a-vce67", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200220-154511531", "type": "monograph", "title": "Model Reduction Tools For Phenomenological Modeling of Input-Controlled Biological Circuits", "author": [ { "family_name": "Pandey", "given_name": "Ayush", "orcid": "0000-0003-3590-4459", "clpid": "Pandey-Ayush" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "We present a Python-based software package to automatically obtain phenomenological models of input-controlled synthetic biological circuits from descriptive models. From the parts and mechanism description of a synthetic biological circuit, it is easy to obtain a chemical reaction model of the circuit under the assumptions of mass-action kinetics using various existing tools. However, using these models to guide design decisions during an experiment is difficult due to a large number of reaction rate parameters and species in the model. Hence, phenomenological models are often developed that describe the effective relationships among the circuit inputs, outputs, and only the key states and parameters. In this paper, we present an algorithm to obtain these phenomenological models in an automated manner using a Python package for circuits with inputs that control the desired outputs. This model reduction approach combines the common assumptions of time-scale separation, conservation laws, and species' abundance to obtain the reduced models that can be used for design of synthetic biological circuits. We consider an example of a simple gene expression circuit and another example of a layered genetic feedback control circuit to demonstrate the use of the model reduction procedure.", "doi": "10.1101/2020.02.15.950840", "publication_date": "2020-02-20" }, { "id": "authors:c1whe-kj281", "collection": "authors", "collection_id": "c1whe-kj281", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200220-083645813", "type": "monograph", "title": "A geometric and structural approach to the analysis and design of biological circuit dynamics: a theory tailored for synthetic biology", "author": [ { "family_name": "Marken", "given_name": "John P.", "orcid": "0000-0001-9696-088X", "clpid": "Marken-J-P" }, { "family_name": "Xiao", "given_name": "Fangzhou", "orcid": "0000-0002-5001-5644", "clpid": "Xiao-Fangzhou" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "Much of the progress in developing our ability to successfully design genetic circuits with predictable dynamics has followed the strategy of molding biological systems to fit into conceptual frameworks used in other disciplines, most notably the engineering sciences. Because biological systems have fundamental differences from systems in these other disciplines, this approach is challenging and the insights obtained from such analyses are often not framed in a biologically-intuitive way. Here, we present a new theoretical framework for analyzing the dynamics of genetic circuits that is tailored towards the unique properties associated with biological systems and experiments. Our framework approximates a complex circuit as a set of simpler circuits, which the system can transition between by saturating its various internal components. These approximations are connected to the intrinsic structure of the system, so this representation allows the analysis of dynamics which emerge solely from the system's structure. Using our framework, we analyze the presence of structural bistability in a leaky autoactivation motif and the presence of structural oscillations in the Repressilator.", "doi": "10.1101/2020.02.18.953620", "publication_date": "2020-02-17" }, { "id": "authors:d5gv5-t0h14", "collection": "authors", "collection_id": "d5gv5-t0h14", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200128-150452496", "type": "monograph", "title": "Theoretical Design of Paradoxical Signaling-Based Synthetic Population Control Circuit in E. coli", "author": [ { "family_name": "Mayalu", "given_name": "Micha\u00eblle N.", "orcid": "0000-0002-9678-0157", "clpid": "Mayalu-M-N" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "We have developed a mathematical framework to analyze the cooperative control of cell population homeostasis via paradoxical signaling in synthetic contexts. Paradoxical signaling functions through quorum sensing (where cells produce and release a chemical signal as a function of cell density). Precisely, the same quorum sensing signal provides both positive (proliferation) and negative (death) feedback in different signal concentration regimes. As a consequence, the relationship between intercellular quorum sensing signal concentration and net growth rate (cell proliferation minus death rates) can be non-monotonic. This relationship is a condition for robustness to certain cell mutational overgrowths and allows for increased stability in the presence of environmental perturbations. Here, we explore stability and robustness of a conceptualized synthetic circuit. Furthermore, we asses possible design principles that could exist among a subset of paradoxical circuit implementations. This analysis sparks the development a bio-molecular control theory to identify ideal underlying characteristics for paradoxical signaling control systems.", "doi": "10.1101/2020.01.27.921734", "publication_date": "2020-01-28" }, { "id": "authors:waevr-jpt88", "collection": "authors", "collection_id": "waevr-jpt88", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200402-143200982", "type": "monograph", "title": "Counter-example Guided Learning of Bounds on Environment Behavior", "author": [ { "family_name": "Chen", "given_name": "Yuxiao", "orcid": "0000-0001-5276-7156", "clpid": "Chen-Yuxiao" }, { "family_name": "Dathathri", "given_name": "Sumanth", "clpid": "Dathathri-S" }, { "family_name": "Phan-Minh", "given_name": "Tung", "clpid": "Phan-Minh-Tung" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "There is a growing interest in building autonomous systems that interact with complex environments. The difficulty associated with obtaining an accurate model for such environments poses a challenge to the task of assessing and guaranteeing the system's performance. We present a data-driven solution that allows for a system to be evaluated for specification conformance without an accurate model of the environment. Our approach involves learning a conservative reactive bound of the environment's behavior using data and specification of the system's desired behavior. First, the approach begins by learning a conservative reactive bound on the environment's actions that captures its possible behaviors with high probability. This bound is then used to assist verification, and if the verification fails under this bound, the algorithm returns counter-examples to show how failure occurs and then uses these to refine the bound. We demonstrate the applicability of the approach through two case-studies: i) verifying controllers for a toy multi-robot system, and ii) verifying an instance of human-robot interaction during a lane-change maneuver given real-world human driving data.", "doi": "10.48550/arXiv.2001.07233", "publisher": "arXiv", "publication_date": "2020-01-20" }, { "id": "authors:drhjw-a6n92", "collection": "authors", "collection_id": "drhjw-a6n92", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20191202-140340910", "type": "monograph", "title": "Construction of an inducible amyloid expression circuit in Bacillus megaterium: A case study with CsgA and TasA", "author": [ { "family_name": "Larsson", "given_name": "Elin M.", "orcid": "0000-0003-1341-5937", "clpid": "Larsson-E-M" }, { "family_name": "McManus", "given_name": "John B.", "clpid": "McManus-John-B" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "Environmental applications of synthetic biology such as water remediation require engineered strains to function robustly in a fluctuating and potentially hostile environment. The construction of synthetic biofilm formation circuits could potentially alleviate this issue by promoting cell survival. Towards this end, we construct a xylose-inducible system for the expression of the functional amyloids CsgA and TasA in the soil bacterium Bacillus megaterium. We find that although both amyloids are expressed, only TasA is successfully exported from the cells. Furthermore, expression of CsgA results in a significant growth penalty for the cells while expression of TasA does not. Finally, we show that TasA expression conveys a small but detectable increase in cells' adhesion to nickel beads. These results suggest that TasA is a promising candidate for future work on synthetic biofilm formation in B. megaterium.", "doi": "10.1101/858266", "publication_date": "2019-11-29" }, { "id": "authors:8grfs-rnn49", "collection": "authors", "collection_id": "8grfs-rnn49", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20190731-095458774", "type": "monograph", "title": "Modeling predicts that CRISPR-based activators, unlike CRISPR-based repressors, scale well with increasing gRNA competition and dCas9 bottlenecking", "author": [ { "family_name": "Clamons", "given_name": "Samuel", "orcid": "0000-0002-7993-2278", "clpid": "Clamons-Samuel-E" }, { "family_name": "Murray", "given_name": "Richard", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "Synthetic transcriptional networks built from CRISPR-based repressors (CRISPRi) rely on shared use of a core dCas9 protein. In E. coli, CRISPRi cannot sup- port more than about a dozen simultaneous gRNAs before the fold repression of any individual gRNA drops below 10x. We show with a simple model based on previous characterization of competition in CRISPRi that activation by CRISPR-based activators (CRISPRa) is much less sensitive to dCas9 bottle- necking than CRISPRi. We predict that E. coli should be able to support dozens to hundreds of CRISPRa gRNAs at > 10-fold activation.", "doi": "10.1101/719278", "publication_date": "2019-07-30" }, { "id": "authors:ptvj6-bm918", "collection": "authors", "collection_id": "ptvj6-bm918", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200131-124409997", "type": "monograph", "title": "Cell-Free Extract Data Variability Reduction in the Presence of Structural Non-Identifiability", "author": [ { "family_name": "Singhal", "given_name": "Vipul", "clpid": "Singhal-V" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "The bottom up design of genetic circuits to control cellular behavior is one of the central objectives within Synthetic Biology. Performing design iterations on these circuits in vivo is often a time consuming process, which has led to E. coli cell extracts to be used as simplified circuit prototyping environments. Cell extracts, however, display large batch-to-batch variability in gene expression. In this paper, we develop the theoretical groundwork for a model based calibration methodology for correcting this variability. We also look at the interaction of this methodology with the phenomenon of parameter (structural) non-identifiability, which occurs when the parameter identification inverse problem has multiple solutions. In particular, we show that under certain consistency conditions on the sets of output-indistinguishable parameters, data variability reduction can still be performed, and when the parameter sets have a certain structural feature called covariation, our methodology may be modified in a particular way to still achieve the desired variability reduction.", "publisher": "Caltech Library", "publication_date": "2019-07" }, { "id": "authors:xtt51-tpg86", "collection": "authors", "collection_id": "xtt51-tpg86", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20190604-143031841", "type": "monograph", "title": "Bacterial Controller Aided Wound Healing: A Case Study in Dynamical Population Controller Design", "author": [ { "family_name": "Green", "given_name": "Leopold N.", "orcid": "0000-0001-5479-6970", "clpid": "Green-L-N" }, { "family_name": "Hu", "given_name": "Chelsea Y.", "orcid": "0000-0002-2211-1778", "clpid": "Hu-Chelsea-Y" }, { "family_name": "Ren", "given_name": "Xinying Y.", "clpid": "Ren-Xinying-Y" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "Wound healing is a complicated biological process consisting of many types of cellular dynamics and functions regulated by chemical and molecular signals. Recent advances in synthetic biology have made it possible to predictably design and build closed-loop controllers that can function appropriately alongside biological species. In this paper we develop a simple dynamical population model mimicking the sequential relay-like dynamics of cellular populations involved in the wound healing process. Our model consists of four nodes and five signals whose parameters we can tune to simulate various chronic healing conditions. We also develop a set of regulator functions based on type-1 incoherent feed forward loops (IFFL) that can sense the change from acute healing to incomplete chronic wounds, improving the system in a timely manner. Both the wound healing and type-1 IFFL controller architectures are compatible with available synthetic biology experimental tools for potential applications.", "doi": "10.1101/659714", "publication_date": "2019-06-04" }, { "id": "authors:s4jjh-qwf08", "collection": "authors", "collection_id": "s4jjh-qwf08", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20190528-093001677", "type": "monograph", "title": "Design of a genetic layered feedback controller in synthetic biological circuitry", "author": [ { "family_name": "Hu", "given_name": "Chelsea Y.", "orcid": "0000-0002-2211-1778", "clpid": "Hu-Chelsea-Y" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "Feedback control is the key to achieve robust performances for many engineered systems. However, its application in biological contexts is still largely unexplored. In this work, we designed, analyzed and simulated a layered controller functioning at both molecular and populational levels. First, we used a minimal model of three states to represent a system where state A activates state B; state R is a by-product of state B that acts as a negative feedback regulating both state A, B, and sequentially R. We call the feedback applied to state B a cis feedback and the one applied to state A a trans feedback. Through stability analysis via linearization at equilibrium and sensitivity analysis at transient state, we found that the cis feedback attenuates disturbances better but recovers slower; the trans feedback recovers faster but has more dramatic responses to fluctuations; the layered feedback demonstrates both advantageous traits of the two single layers. Then we designed two versions of synthetic genetic circuits to implement the layered controller in living cells. One version with an sRNA as regulator R, the other with a transcription factor protein as the regulator R. The analysis and dynamical simulation of the models confirmed the analytical results from the minimal model. At the same time, we found that the protein regulated feedback controls have faster recovery speed but the RNA version has a stronger disturbance attenuation effect.", "doi": "10.1101/647057", "publication_date": "2019-05-24" }, { "id": "authors:d7326-k9d39", "collection": "authors", "collection_id": "d7326-k9d39", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20190517-100226134", "type": "monograph", "title": "An automated model reduction tool to guide the design and analysis of synthetic biological circuits", "author": [ { "family_name": "Pandey", "given_name": "Ayush", "orcid": "0000-0003-3590-4459", "clpid": "Pandey-Ayush" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "We present an automated model reduction algorithm that uses quasi-steady state approximation to minimize the error between the desired outputs. Additionally, the algorithm minimizes the sensitivity of the error with respect to parameters to ensure robust performance of the reduced model in the presence of parametric uncertainties. We develop the theory for this model reduction algorithm and present the implementation of the algorithm that can be used to perform model reduction of given SBML models. To demonstrate the utility of this algorithm, we consider the design of a synthetic biological circuit to control the population density and composition of a consortium consisting of two different cell strains. We show how the model reduction algorithm can be used to guide the design and analysis of this circuit.", "doi": "10.1101/640276", "publication_date": "2019-05-17" }, { "id": "authors:0s3f2-3dh59", "collection": "authors", "collection_id": "0s3f2-3dh59", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200131-092300001", "type": "monograph", "title": "Control of density and composition in an engineered two-member bacterial community", "author": [ { "family_name": "McCardell", "given_name": "Reed D.", "clpid": "McCardell-R-D" }, { "family_name": "Pandey", "given_name": "Ayush", "orcid": "0000-0003-3590-4459", "clpid": "Pandey-Ayush" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "As studies continue to demonstrate how our health is related to the status of our various commensal microbiomes, synthetic biologists are developing tools and approaches to control these microbiomes and stabilize healthy states or remediate unhealthy ones. Building on previous work to control bacterial communities, we have constructed a synthetic two-member bacterial consortium engineered to reach population density and composition steady states set by inducer inputs. We detail a screening strategy to search functional parameter space in this high-complexity genetic circuit as well as initial testing of a functional two-member circuit.\n\nWe demonstrate non-independent changes in total population density and composition steady states with a limited set of varying inducer concentrations. After a dilution to perturb the system from its steady state, density and composition steady states are not regained. Modeling and simulation suggest a need for increased degradation of intercellular signals to improve circuit performance. Future experiments will implement increased signal degradation and investigate the robustness of control of each characteristic to perturbations from steady states.", "doi": "10.1101/632174", "publication_date": "2019-05-09" }, { "id": "authors:g25sc-rrr18", "collection": "authors", "collection_id": "g25sc-rrr18", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20190422-091140053", "type": "monograph", "title": "Integrase-mediated differentiation circuits improve evolutionary stability of burdensome and toxic functions in E. coli", "author": [ { "family_name": "Williams", "given_name": "Rory L.", "orcid": "0000-0003-2605-5790", "clpid": "Williams-Rory-L" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "Advances in synthetic biology, bioengineering, and computation allow us to rapidly and reliably program cells with increasingly complex and useful functions. However, because the functions we engineer cells to perform are typically unnecessary for cellular survival and burdensome to cell growth, they can be rapidly lost due to the processes of mutation and natural selection. To improve the evolutionary stability of engineered functions in a general manner, we developed an integrase-recombination-based differentiation gene circuit in Escherichia coli. In this system, differentiated cells uniquely carry out burdensome or toxic engineered functions but have limited capacity to grow (terminal differentiation), preventing the propagation of selectively advantageous loss of function mutations that inevitably arise. To experimentally implement terminal differentiation, we co-opted the R6K plasmid system, using differentiation to simultaneously activate T7 RNAP-driven expression of arbitrary engineered functions, and inactivate expression of \u03c0 protein (an essential factor for R6K plasmid replication), thereby allowing limitation of differentiated cell growth through antibiotic selection. We experimentally demonstrate terminal differentiation increases both duration and magnitude of high-burden T7 RNAP-driven expression, and that its evolutionary stability can be further improved with strategic redundancy. Using burdensome overexpression of a fluorescent protein as a model engineered function, our terminal differentiation circuit results in a ~2.8-fold (single-cassette) and ~4.2-fold (two-cassette) increase of total fluorescent protein produced compared to high-burden naive expression in which all cells inducibly express T7 RNAP. Finally, we demonstrate that differentiation can enable the expression of even toxic functions, a feat not achieved to our knowledge by any other strategy for addressing long-term evolutionary stability. Overall, this study provides an effective generalizable strategy for protecting engineered functions from evolutionary degradation.", "doi": "10.1101/614529", "publication_date": "2019-04-21" }, { "id": "authors:yks7t-y7b17", "collection": "authors", "collection_id": "yks7t-y7b17", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20190402-080939441", "type": "monograph", "title": "Quantitative characterization of random partitioning in the evolution of plasmid-encoded traits", "author": [ { "family_name": "Halleran", "given_name": "Andrew D.", "orcid": "0000-0001-8720-1451", "clpid": "Halleran-A-D" }, { "family_name": "Flores-Bautista", "given_name": "Emanuel", "clpid": "Flores-Bautista-E" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "Plasmids are found across bacteria, archaea, and eukaryotes and play an important role in evolution. Plasmids exist at different copy numbers, the number of copies of the plasmid per cell, ranging from a single plasmid per cell to hundreds of plasmids per cell. This feature of a copy number greater than one can lead to a population of plasmids within a single cell that are not identical clones of one another, but rather have individual mutations that make a given plasmid unique. During cell division, this population of plasmids is partitioned into the two daughter cells, resulting in a random distribution of different plasmid variants in each daughter. In this study, we use stochastic simulations to investigate how random plasmid partitioning compares to a perfect partitioning model. Our simulation results demonstrate that random plasmid partitioning accelerates mutant allele fixation when the allele is beneficial and the selection is in an additive or recessive regime where increasing the copy number of the beneficial allele results in additional benefit for the host. This effect does not depend on the size of the benefit conferred or the mutation rate, but is magnified by increasing plasmid copy number.", "doi": "10.1101/594879", "publication_date": "2019-03-31" }, { "id": "authors:hmep9-tfs13", "collection": "authors", "collection_id": "hmep9-tfs13", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20190328-093304845", "type": "monograph", "title": "Addressable, \"Packet-Based\" Intercellular Communication through Plasmid Conjugation", "author": [ { "family_name": "Marken", "given_name": "John P.", "orcid": "0000-0001-9696-088X", "clpid": "Marken-J-P" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "We develop a system for implementing \"packet-based\" intercellular communication in an engineered bacterial population via conjugation. Our system uses gRNA-based identification markers that allow messages to be addressed to specific strains via Cas9-mediated cleavage of messages sent to the wrong recipient, which we show reduces plasmid transfer by four orders of magnitude. Integrase-mediated editing of the address on the message plasmid allows cells to dynamically update the message's recipients in vivo. As a proof-of-concept demonstration of our system, we propose a linear path scheme that would propagate a message sequentially through the strains of a population in a defined order.", "doi": "10.1101/591552", "publication_date": "2019-03-28" }, { "id": "authors:40qy9-86d52", "collection": "authors", "collection_id": "40qy9-86d52", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20191029-152953038", "type": "monograph", "title": "Voluntary lane-change policy synthesis with reactive control\n improvisation", "author": [ { "family_name": "Ge", "given_name": "Jin I.", "orcid": "0000-0001-6429-9337", "clpid": "Ge-Jin-I" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "In this paper, we propose reactive control improvisation\nto synthesize voluntary lane-change policy that meets\nhuman preferences under given traffic environments. We first\ntrain Markov models to describe traffic patterns and the motion\nof vehicles responding to such patterns using traffic data. The\ntrained parameters are calibrated using control improvisation\nto ensure the traffic scenario assumptions are satisfied. Based\non the traffic pattern, vehicle response models, and Bayesian\nswitching rules, the lane-change environment for an automated\nvehicle is modeled as a Markov decision process. Based on\nhuman lane-change behaviors, we train a voluntary lane-change\npolicy using explicit-duration Markov decision process.\nParameters in the lane-change policy are calibrated through\nreactive control improvisation to allow an automated car to\npursue faster speed while maintaining desired frequency of\nlane-change maneuvers in various traffic environments.", "publisher": "Caltech Library", "publication_date": "2018-12" }, { "id": "authors:zgewf-02c87", "collection": "authors", "collection_id": "zgewf-02c87", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20181107-093406633", "type": "monograph", "title": "Design Guidelines For Sequestration Feedback Networks", "author": [ { "family_name": "Baetica", "given_name": "Ania-Ariadna", "orcid": "0000-0003-0421-8181", "clpid": "Baetica-A-A" }, { "family_name": "Leong", "given_name": "Yoke Peng", "orcid": "0000-0001-8560-8856", "clpid": "Leong-Yoke-Peng" }, { "family_name": "Olsman", "given_name": "Noah", "orcid": "0000-0002-4351-3880", "clpid": "Olsman-N" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "Integral control is commonly used in mechanical and electrical systems to ensure perfect adaptation. A proposed design of integral control for synthetic biological systems employs the sequestration of two biochemical controller species. The unbound amount of controller species captures the integral of the error between the current and the desired state of the system. However, implementing integral control inside bacterial cells using sequestration feedback has been challenging due to the controller molecules being degraded and diluted. Furthermore, integral control can only be achieved under stability conditions that not all sequestration feedback networks fulfill. In this work, we give guidelines for ensuring stability and good performance (small steady-state error) in sequestration feedback networks. Our guidelines provide simple tuning options to obtain a flexible and practical biological implementation of sequestration feedback control. Using tools and metrics from control theory, we pave the path for the systematic design of synthetic biological systems.", "doi": "10.1101/455493", "publication_date": "2018-10-30" }, { "id": "authors:1efq8-g0238", "collection": "authors", "collection_id": "1efq8-g0238", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20181008-162020352", "type": "monograph", "title": "Context Dependence of Biological Circuits", "author": [ { "family_name": "Catanach", "given_name": "Thomas A.", "orcid": "0000-0002-4321-3159", "clpid": "Catanach-T-A" }, { "family_name": "McCardell", "given_name": "Reed", "clpid": "McCardell-R-D" }, { "family_name": "Baetica", "given_name": "Ania-Ariadna", "orcid": "0000-0003-0421-8181", "clpid": "Baetica-A-A" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "It has been an ongoing scientific debate whether biological parameters are conserved across experimental setups with different media, pH values, and other experimental conditions. Our work explores this question using Bayesian probability as a rigorous framework to assess the biological context of parameters in a model of the cell growth controller in You et al. When this growth controller is uninduced, the E. coli cell population grows to carrying capacity; however, when the circuit is induced, the cell population growth is regulated to remain well below carrying capacity. This growth control controller regulates the E. coli cell population by cell to cell communication using the signaling molecule AHL and by cell death using the bacterial toxin CcdB. \n\nTo evaluate the context dependence of parameters such as the cell growth rate, the carrying capacity, the AHL degradation rate, the leakiness of AHL, the leakiness of toxin CcdB, and the IPTG induction factor, we collect experimental data from the growth control circuit in two different media, at two different pH values, and with several induction levels. We define a set of possible context dependencies that describe how these parameters may differ with the experimental conditions and we develop mathematical models of the growth controller across the different experimental contexts. We then determine whether these parameters are shared across experimental contexts or whether they are context dependent. For each of these possible context dependencies, we use Bayesian inference to assess its plausibility and to estimate the parameters of the growth controller. Ultimately, we find that there is significant experimental context dependence in this circuit. Moreover, we also find that the estimated parameter values are sensitive to our assumption of a context relationship.", "doi": "10.1101/360040", "publication_date": "2018-07-03" }, { "id": "authors:gfm8p-cqf85", "collection": "authors", "collection_id": "gfm8p-cqf85", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20181030-140537131", "type": "monograph", "title": "Long-distance communication in synthetic bacterial consortia through active signal propagation", "author": [ { "family_name": "Parkin", "given_name": "James M.", "orcid": "0000-0002-4058-2338", "clpid": "Parkin-J-M" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "A synthetic cell-cell signaling circuit should ideally be (1) metabolically lightweight, (2) insulated from endogenous gene networks, and (3) excitable rather than oscillatory or bistable. To accomplish these three features, we propose a synchronized pulse-generating circuit based on the design of published synchronized oscillators. This communication module employs a pulse generator built using Lux-type quorum sensing components and an IFFL transcriptional circuit. Both the input and output of this module are AHLs, the quorum sensing signaling molecule. Cells bearing this module therefore act as an excitable medium, producing a pulse of AHL when stimulated by exogenous AHL. Using simulation and microscopy, we demonstrate how this circuit enables traveling pulses of AHL production through microcolonies growing in two dimensions. Traveling pulses achieve cell-cell communication at longer distances than can be achieved by diffusion of signal from sender to receiver cells and may permit more sophisticated coordination in synthetic consortia.", "doi": "10.1101/321307", "publication_date": "2018-05-14" }, { "id": "authors:687er-8c179", "collection": "authors", "collection_id": "687er-8c179", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20190205-112328842", "type": "monograph", "title": "Detecting Adversarial Examples via Neural Fingerprinting", "author": [ { "family_name": "Dathathri", "given_name": "Sumanth", "clpid": "Dathathri-S" }, { "family_name": "Zheng", "given_name": "Stephan", "clpid": "Zheng-Stephan" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" }, { "family_name": "Yue", "given_name": "Yisong", "orcid": "0000-0001-9127-1989", "clpid": "Yue-Yisong" } ], "abstract": "Deep neural networks are vulnerable to adversarial examples, which dramatically alter model output using small input changes. We propose Neural Fingerprinting, a simple, yet effective method to detect adversarial examples by verifying whether model behavior is consistent with a set of secret fingerprints, inspired by the use of biometric and cryptographic signatures. The benefits of our method are that 1) it is fast, 2) it is prohibitively expensive for an attacker to reverse-engineer which fingerprints were used, and 3) it does not assume knowledge of the adversary. In this work, we pose a formal framework to analyze fingerprints under various threat models, and characterize Neural Fingerprinting for linear models. For complex neural networks, we empirically demonstrate that Neural Fingerprinting significantly improves on state-of-the-art detection mechanisms by detecting the strongest known adversarial attacks with 98-100% AUC-ROC scores on the MNIST, CIFAR-10 and MiniImagenet (20 classes) datasets. In particular, the detection accuracy of Neural Fingerprinting generalizes well to unseen test-data under various black- and whitebox threat models, and is robust over a wide range of hyperparameters and choices of fingerprints.", "doi": "10.48550/arXiv.1803.03870", "publisher": "arXiv", "publication_date": "2018-03-11" }, { "id": "authors:vr6jb-n3x89", "collection": "authors", "collection_id": "vr6jb-n3x89", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200131-145354147", "type": "monograph", "title": "Hiding variables when decomposing specifications into GR(1) contracts", "author": [ { "family_name": "Filippidis", "given_name": "Ioannis", "orcid": "0000-0003-4704-3334", "clpid": "Filippidis-I" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "We propose a method for eliminating variables from component specifications during the decomposition of GR(1) properties into contracts. The variables that can be eliminated are identified by parameterizing the communication architecture to investigate the dependence of realizability on the availability of information. We prove that the selected variables can be hidden from other components, while still expressing the resulting specification as a game with full information with respect to the remaining variables. The values of other variables need not be known all the time, so we hide them for part of the time, thus reducing the amount of information that needs to be communicated between components. We improve on our previous results on algorithmic decomposition of GR(1) properties, and prove existence of decompositions in the full information case. We use semantic methods of computation based on binary decision diagrams. To recover the constructed specifications so that humans can read them, we implement exact symbolic minimal covering over the lattice of integer orthotopes, thus deriving minimal formulae in disjunctive normal form over integer variable intervals.", "publisher": "Caltech Library", "publication_date": "2017-12" }, { "id": "authors:dme00-2nb41", "collection": "authors", "collection_id": "dme00-2nb41", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20181031-100007899", "type": "monograph", "title": "Modeling Dynamic Transcriptional Circuits with CRISPRi", "author": [ { "family_name": "Clamons", "given_name": "Samuel", "orcid": "0000-0002-7993-2278", "clpid": "Clamons-Samuel-E" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "Targeted transcriptional repression with catalytically inactive Cas9 (CRISPRi) promises to reproduce the functions of traditional synthetic transcriptional circuits, but with better orthogonality, programmability, and extensibility. However, CRISPRi lacks obvious cooperativity\u2013a feature classically considered critical for several classic gene regulatory circuits. We use a simple dynamical model of CRISPRi to show that it can be used to build repressilators, toggle switches, and incoherent feed-forward loops. We also show that the function some of these circuits are expected to be sensitive to several key parameters, and we provide specifications for those parameters. Our modeling reveals key engineering requirements and considerations for the construction of dynamic CRISPRi circuits, and provides a roadmap for building those circuits.", "doi": "10.1101/225318", "publication_date": "2017-11-27" }, { "id": "authors:q0h9k-f8c44", "collection": "authors", "collection_id": "q0h9k-f8c44", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20181031-100430313", "type": "monograph", "title": "Proof of concept continuous event logging in living cells", "author": [ { "family_name": "Shur", "given_name": "Andrey", "clpid": "Shur-Andrey" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "Cells must detect and respond to molecular events such as the presence or absence of specific small molecules. To accomplish this, cells have evolved methods to measure the presence and concentration of these small molecules in their environment and enact changes in gene expression or behavior. However, cells don't usually change their DNA in response to outside stimuli. In this work, we have engineered a genetic circuit that can enact specific and controlled genetic changes in response to small molecule stimuli. Known DNA sequences can be repeatedly integrated in a genomic array such that their identity and order encodes information about past small molecule concentrations that the cell has experienced. To accomplish this, we use catalytically inactive CRISPR-Cas9 (dCas9) to bind to and block attachment sites for the integrase Bxb1. Therefore, through the co-expression of dCas9 and guide RNA, Bxb1 can be directed to integrate one of two engineered plasmids, which correspond to two orthogonal small molecule inducers that can be recorded with this system. We identified the optimal location of guide RNA binding to the Bxb1 attP integrase attachment site, and characterized the detection limits of the system by measuring the minimal small molecule concentration and shortest induction time necessary to produce measurable differences in array composition as read out by Oxford Nanopore sequencing technology.", "doi": "10.1101/225151", "publication_date": "2017-11-25" }, { "id": "authors:yyk8w-71j62", "collection": "authors", "collection_id": "yyk8w-71j62", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20181029-141247546", "type": "monograph", "title": "Control of bacterial population density with population feedback and molecular sequestration", "author": [ { "family_name": "McCardell", "given_name": "Reed D.", "clpid": "McCardell-R-D" }, { "family_name": "Huang", "given_name": "Shan", "orcid": "0000-0001-5575-4510", "clpid": "Huang-Shan" }, { "family_name": "Green", "given_name": "Leopold N.", "orcid": "0000-0001-5479-6970", "clpid": "Green-L-N" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "Genetic engineering technology has become sophisticated enough to allow precise manipulation of bacterial genetic material. Engineering efforts with these technologies have created modified bacteria for various medical, industrial, and environmental purposes, but organisms designed for specific functions require improvements in stability, longevity, or efficiency of function. Most bacteria live in multispecies communities, whose composition may be closely linked to the effect the community has on the environment. Bacterial engineering efforts will benefit from building communities with regulated compositions, which will enable more stable and powerful community functions. We present a design of a synthetic two member bacterial community capable of maintaining its composition at a defined ratio of [cell type 1] : [cell type 2]. We have constructed the genetic motif that will act in each cell in the two member community, containing an AHL-based negative feedback loop that activates ccdB toxin, which caps population density with increasing feedback strength. It also contains one of two ccdB sequestration modules, either the ccdA protein antitoxin, or an RNA device which prevents transcription and translation of ccdB mRNA, that rescues capped population density with induction. We compare absorbance and colony counting methods of estimating bacterial population density, finding that absorbance-based methods overestimate viable population density when ccdB toxin is used to control population density. Prior modeling results show that two cell types containing this genetic circuit motif that reciprocally activate the other's ccdB sequestration device will establish a steady state ratio of cell types. Experimental testing and tuning the full two member community will help us improve our modeling of multi-member bacterial communities, learn more about the strengths and weaknesses of our design for community composition control, and identify general principles of design of compositionally-regulated microbial communities.", "doi": "10.1101/225045", "publication_date": "2017-11-25" }, { "id": "authors:6vkse-s0298", "collection": "authors", "collection_id": "6vkse-s0298", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20180927-114225422", "type": "monograph", "title": "Hard Limits And Performance Tradeoffs In A Class Of Sequestration Feedback Systems", "author": [ { "family_name": "Olsman", "given_name": "Noah", "orcid": "0000-0002-4351-3880", "clpid": "Olsman-N" }, { "family_name": "Baetica", "given_name": "Ania-Ariadna", "orcid": "0000-0003-0421-8181", "clpid": "Baetica-A-A" }, { "family_name": "Xiao", "given_name": "Fangzhou", "orcid": "0000-0002-5001-5644", "clpid": "Xiao-Fangzhou" }, { "family_name": "Leong", "given_name": "Yoke Peng", "orcid": "0000-0001-8560-8856", "clpid": "Leong-Yoke-Peng" }, { "family_name": "Murray", "given_name": "Richard", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" }, { "family_name": "Doyle", "given_name": "John", "orcid": "0000-0002-1828-2486", "clpid": "Doyle-J-C" } ], "abstract": "Feedback regulation is pervasive in biology at both the organismal and cellular level. In this article, we explore the properties of a particular biomolecular feedback mechanism implemented using the sequestration binding of two molecules. Our work develops an analytic framework for understanding the hard limits, performance tradeoffs, and architectural properties of this simple model of biological feedback control. Using tools from control theory, we show that there are simple parametric relationships that determine both the stability and the performance of these systems in terms of speed, robustness, steady-state error, and leakiness. These findings yield a holistic understanding of the behavior of sequestration feedback and contribute to a more general theory of biological control systems.", "doi": "10.1101/222042", "publication_date": "2017-11-20" }, { "id": "authors:43g2m-8t676", "collection": "authors", "collection_id": "43g2m-8t676", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20181031-100811065", "type": "monograph", "title": "Length and time scales of cell-cell signaling circuits in agar", "author": [ { "family_name": "Doong", "given_name": "Joy", "orcid": "0000-0001-8987-6903", "clpid": "Doong-Joy" }, { "family_name": "Parkin", "given_name": "James", "orcid": "0000-0002-4058-2338", "clpid": "Parkin-J-M" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "A community of genetically heterogeneous cells embedded in an unmixed medium allows for sophisticated operations by retaining spatial differentiation and coordinating division-of-labor. To establish the principles of engineering reliable cell-cell communication in a heterogeneous environment, we examined how circuit parameters and spatial placement affect the range of length and time scales over which simple communication circuits interact. We constructed several \"sender\" and \"receiver\" strains with quorum-sensing signaling circuits. The sender cell colony produces acyl homoserine lactones (AHL), which diffuse across the semisolid medium. The receiver cell colony detects these signal molecules and reports by fluorescence. We have found that a single colony of one sender variant is sufficient to induce receiver response at more than 1.5cm separation. Furthermore, AHL degradase expression in receiver colonies produces a signal threshold effect and reduces the response level in subsequent receiver colonies. Finally, our investigation on the spatial placement of colonies gave rise to the design of a multicellular long-range communication array consisting of two alternating colony types. Its signal response successfully propagated colony-by-colony along a six-colony array spanning 4.8cm at a transmission velocity of 12.8 hours per colony or 0.075cm per hour. In addition, we have developed a reaction-diffusion model that recreates the observed behaviors of the many performed experiments using data-informed parameter estimates of signal diffusion, gene expression, and nutrient consumption. These results demonstrate that a mixed community of colonies can enable new patterning programs, and the corresponding model will facilitate the rational design of complex communication networks.", "doi": "10.1101/220244", "publication_date": "2017-11-18" }, { "id": "authors:kc00w-e6x58", "collection": "authors", "collection_id": "kc00w-e6x58", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20180430-092750634", "type": "monograph", "title": "System-level studies of a cell-free transcription-translation platform for metabolic engineering", "author": [ { "family_name": "Wu", "given_name": "Yong Y.", "clpid": "Wu-Yong-Y" }, { "family_name": "Sato", "given_name": "Hirokazu", "clpid": "Sato-Hirokazu" }, { "family_name": "Huang", "given_name": "Hongjun", "clpid": "Huang-Hongjun" }, { "family_name": "Culler", "given_name": "Stephanie J.", "clpid": "Culler-S-J" }, { "family_name": "Khandurina", "given_name": "Julia", "clpid": "Khandurina-J" }, { "family_name": "Nagarajan", "given_name": "Harish", "clpid": "Nagarajan-H" }, { "family_name": "Yang", "given_name": "Tae Hoon", "clpid": "Yang-Tae-Hoon" }, { "family_name": "Van Dien", "given_name": "Stephen", "clpid": "Van-Dien-S" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "Current methods for assembling biosynthetic pathways in microorganisms require a process of repeated trial and error and have long design-build-test cycles. We describe the use of a cell-free transcription-translation (TX-TL) system as a biomolecular breadboard for the rapid engineering of the 1,4-butanediol (BDO) pathway. We demonstrate the reliability of TX-TL as a platform for engineering biological systems by undertaking a careful characterization of its transcription and translation capabilities and provide a detailed analysis of its metabolic output. Using TX-TL to survey the design space of the BDO pathway enables rapid tuning of pathway enzyme expression levels for improved product yield. Leveraging TX-TL to screen enzyme variants for improved catalytic activity accelerates design iterations that can be directly applied to in vivo strain development.", "doi": "10.1101/172007", "publication_date": "2017-08-03" }, { "id": "authors:ckas1-ccx41", "collection": "authors", "collection_id": "ckas1-ccx41", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170705-110144869", "type": "monograph", "title": "Prototyping And Implementation Of A Novel Feedforward Loop In A Cell-Free Transcription-Translation System And Cells", "author": [ { "family_name": "Guo", "given_name": "Shaobin", "orcid": "0000-0001-9736-4078", "clpid": "Guo-Shaobin" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "Building novel synthetic biological devices is a time-consuming task because of the lengthy cell-based testing and optimization processes. Recent progress made in the cell-free field suggests that the utilization of mathematical models and cell-free transcription-translation testing platforms to systematically design and test novel synthetic biocircuits may help streamline some of the processes. Here we present a study of building a novel functional biological network motif from scratch with the aid of the mathematical modeling and the cell-free prototyping. In this work, we demonstrated that we were able to make a 3-promoter feedforward circuit from a concept to a working biocircuit in cells within a month. We started with performing simulations with a cell-free transcription\u2013translation simulation toolbox. After verifying the feasibility of the circuit design, we used a fast assembling method to build the constructs and used the linear DNAs directly in the cell-free system for prototyping. After additional tests and assemblies, we implemented the circuit in plasmid forms in cells and showed that the in vivo results were consistent with the simulations and the outcomes in the cell-free platform. This study showed the usefulness of modeling and prototyping in building synthetic biocircuits and that we can use these tools to help streamline the process of circuit optimizations in future studies.", "doi": "10.1101/123190", "publication_date": "2017-04-02" }, { "id": "authors:69e82-62n69", "collection": "authors", "collection_id": "69e82-62n69", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170705-103731007", "type": "monograph", "title": "Implementation and System Identification of a Phosphorylation-Based Insulator in a Cell-Free Transcription-Translation System", "author": [ { "family_name": "Guo", "given_name": "Shaobin", "orcid": "0000-0001-9736-4078", "clpid": "Guo-Shaobin" }, { "family_name": "Yeung", "given_name": "Enoch", "orcid": "0000-0001-7630-7429", "clpid": "Yeung-Enoch" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "An outstanding challenge in the design of synthetic biocircuits is the development of a robust and efficient strategy for interconnecting functional modules. Recent work demonstrated that a phosphorylation-based insulator (PBI) implementing a dual strategy of high gain and strong negative feedback can be used as a device to attenuate retroactivity. This paper describes the implementation of such a biological circuit in a cell-free transcription-translation system and the structural identifiability of the PBI in the system. We first show that the retroactivity also exists in the cell-free system by testing a simple negative regulation circuit. Then we demonstrate that the PBI circuit helps attenuate the retroactivity significantly compared to the control. We consider a complex model that provides an intricate description of all chemical reactions and leveraging specific physiologically plausible assumptions. We derive a rigorous simplified model that captures the output dynamics of the PBI. We performed standard system identification analysis and determined that the model is globally identifiable with respect to three critical parameters. These three parameters are identifiable under specific experimental conditions and we performed these experiments to estimate the parameters. Our experimental results suggest that the functional form of our simplified model is sufficient to describe the reporter dynamics and enable parameter estimation. In general, this research illustrates the utility of the cell-free expression system as an alternate platform for biocircuit implementation and system identification and it can provide interesting insights into future biological circuit designs.", "doi": "10.1101/122606", "publication_date": "2017-04-02" }, { "id": "authors:xysr9-7pt09", "collection": "authors", "collection_id": "xysr9-7pt09", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200131-144053728", "type": "monograph", "title": "Fast Automatic Verification of Large-Scale Systems with Lookup Tables", "author": [ { "family_name": "Arichega", "given_name": "Nikos", "clpid": "Arichega-N" }, { "family_name": "Dathathri", "given_name": "Sumanth", "clpid": "Dathathri-S" }, { "family_name": "Vernekar", "given_name": "Shashank", "clpid": "Vernekar-S" }, { "family_name": "Gao", "given_name": "Sicun", "clpid": "Gao-Sicun" }, { "family_name": "Shiraishi", "given_name": "Shin'Ichi", "clpid": "Shiraishi-Shinichi" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "Modern safety-critical systems are difficult to formally verify, largely due to their large scale. In particular, the widespread use of lookup tables in embedded systems across diverse industries, such as aeronautics and automotive systems, create a critical obstacle to the scalability of formal verification. This paper presents a novel approach for the formal verification of large-scale systems with lookup tables. We use a learning-based technique to automatically learn abstractions of the lookup tables and use the abstractions to then prove the desired property. If the verification fails, we propose a falsification heuristic to search for a violation of the specification. In contrast with previous work on lookup table verification, our technique is completely automatic, making it ideal for deployment in a production environment. To our knowledge, our approach is the only technique that can automatically verify large-scale systems lookup with tables. \n\nWe illustrate the effectiveness of our technique on a benchmark which cannot be handled by the commercial tool SLDV, and we demonstrate the performance improvement provided by our technique.", "publisher": "Caltech Library", "publication_date": "2017-04" }, { "id": "authors:0xzfx-sm402", "collection": "authors", "collection_id": "0xzfx-sm402", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20190410-120622960", "type": "monograph", "title": "Model Predictive Control for Signal Temporal Logic Specification", "author": [ { "family_name": "Raman", "given_name": "Vasumathi", "clpid": "Raman-V" }, { "family_name": "Donz\u00e9", "given_name": "Alexandre", "clpid": "Donz\u00e9-A" }, { "family_name": "Maasoumy", "given_name": "Mehdi", "clpid": "Maasoumy-M" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" }, { "family_name": "Sangiovanni-Vincentelli", "given_name": "Alberto", "orcid": "0000-0003-1298-8389", "clpid": "Sangiovanni-Vincentelli-A-L" }, { "family_name": "Seshia", "given_name": "Sanjit A.", "clpid": "Seshia-S-A" } ], "abstract": "We present a mathematical programming-based method for model predictive control of cyber-physical systems subject to signal temporal logic (STL) specifications. We describe the use of STL to specify a wide range of properties of these systems, including safety, response and bounded liveness. For synthesis, we encode STL specifications as mixed integer-linear constraints on the system variables in the optimization problem at each step of a receding horizon control framework. We prove correctness of our algorithms, and present experimental results for controller synthesis for building energy and climate control.", "doi": "10.48550/arXiv.1703.09563", "publisher": "arXiv", "publication_date": "2017-03-28" }, { "id": "authors:pds01-11065", "collection": "authors", "collection_id": "pds01-11065", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20190325-142752006", "type": "monograph", "title": "Fast and flexible simulation and parameter estimation for synthetic biology using bioscrape", "author": [ { "family_name": "Swaminathan", "given_name": "Anandh", "orcid": "0000-0001-9935-6530", "clpid": "Swaminathan-A" }, { "family_name": "Poole", "given_name": "William", "orcid": "0000-0002-2958-6776", "clpid": "Poole-William" }, { "family_name": "Pandey", "given_name": "Ayush", "orcid": "0000-0003-3590-4459", "clpid": "Pandey-Ayush" }, { "family_name": "Hsiao", "given_name": "Victoria", "orcid": "0000-0001-9297-1522", "clpid": "Hsiao-Victoria" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "In systems and synthetic biology, it is common to build chemical reaction network (CRN) models of biochemical circuits and networks. Although automation and other high-throughput techniques have led to an abundance of data enabling data-driven quantitative modeling and parameter estimation, the intense amount of simulation needed for these methods still frequently results in a computational bottleneck. Here we present bioscrape (Bio-circuit Stochastic Single-cell Reaction Analysis and Parameter Estimation) - a Python package for fast and flexible modeling and simulation of highly customizable chemical reaction networks. Specifically, bioscrape supports deterministic and stochastic simulations, which can incorporate delay, cell growth, and cell division. All functionalities - reaction models, simulation algorithms, cell growth models, partioning models, and Bayesian inference - are implemented as interfaces in an easily extensible and modular object-oriented framework. Models can be constructed via Systems Biology Markup Language (SBML) or specified programmatically via a Python API. Simulation run times obtained with the package are comparable to those obtained using C code - this is particularly advantageous for computationally expensive applications such as Bayesian inference or simulation of cell lineages. We first show the package's simulation capabilities on a variety of example simulations of stochastic gene expression. We then further demonstrate the package by using it to do parameter inference on a model of integrase enzyme-mediated DNA recombination dynamics with experimental data. The bioscrape package is publicly available online (https://github.com/biocircuits/bioscrape) along with more detailed documentation and examples.", "doi": "10.1101/121152", "publication_date": "2017-03-27" }, { "id": "authors:8cwyv-jbk14", "collection": "authors", "collection_id": "8cwyv-jbk14", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170705-101737121", "type": "monograph", "title": "Quantitative Modeling of Integrase Dynamics Using a Novel Python Toolbox for Parameter Inference in Synthetic Biology", "author": [ { "family_name": "Swaminathan", "given_name": "Anandh", "orcid": "0000-0001-9935-6530", "clpid": "Swaminathan-A" }, { "family_name": "Hsiao", "given_name": "Victoria", "orcid": "0000-0001-9297-1522", "clpid": "Hsiao-Victoria" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "The recent abundance of high-throughput data for biological circuits enables data-driven quantitative modeling and parameter estimation. Common modeling issues include long computational times during parameter estimation, and the need for many iterations of this cycle to match data. Here, we present BioSCRAPE (Bio-circuit Stochastic Single-cell Reaction Analysis and Parameter Estimation) - a Python package for fast and flexible modeling and simulation for biological circuits. The BioSCRAPE package can be used for deterministic or stochastic simulations and can incorporate delayed reactions, cell growth, and cell division. Simulation run times obtained with the package are comparable to those obtained using C code - this is particularly advantageous for computationally expensive applications such as Bayesian inference or simulation of cell lineages. We first show the package's simulation capabilities on a variety of example simulations of stochastic gene expression. We then further demonstrate the package by using it to do parameter inference for a model of integrase dynamics using experimental data. The BioSCRAPE package is publicly available online along with more detailed documentation and examples.", "doi": "10.1101/121152", "publication_date": "2017-03-27" }, { "id": "authors:x90ch-0e880", "collection": "authors", "collection_id": "x90ch-0e880", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170627-105933916", "type": "monograph", "title": "Engineering pulsatile communication in bacterial consortia", "author": [ { "family_name": "Parkin", "given_name": "James M.", "orcid": "0000-0002-4058-2338", "clpid": "Parkin-J-M" }, { "family_name": "Hsiao", "given_name": "Victoria", "orcid": "0000-0001-9297-1522", "clpid": "Hsiao-Victoria" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "Lux-type quorum sensing systems enable communication in bacteria with only two protein components: a signal synthase and an inducible transcription activator. The simplicity of these systems makes them a popular choice for engineering collaborative behaviors in synthetic bacterial consortia, such as photographic edge detection and synchronized oscillation. To add to this body of work, we propose a pulsatile communication circuit that enables dynamic patterning and long-distance communication analogous to action potentials traveling through nerve tissue. We employed a model-driven design paradigm involving incremental characterization of in vivo design candidates with increasing circuit complexity. Beginning with a simple inducible reporter system, we screened a small number of circuits varying in their promoter and ribosomal binding site strengths. From this candidate pool, we selected a candidate to be the seed network for the subsequent round of more complex circuit variants, likewise variable in promoter and RBS strengths. The selection criteria at each level of complexity is tailored to optimize a different desirable performance characteristic. By this approach we individually optimized reporter signal-to-background ratio, pulsatile response to induction, and quiescent basal transcription, avoiding large library screens while ensuring robust performance of the composite circuit.", "doi": "10.1101/111906", "publication_date": "2017-02-26" }, { "id": "authors:rta0b-y7810", "collection": "authors", "collection_id": "rta0b-y7810", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170627-105346578", "type": "monograph", "title": "Repressing Integrase attachment site operation with CRISPR-Cas9 in E. coli", "author": [ { "family_name": "Shur", "given_name": "Andrey", "clpid": "Shur-A" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "Serine integrases are bacteriophage proteins responsible for integrating the phage genome into that of the host. Synthetic biologists have co-opted these proteins into useful tools for permanent DNA logic, utilizing their specific DNA recombination abilities to build synthetic cell differentiation and genetic memory systems. Each integrase has a specific pair of DNA sequences (attP/attB sites) that it recombines, but multiple identical sites can result in unpredictable recombination. We have developed a way to control integrase activity on identical attP/attB sites by using catalytically dead Cas9 (dCas9) as a programmable binding protein that can compete with integrase for binding to specific attachment sites. Utilizing a plasmid that contains two identical Bxb1 attP sites, integration can be repressed up to 8 fold at either one of the two attP sites when guide RNA and dCas9 are present. Guide RNA sequences that bind specifically to attB, or either of two attP sites, have been developed. Future goals are to utilize this technology to construct larger and more complex integrase logic circuits.", "doi": "10.1101/110254", "publication_date": "2017-02-21" }, { "id": "authors:a2gp3-q3v71", "collection": "authors", "collection_id": "a2gp3-q3v71", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170619-142716206", "type": "monograph", "title": "Expressing Biologically Active Membrane Proteins in a Cell-Free Transcription-Translation Platform", "author": [ { "family_name": "Guo", "given_name": "Shaobin", "orcid": "0000-0001-9736-4078", "clpid": "Guo-Shaobin" }, { "family_name": "Vaish", "given_name": "Amit", "clpid": "Vaish-A" }, { "family_name": "Chen", "given_name": "Qing", "clpid": "Chen-Qing" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "Cell-free transcription-translation platforms have been widely utilized to express soluble proteins in basic synthetic biological circuit prototyping. From a synthetic biology point of view, it is critical to express membrane proteins in cell-free transcription-translation systems, and use them directly in biocircuits, considering the fact that histidine kinases, G-protein coupled receptors (GPCRs) and other important biosensors are all membrane proteins. Previous studies have expressed membrane proteins in cell-free systems with the help of detergents, liposomes or nanodiscs, but have not demonstrated the ability to prototype circuit behavior for the purpose of testing more complex circuit functions involving membrane-bound proteins. Built on previous efforts, in this work we demonstrated that we could co-translationally express solubilized and active membrane proteins in our cell-free TX-TL platform with membrane-like materials. We first tested the expression of several constructs with \u03b21 and \u03b22 adrenergic receptors in TX-TL and observed significant insoluble membrane protein production. The addition of nanodiscs to the cell free expression system enabled solubilization of membrane proteins. Nanodisc is lipoprotein- based membrane-like material. The activity of \u03b22 adrenergic receptor was tested with both fluorescence and Surface Plasmon Resonance (SPR) binding assays by monitoring the specific binding response of small-molecule binders, carazolol and norepinephrine. Our results suggest that it is promising to use cell-free expression systems to prototype synthetic biocircuits involving single chain membrane proteins without extra procedures. This data made us one step closer to testing complex membrane protein circuits in cell-free environment.", "doi": "10.1101/104455", "publication_date": "2017-01-30" }, { "id": "authors:w8q5t-t4h42", "collection": "authors", "collection_id": "w8q5t-t4h42", "cite_using_url": "https://resolver.caltech.edu/CaltechCDSTR:2016.004", "type": "monograph", "title": "Formalizing synthesis in TLA+", "author": [ { "family_name": "Filippidis", "given_name": "Ioannis", "orcid": "0000-0003-4704-3334", "clpid": "Filippidis-I" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "This report proposes a TLA+ definition for the problem of constructing a strategy that implements a temporal property. It is based on a note by Lamport [1] that outlines a formalization of realizability in TLA. The modified definition proposed here is expressed axiomatically in TLA+. Specifying what function is acceptable as a strategy requires care, so that a function with empty domain be avoided, while ensuring that the strategy will not need to have a domain too large to be a set. \n\nWe prove that initial conditions should appear in assumptions only, unless an initial predicate is added to the definition of a realization. We show that a specification should include an assumption about a set of initial values to ensure that realizability does not become unprovable. We discuss what form of open-system properties expressed with the \"while- plus\" operator -+-> are realizable. \n\nWe formalize the notions of interleaving and disjoint-state behaviors, based on definitions given by Lamport and Abadi, and consider the notion of interleaving for an open-system property. We give examples of expressing different forms of games in TLA+ using the proposed definition, including games with partial information.", "publisher": "Caltech Library", "publication_date": "2016-12-23" }, { "id": "authors:2gzmb-ja750", "collection": "authors", "collection_id": "2gzmb-ja750", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200205-073243713", "type": "monograph", "title": "Identifying and exploiting tolerance to unexpected jumps in synthesized strategies for GR(1) specifications", "author": [ { "family_name": "Dathathri", "given_name": "Sumanth", "clpid": "Dathathri-S" }, { "family_name": "Livingston", "given_name": "Scott C.", "clpid": "Livingston-S-C" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "When used as part of a hybrid controller, finite-memory strategies synthesized from LTL specifications rely on an accurate dynamics model in order to ensure correctness of trajectories. In the presence of uncertainty about this underlying model, there may exist unexpected trajectories that manifest as unexpected transitions under control of the strategy. \n\nWhile some disturbances can be captured by augmenting the dynamics model, such approaches may be conservative in that bisimulations may fail to exist for which strategies can be synthesized. In this paper, we characterize the tolerance of such hybrid controllers - synthesized for generalized reactivity(1) specifications- to disturbances that appear as unexpected jumps (transitions) to states in the discrete strategy part of the controller. \n\nAs a first step, we show robustness to certain unexpected transitions that occur in a finite-manner, i.e., despite a certain number of unexpected jumps, the sequence of states obtained will still meet a stricter specification and hence the original specification. Additionally, we propose algorithms to improve robustness by increasing tolerance to additional disturbances. \n\nA robot gridworld example is presented to demonstrate the application of the developed ideas and also to obtain empirical computational and memory cost estimates.", "publisher": "Caltech Library", "publication_date": "2016-12" }, { "id": "authors:5v63h-c7q73", "collection": "authors", "collection_id": "5v63h-c7q73", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170313-102144883", "type": "monograph", "title": "The Effect of Compositional Context on Synthetic Gene Networks", "author": [ { "family_name": "Yeung", "given_name": "Enoch", "orcid": "0000-0001-7630-7429", "clpid": "Yeung-Enoch" }, { "family_name": "Dy", "given_name": "Aaron J.", "orcid": "0000-0003-0535-517X", "clpid": "Dy-Aaron-J" }, { "family_name": "Martin", "given_name": "Kyle B.", "clpid": "Martin-K-B" }, { "family_name": "Ng", "given_name": "Andrew H.", "clpid": "Ng-Andrew-H" }, { "family_name": "Del Vecchio", "given_name": "Domitilla", "orcid": "0000-0001-6472-8576", "clpid": "Del-Vecchio-D" }, { "family_name": "Beck", "given_name": "James L.", "clpid": "Beck-J-L" }, { "family_name": "Collins", "given_name": "James J.", "clpid": "Collins-J-J" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "It is well known that synthetic gene expression is highly sensitive to how genetic elements (promoter structure, spacing regions between promoter and coding sequences, ribosome binding sites, etc.) are spatially configured. An important topic that has received far less attention is how the compositional context, or spatial arrangement, of entire genes within a synthetic gene network affects their individual expression levels. In this paper we show, both quantitatively and qualitatively, that compositional context significantly alters transcription levels in synthetic gene networks. We demonstrate that key characteristics of gene induction, such as ultra-sensitivity and dynamic range, strongly depend on compositional context. We postulate that supercoiling can be used to explain this interference and validate this hypothesis through modeling and a series of in vitro supercoiling relaxation experiments. This compositional interference enables a novel form of feedback in synthetic gene networks. We illustrate the use of this feedback by redesigning the toggle switch to incorporate compositional context. We show the context-optimized toggle switch has improved threshold detection and memory properties.", "doi": "10.1101/083329", "publication_date": "2016-11-30" }, { "id": "authors:ecmh2-yw767", "collection": "authors", "collection_id": "ecmh2-yw767", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170206-084448312", "type": "monograph", "title": "A Bayesian approach to inferring chemical signal timing and amplitude in a temporal logic gate using the cell population distributional response", "author": [ { "family_name": "Baetica", "given_name": "Ania A.", "orcid": "0000-0003-0421-8181", "clpid": "Baetica-A-A" }, { "family_name": "Catanach", "given_name": "Thomas A.", "orcid": "0000-0002-4321-3159", "clpid": "Catanach-T-A" }, { "family_name": "Hsiao", "given_name": "Victoria", "orcid": "0000-0001-9297-1522", "clpid": "Hsiao-Victoria" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" }, { "family_name": "Beck", "given_name": "James L.", "clpid": "Beck-J-L" } ], "abstract": "Stochastic gene expression poses an important challenge for engineering robust behaviors in a heterogeneous cell population. Cells address this challenge by operating on distributions of cellular responses generated by noisy processes. Similarly, a previously published temporal logic gate considers the distribution of responses across a cell population under chemical inducer pulsing events. The design uses a system of two integrases to engineer an E. coli strain with four DNA states that records the temporal order of two chemical signal events. The heterogeneous cell population response was used to infer the timing and duration of the two chemical signals for a small set of events. Here we use the temporal logic gate system to address the problem of extracting information about chemical signal events. We use the heterogeneous cell population response to infer whether any event has occurred or not and also to infer its properties such as timing and amplitude. Bayesian inference provides a natural framework to answer our questions about chemical signal occurrence, timing, and amplitude. We develop a probabilistic model that incorporates uncertainty in the how well our model captures the cell population and in how well a sample of measured cells represents the entire population. Using our probabilistic model and cell population measurements taken every five minutes on generated data, we ask how likely it was to observe the data for parameter values that describe square-shaped inducer pulses. We compare the likelihood functions associated with the probabilistic models for the event with the chemical signal pulses turned on versus turned off. Hence, we can determine whether an event of chemical induction of integrase expression has occurred or not. Using Markov Chain Monte Carlo, we sample the posterior distribution of chemical pulse parameters to identify likely pulses that produce the data measurements. We implement this method and obtain accurate results for detecting chemical inducer pulse timing, length, and amplitude. We can detect and identify chemical inducer pulses as short as half an hour, as well as all pulse amplitudes that fall under biologically relevant conditions.", "doi": "10.1101/087379", "publication_date": "2016-11-14" }, { "id": "authors:jqgxb-0tw77", "collection": "authors", "collection_id": "jqgxb-0tw77", "cite_using_url": "https://resolver.caltech.edu/CaltechCDSTR:2016.003", "type": "monograph", "title": "Symbolic construction of GR(1) contracts for systems with full information", "author": [ { "family_name": "Filippidis", "given_name": "Ioannis", "orcid": "0000-0003-4704-3334", "clpid": "Filippidis-I" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "This work proposes a symbolic algorithm for the construction of assume-guarantee specifications that allow multiple agents to cooperate. Each agent is assigned goals expressed in a fragment of linear temporal logic known as generalized Streett with one pair, GR(1). These goals may be unrealizable, unless each agent makes additional assumptions, about the behavior of other agents. The algorithm constructs a contract among the agents, in that only the infinite behavior of the given goals is constrained, known as liveness, not the finite one, known as safety. This defers synthesis to a later stage of refinement, modularizing the design process. We prove that there exist GR(1) games that do not admit any refining GR(1) contract. For this reason, we formulate contracts with nested GR(1) properties and auxiliary communication variables, and prove that they always exist. The algorithm's fixpoint structure is similar to GR(1) synthesis, enjoying time complexity polynomial in the number of states, and linear in number of recurrence goals.", "doi": "10.1109/ACC.2016.7525009", "publisher": "California Institute of Technology", "publication_date": "2016-07-06" }, { "id": "authors:8snkc-0z872", "collection": "authors", "collection_id": "8snkc-0z872", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200205-074759124", "type": "monograph", "title": "Stochastic Gene Expression in Single Gene Oscillator Variants", "author": [ { "family_name": "Swaminathan", "given_name": "Anandh", "orcid": "0000-0001-9935-6530", "clpid": "Swaminathan-A" }, { "family_name": "Gomez", "given_name": "Marcella M.", "clpid": "Gomez-M-M" }, { "family_name": "Shis", "given_name": "David L.", "clpid": "Shis-D-L" }, { "family_name": "Bennett", "given_name": "Matthew R.", "clpid": "Bennett-M-R" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "It is infeasible to understand all dynamics in cell, but we can aim to understand the impact of design choices under our control. Here we consider a single gene oscillator as a case study to understand the influence of DNA copy number and repressor choice on the resulting dynamics. We first switch the repressor in the oscillator from the originally published lacI to treRL, a chimeric repressor with a lacI DNA binding domain that is inducible by trehalose. This slightly modified system produces faster and more regular oscillations than the original lacI oscillator. We then compare the treRL oscillator at three different DNA copy numbers. The period and amplitude of oscillations increases as the copy number is decreased. We cannot explain the change in period with differential equation models without changing delays or degradation rates. The correlation and phase coherence between daughter cells after cell division also tend to fall off faster for the lower copy oscillator variants. These results suggest that lower copy number variants of our single gene oscillator produce more synchronized oscillations.", "publisher": "Caltech Library", "publication_date": "2016-07" }, { "id": "authors:w8vjc-rwm94", "collection": "authors", "collection_id": "w8vjc-rwm94", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20160706-081948550", "type": "monograph", "title": "The role of single occupancy effects on integrase dynamics in a cell-free system", "author": [ { "family_name": "Artavanis", "given_name": "Georgios", "clpid": "Artavanis-G" }, { "family_name": "Hsiao", "given_name": "Victoria", "orcid": "0000-0001-9297-1522", "clpid": "Hsiao-Victoria" }, { "family_name": "Hayes", "given_name": "Clarmyra A.", "clpid": "Hayes-C-A" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "Phage integrase-based circuits are an alternative approach to relying on transcriptional and translational repression for biomolecular circuits. Previous research has shown that circuits based on integrases can perform a variety of functions, including counters, Boolean logic operators, memory modules and temporal event detectors. It is therefore essential to develop a principled theoretical and experimental framework for the design, implementation and study of such circuits. One of the fundamental questions that such a framework should address concerns the functionality limitations and temporal dynamics of the integrases as regulatory elements. Here, we test the functionality of several large serine integrases from a recently published library in a cell-free transcription-translation (TX-TL) platform. Additionally, we use a combination of experimental data and models to investigate integrase dynamics as a function of enzyme concentration and number of binding sites.\nWe report that sequestration of integrase molecules, either in the form of monomers or dimers, by the integrase's own binding sites dominates integrase dynamics, and that the delay in the activation of the reporter is negatively correlated with integrase plasmid concentration. We have validated our sequestration hypothesis by building a model with MATLAB's SimBiology toolbox, and running simulations with various integrase and binding sites concentrations. The simulation results qualitatively match the experimental results, and offer further insights into the system.", "doi": "10.1101/059675", "publication_date": "2016-06-18" }, { "id": "authors:r390p-tb835", "collection": "authors", "collection_id": "r390p-tb835", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20160502-104806241", "type": "monograph", "title": "Development of prokaryotic cell-free systems for synthetic biology", "author": [ { "family_name": "Chiao", "given_name": "Abel C.", "clpid": "Chiao-Abel-C" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" }, { "family_name": "Sun", "given_name": "Zachary Z.", "orcid": "0000-0002-9425-2924", "clpid": "Sun-Zachary-Z" } ], "abstract": "Prokaryotic cell-free systems are currently heavily used for the production of protein that can be otherwise challenging to produce in cells. However, historically cell-free systems were used to explore natural phenomena before the advent of genetic modification and transformation technology. Recently, synthetic biology has seen a resurgence of this historical use of cell-free systems as a prototyping tool of synthetic and natural genetic circuits. For these cell-free systems to be effective prototyping tools, an understanding of cell-free system mechanics must be established that is not purely protein-expression driven. Here we discuss the development of E. coli-based cell-free systems, with an emphasis on documenting published extract and energy preparation methods into a uniform format. We also discuss additional considerations when applying cell-free systems to synthetic biology.", "doi": "10.1101/048710", "publication_date": "2016-04-15" }, { "id": "authors:23z2y-ypm37", "collection": "authors", "collection_id": "23z2y-ypm37", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200205-075449007", "type": "monograph", "title": "Design and application of stationary phase combinatorial promoters", "author": [ { "family_name": "Hsiao", "given_name": "Victoria", "orcid": "0000-0001-9297-1522", "clpid": "Hsiao-Victoria" }, { "family_name": "Cheng", "given_name": "Aileen", "clpid": "Cheng-Aileen" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "Current bacterial synthetic circuits rely on the fast dilution and high protein expression that occurs during exponential phase. However, constant exponential phase is both difficult to ensure in a lab environment and almost certainly impractical in any natural setting. Here, we characterize the performance of 13 E. coli native \u03c338 promoters, as well as a previously identified \u03c338 consensus promoter. We then make tetO combinatorial versions of the three strongest promoters to allow for inducible delayed expression. The design of these combinatorial promoters allows for design of circuits with inducible stationary phase activity that can be used for phase-dependent delays in dynamic circuits or spatial partitioning of biofilms.", "publisher": "Caltech Library", "publication_date": "2016-03-29" }, { "id": "authors:k3yy2-xjd16", "collection": "authors", "collection_id": "k3yy2-xjd16", "cite_using_url": "https://resolver.caltech.edu/CaltechCDSTR:2016.001", "type": "monograph", "title": "Interfacing TuLiP with the JPL Statechart Autocoder: Initial progress toward synthesis of flight software from formal specifications", "author": [ { "family_name": "Dathathri", "given_name": "Sumanth", "clpid": "Dathathri-S" }, { "family_name": "Livingston", "given_name": "Scott C.", "clpid": "Livingston-S-C" }, { "family_name": "Reder", "given_name": "Leonard J.", "clpid": "Reder-L-J" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "This paper describes the implementation of an interface connecting the two tools : the JPL SCA (Statechart Autocoder) and TuLiP (Temporal Logic Planning Toolbox) to enable the automatic synthesis of low level implementation code directly from formal specifications. With system dynamics, bounds on uncertainty and formal specifications as inputs, TuLiP synthesizes Mealy machines that are correct-by-construction. An interface is built that automatically translates these Mealy machines into UML statecharts. The SCA accepts the UML statecharts (as XML files) to synthesize flight-certified implementation code. The functionality of the interface is demonstrated through three example systems of varying complexity a) a simple thermostat b) a simple speed controller for an autonomous vehicle and c) a more complex speed controller for an autonomous vehicle with a map-element. In the thermostat controller, there is a specification regarding the desired temperature range that has to be met despite disturbance from the environment. Similarly, in the speed-controllers there are specifications about safe driving speeds depending on sensor health (sensors fail unpredictably) and the map-location. The significance of these demonstrations is the potential circumventing of some of the manual design of statecharts for flight software/controllers. As a result, we expect that less testing and validation will be necessary. In applications where the products of synthesis are used alongside manually designed components, extensive testing or new certificates of correctness of the composition may still be required.", "publisher": "California Institute of Technology", "publication_date": "2016-03-08" }, { "id": "authors:7kc93-tpm90", "collection": "authors", "collection_id": "7kc93-tpm90", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200205-081111268", "type": "monograph", "title": "Global Dynamical Structure Reconstruction from Reconstructed Dynamical Structure Subnetworks: Applications to Biochemical Reaction Networks", "author": [ { "family_name": "Yeung", "given_name": "Enoch", "orcid": "0000-0001-7630-7429", "clpid": "Yeung-Enoch" }, { "family_name": "Kim", "given_name": "Jongmin", "orcid": "0000-0002-2713-1006", "clpid": "Kim-Jongmin" }, { "family_name": "Gon\u00e7alves", "given_name": "Jorge M.", "orcid": "0000-0002-5228-6165", "clpid": "Gon\u00e7alves-J-M" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "In this paper we consider the problem of network reconstruction, with applications to biochemical reaction networks. In particular, we consider the problem of global network reconstruction when there are a limited number of sensors that can be used to simultaneously measure state information. We introduce dynamical structure functions as a way to formulate the network reconstruction problem and motivate their usage with an example physical system from synthetic biology. In particular, we argue that in synthetic biology research, network verification is paramount to robust circuit operation and thus, network reconstruction is an invaluable tool. Nonetheless, we argue that existing approaches for reconstruction are hampered by limited numbers of biological sensors with high temporal resolution. In this way, we motivate the global network reconstruction problem using partial network information and prove that by performing a series of reconstruction experiments, where each experiment reconstructs a subnetwork dynamical structure function, the global dynamical structure function can be recovered in most cases. We illustrate these reconstruction techniques on a recently developed four gene biocircuit, an event detector, and show that it is capable of differentiating the temporal order of input events.", "publisher": "Caltech Library", "publication_date": "2015-12" }, { "id": "authors:sm57v-ryc97", "collection": "authors", "collection_id": "sm57v-ryc97", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200205-074505122", "type": "monograph", "title": "Quantitative Performance Bounds in Biomolecular Circuits due to Temperature Uncertainty", "author": [ { "family_name": "Sen", "given_name": "Shaunak", "orcid": "0000-0002-1412-8633", "clpid": "Sen-Shaunak" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "Performance of biomolecular circuits is affected by changes in temperature, due to its influence on underlying reaction rate parameters. While these performance variations have been estimated using Monte Carlo simulations, how to analytically bound them is generally unclear. To address this, we apply control-theoretic representations of uncertainty to examples of different biomolecular circuits, developing a framework to represent uncertainty due to temperature. We estimate bounds on the steady-state performance of these circuits due to temperature uncertainty. Through an analysis of the linearised dynamics, we represent this uncertainty as a feedback uncertainty and bound the variation in the magnitude of the input-output transfer function, providing a estimate of the variation in frequency-domain properties. Finally, we bound the variation in the time trajectories, providing an estimate of variation in time-domain properties. These results should enable a framework for analytical characterisation of uncertainty in biomolecular circuit performance due to temperature variation and may help in estimating relative performance of different controllers.", "publisher": "Caltech Library", "publication_date": "2015-12" }, { "id": "authors:tern8-9md37", "collection": "authors", "collection_id": "tern8-9md37", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200204-162407534", "type": "monograph", "title": "Synthesis of Distributed Longitudinal Control Protocols for a Platoon of Autonomous Vehicles", "author": [ { "family_name": "Han", "given_name": "Duo", "clpid": "Han-Duo" }, { "family_name": "Mo", "given_name": "Yilin", "orcid": "0000-0001-7937-6737", "clpid": "Mo-Yilin" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "We develop a framework for control protocol synthesis for a platoon of autonomous vehicles subject to temporal logic specifications. We describe the desired behavior of the platoon in a set of linear temporal logic formulas, such as collision avoidance, close spacing or comfortability. The problem of decomposing a global specification for the platoon into distributed specification for each pair of adjacent vehicles is hard to solve. We use the invariant specifications to tackle this problem and the decomposition is proved to be scalable.. Based on the specifications in Assumption/Guarantee form, we can construct a two-player game (between the vehicle and its closest leader) locally to automatically synthesize a controller protocol for each vehicle. Simulation example for a distributed vehicles control problem is also shown.", "publisher": "Caltech Library", "publication_date": "2015-12" }, { "id": "authors:dsxn4-zbq65", "collection": "authors", "collection_id": "dsxn4-zbq65", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200205-080035495", "type": "monograph", "title": "Finding stationary solutions to the chemical master equation by gluing state spaces at one or two states recursively", "author": [ { "family_name": "Meng", "given_name": "Xianglin", "clpid": "Meng-Xianglin" }, { "family_name": "Baetica", "given_name": "Ania A.", "orcid": "0000-0003-0421-8181", "clpid": "Baetica-A-A" }, { "family_name": "Singhal", "given_name": "Vipul", "clpid": "Singhal-V" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "Noise is indispensible to key cellular activities, including gene expression coordination and probabilistic differentiation. Stochastic models, such as the chemical master equation (CME), are essential to model noise in the levels of cellular components. In the CME framework, each state is associated with the molecular counts of all component species, and specifies the probability for the system to have that set of molecular counts. Analytic solutions to the CME are rarely known but can bring exciting benefits. For instance, simulations of biochemical reaction networks that are multiscale in time can be sped up tremendously by incorporating analytic solutions of the slow time-scale dynamics. Analytic solutions also enable the design of stationary distributions with properties such as the modality of the distribution, the mean expression level, and the level of noise. One way to derive the analytic steady state response of a biochemical reaction network was recently proposed by (M\u00e9lyk\u00fati et al. 2014). The paper recursively glues simple state spaces together, for which we have analytic solutions, at one or two states. \n\nIn this work, we explore the benefits and limitations of the gluing technique proposed by M\u00e9lyk\u00fati et al., and introduce recursive algorithms that use the technique to solve for the analytic steady state response of stochastic biochemical reaction networks. We give formal characterizations of the set of reaction networks whose state spaces can be obtained by carrying out single-point gluing of paths, cycles or both sequentially. We find that the dimension of the state space of a reaction network equals the maximum number of linearly independent reactions in the system. We then characterize the complete set of stochastic biochemical reaction networks that have elementary reactions and two-dimensional state spaces. As an example, we propose a recursive algorithm that uses the gluing technique to solve for the steady state response of a mass-conserving system with two connected monomolecular reversible reactions. Even though the gluing technique can only construct finite state spaces, we find that, by taking the size of a finite state space to infinity, the steady state response can converge to the analytic solution on the resulting infinite state space. \n\nFinally, we illustrate the aforementioned ideas with the example of two interconnected transcriptional components, which was first studied by (Ghaemi and Del Vecchio 2012).", "publisher": "Caltech Library", "publication_date": "2015-11-24" }, { "id": "authors:w6fa6-hw749", "collection": "authors", "collection_id": "w6fa6-hw749", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200214-151424905", "type": "monograph", "title": "Robust Model Predictive Control for Signal Temporal Logic Synthesis", "author": [ { "family_name": "Farahani", "given_name": "Samira S.", "clpid": "Farahani-S-S" }, { "family_name": "Raman", "given_name": "Vasumathi", "clpid": "Raman-V" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "Most automated systems operate in uncertain or adversarial conditions, and have to be capable of reliably reacting to changes in the environment. The focus of this paper is on automatically synthesizing reactive controllers for cyber-physical systems subject to signal temporal logic (STL) specifications. We build on recent work that encodes STL specifications as mixed integer linear constraints on the variables of a discrete-time model of the system and environment dynamics. To obtain a reactive controller, we present solutions to the worst-case model predictive control (MPC) problem using a suite of mixed integer linear programming techniques. We demonstrate the comparative effectiveness of several existing worst-case MPC techniques, when applied to the problem of control subject to temporal logic specifications; our empirical results emphasize the need to develop specialized solutions for this domain.", "publisher": "Caltech Library", "publication_date": "2015-10" }, { "id": "authors:ef26x-91m95", "collection": "authors", "collection_id": "ef26x-91m95", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20181029-112222224", "type": "monograph", "title": "Design Space Exploration of the Violacein Pathway in Escherichia coli Based Transcription Translation Cell-Free System (TX-TL)", "author": [ { "family_name": "Nguyen", "given_name": "Phuc H. B.", "clpid": "Nguyen-Phuc-H-B" }, { "family_name": "Wu", "given_name": "Yong Y.", "clpid": "Wu-Yong-Y" }, { "family_name": "Guo", "given_name": "Shaobin", "orcid": "0000-0001-9736-4078", "clpid": "Guo-Shaobin" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "In this study, an Escherichia coli (E. coli) based transcription translation cell-free system (TX-TL) was employed to sample various enzyme expression levels of the violacein pathway. The pathway was successfully reconstructed in TX-TL. Its variation produced different metabolites as evident from the extracts assorted colors. Analysis of the violacein product via UV-Vis absorption and liquid chromatography-mass spectrometry (LC-MS) detected 68 nanograms of violacein per 10 microliters reaction volume. Significant buildup of prodeoxyviolacein intermediate was also detected in the equimolar TX-TL reaction. Finally, design space exploration experiments suggested an improvement in violacein production at high VioC and VioD DNA concentrations.", "doi": "10.1101/027656", "publication_date": "2015-09-27" }, { "id": "authors:xz021-mf017", "collection": "authors", "collection_id": "xz021-mf017", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20150608-094354039", "type": "monograph", "title": "Protein degradation in a TX-TL cell-free expression system using ClpXP protease", "author": [ { "family_name": "Sun", "given_name": "Zachary Z.", "orcid": "0000-0002-9425-2924", "clpid": "Sun-Zachary-Z" }, { "family_name": "Kim", "given_name": "Jongmin", "orcid": "0000-0002-2713-1006", "clpid": "Kim-Jongmin" }, { "family_name": "Singhal", "given_name": "Vipul", "orcid": "0000-0003-1670-1824", "clpid": "Singhal-V" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "An in vitro S30-based Escherichia coli expression system (\"Transcription-Translation\", or \"TX-TL\") has been developed as an alternative prototyping environment to the cell for synthetic circuits [1-5]. Basic circuit elements, such as switches and cascades, have been shown to function in TX-TL, as well as bacteriophage assembly [2, 6]. Circuits can also be prototyped from basic parts within 8 hours, avoiding cloning and transformation steps [7]. However, most published results have been obtained in a \"batch mode\" reaction, where factors that play an important role for in vivo circuit dynamics \u2013 namely protein degradation and protein dilution \u2013 are severely hindered or are not present. This limits the complexity of circuits built in TX-TL without steady-state or continuous-flow solutions [8-10]. However, alternate methods that enable dilution either require extra equipment and expertise or demand lower reaction throughput. We explored the possibility of supplementing TX-TL with ClpXP, an AAA+ protease pair that selectively degrades tagged proteins [11], to provide finely-tuned degradation. The mechanism of ClpXP degradation has been extensively studied both in vitro and in vivo [12-15]. However, it has not been characterized for use in synthetic circuits \u2013 metrics such as toxicity, ATP usage, degradation variation over time, and cellular loading need to be determined. In particular, TX-TL in batch mode is known to be resource limited [16], and ClpXP is known to require significant amounts of ATP to unfold different protein targets [17, 18]. We find that ClpXP's protein degradation dynamics is dependent on protein identity, but can be determined experimentally. Degradation follows Michaels-Menten kinetics, and can be fine tuned by ClpX or ClpP concentration. Added purified ClpX is also not toxic to TX-TL reactions. Therefore, ClpXP provides a controllable way to introduce protein degradation and dynamics into synthetic circuits in TX-TL.", "doi": "10.1101/019695", "publication_date": "2015-05-21" }, { "id": "authors:2gpv1-mjt24", "collection": "authors", "collection_id": "2gpv1-mjt24", "cite_using_url": "https://resolver.caltech.edu/CaltechCDSTR:2015.004", "type": "monograph", "title": "Revisiting the AMBA AHB bus case study", "author": [ { "family_name": "Filippidis", "given_name": "Ioannis", "orcid": "0000-0003-4704-3334", "clpid": "Filippidis-I" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "This report describes a number of changes to the ARM AMBA bus case study from Bloem et al. that lead to significant reduction in synthesis time. In addition, it identifies the reason of blowup for the synthesized strategies in earlier studies as lack of binary decision diagram (BDD) reordering during strategy construction. Enabling dynamic BDD reordering with the group sifting algorithm, we synthesized strategies for as many as 18 masters, with both the original and revised specifications. This conclusion is based on detailed experimental measurements that show the changes of BDD sizes over time for the fixpoint and other variables during the nested fixed point computation, including the cumulative time spent on BDD reordering and the total number of BDD nodes. The measurements were obtained for eight different cases, allowing to compare the original with the revised specifications, with strategy reordering enabled or not, and conjoining the weak fairness guarantees or merging them into a single B\u00fcchi automaton. The revised specification proposed here is expressed using the open Promela language.", "publisher": "California Institute of Technology", "publication_date": "2015-05-12" }, { "id": "authors:f2hsj-f1v61", "collection": "authors", "collection_id": "f2hsj-f1v61", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20150428-075140716", "type": "monograph", "title": "Prototyping 1,4-butanediol (BDO) biosynthesis pathway in a cell-free transcription-translation (TX-TL) system", "author": [ { "family_name": "Wu", "given_name": "Yong Y.", "clpid": "Wu-Yong-Y" }, { "family_name": "Culler", "given_name": "Stephanie", "clpid": "Culler-S-J" }, { "family_name": "Khandurina", "given_name": "Julia", "clpid": "Khandurina-J" }, { "family_name": "Van Dien", "given_name": "Stephen", "clpid": "Van-Dien-S" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "Current methods for assembling metabolic pathways require a process of repeated trial and error and have a long design-build-test cycle. Further, it remains a challenge to precisely tune enzyme expression levels for maximizing target metabolite production. Recently it was shown that a cell-free transcriptional-translation system (TX-TL) can be used to rapidly prototype novel complex biocircuits as well as metabolic pathways. TX-TL systems allow protein expression from multiple DNA pieces, opening up the possibility of modulating concentrations of DNA encoding individual pathway enzymes and testing the related effect on metabolite production. In this work, we demonstrate TX-TL as a platform for exploring the design space of metabolic pathways using a 1,4-BDO biosynthesis pathway as an example. Using TX-TL, we verified enzyme expression and enzyme activity and identified the conversion of 4-hydroxybutyrate to downstream metabolites as a limiting step of the 1,4-BDO pathway. We further tested combinations of various enzyme expression levels and found increasing downstream enzyme expression levels improved 1,4-BDO production.", "doi": "10.1101/017814", "publication_date": "2015-04-09" }, { "id": "authors:fdsg6-fgh34", "collection": "authors", "collection_id": "fdsg6-fgh34", "cite_using_url": "https://resolver.caltech.edu/CaltechCDSTR:2015.003", "type": "monograph", "title": "Synthesis from multi-paradigm specifications", "author": [ { "family_name": "Filippidis", "given_name": "Ioannis", "orcid": "0000-0003-4704-3334", "clpid": "Filippidis-I" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" }, { "family_name": "Holzmann", "given_name": "Gerard J.", "clpid": "Holzmann-G-J" } ], "abstract": "This work proposes a language for describing reactive synthesis problems that integrates imperative and declarative elements. The semantics is defined in terms of two-player turn-based infinite games with full information. Currently, synthesis tools accept linear temporal logic (LTL) as input, but this description is less structured and does not facilitate the expression of sequential constraints. This motivates the use of a structured programming language to specify synthesis problems. Transition systems and guarded commands serve as imperative constructs, expressed in a syntax based on that of the modeling language Promela. The syntax allows defining which player controls data and control flow, and separating a program into assumptions and guarantees. These notions are necessary for input to game solvers. The integration of imperative and declarative paradigms allows using the paradigm that is most appropriate for expressing each requirement. The declarative part is expressed in the LTL fragment of generalized reactivity(1), which admits efficient synthesis algorithms. The implementation translates Promela to input for the Slugs synthesizer and is written in Python.", "publisher": "California Institute of Technology", "publication_date": "2015-03-09" }, { "id": "authors:2bajj-bcd11", "collection": "authors", "collection_id": "2bajj-bcd11", "cite_using_url": "https://resolver.caltech.edu/CaltechCDSTR:2015.002", "type": "monograph", "title": "Cross-entropy Temporal Logic Motion Planning", "author": [ { "family_name": "Livingston", "given_name": "Scott C.", "clpid": "Livingston-S-C" }, { "family_name": "Wolff", "given_name": "Eric M.", "clpid": "Wolff-E-M" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "This paper presents a method for optimal trajectory generation for discrete-time nonlinear systems with linear temporal logic (LTL) task specifications. Our approach is based on recent advances in stochastic optimization algorithms for optimal trajectory generation. These methods rely on estimation of the rare event of sampling optimal trajectories, which is achieved by incrementally improving a sampling distribution so as to minimize the cross-entropy. A key component of these stochastic optimization algorithms is determining whether or not a trajectory is collision-free. We generalize this collision checking to efficiently verify whether or not a trajectory satisfies a LTL formula. Interestingly, this verification can be done in time polynomial in the length of the LTL formula and the trajectory. We also propose a method for efficiently re-using parts of trajectories that only partially satisfy the specification, instead of simply discarding the entire sample. Our approach is demonstrated through numerical experiments involving Dubins car and a generic point-mass model subject to complex temporal logic task specifications.", "doi": "10.1145/2728606.2728635", "publisher": "California Institute of Technology", "publication_date": "2015-02-27" }, { "id": "authors:mmfek-s3154", "collection": "authors", "collection_id": "mmfek-s3154", "cite_using_url": "https://resolver.caltech.edu/CaltechCDSTR:2015.001", "type": "monograph", "title": "Online Horizon Selection in Receding Horizon Temporal Logic Planning", "author": [ { "family_name": "Raman", "given_name": "Vasumathi", "clpid": "Raman-V" }, { "family_name": "F\u00e4lt", "given_name": "Mattias", "clpid": "F\u00e4lt-M" }, { "family_name": "Wongpiromsarn", "given_name": "Tichakorn", "clpid": "Wongpiromsarn-T" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "Temporal logics have proven effective for correct-by-construction synthesis of controllers for a wide range of applications. Receding horizon frameworks mitigate the computational intractability of reactive synthesis for temporal logic, but have thus far been limited by pursuing a single sequence of short horizon problems to the current goal. We propose a receding horizon algorithm for reactive synthesis that automatically determines a path to the currently pursued goal at runtime, in response to a nondeterministic environment. This is achieved by allowing each short horizon to have multiple local goals, and determining which local goal to pursue based on the current global goal, currently perceived environment and a pre-computed invariant dependent on each global goal. We demonstrate the utility of this additional flexibility in grant-response tasks, using a search-and-rescue example. Moreover, we show that these goal-dependent invariants mitigate the conservativeness of the receding horizon approach.", "publisher": "California Institute of Technology", "publication_date": "2015-02" }, { "id": "authors:14zdd-4sy64", "collection": "authors", "collection_id": "14zdd-4sy64", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200214-103858802", "type": "monograph", "title": "Systematic Design and Implementation of a Novel Synthetic Fold-Change Detector Biocircuit In Vivo", "author": [ { "family_name": "Guo", "given_name": "Shaobin", "orcid": "0000-0001-9736-4078", "clpid": "Guo-Shaobin" }, { "family_name": "Hori", "given_name": "Yutaka", "orcid": "0000-0002-3253-4985", "clpid": "Hori-Yutaka" }, { "family_name": "Murray", "given_name": "Richard", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "Biological signaling systems not only detect the absolute levels of the signals, but are also able to sense the fold-changes of the signals. The ability to detect fold-changes provides a powerful tool for biological organisms to adapt to the changes in environment. Here we present the first novel synthetic fold-change detector (FCD) circuit built from ground up in vivo. We systematically designed the FCD circuit in silico, prototyped it in cell-free transcription-translation platform (TX-TL), and eventually implemented it in E. coli cells. We were able to show that the FCD circuit can not only generate pulse-like behavior in response to input, but also produce the same pulse response with inputs of the same fold-change, despite of different absolute signal levels.", "publisher": "Caltech Library", "publication_date": "2015-02" }, { "id": "authors:6yhyr-vne94", "collection": "authors", "collection_id": "6yhyr-vne94", "cite_using_url": "https://resolver.caltech.edu/CaltechCDSTR:2014.001", "type": "monograph", "title": "Hot-swapping robot task goals in reactive formal synthesis", "author": [ { "family_name": "Livingston", "given_name": "Scott C.", "clpid": "Livingston-S-C" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "We consider the problem of synthesizing robot controllers to realize a task that unpredictably changes with time. Tasks are formally expressed in the GR(1) fragment of temporal logic, in which some of the variables are set by an\nadversary. The task changes by the addition or removal of goals, which occurs online (i.e., at run-time). We present an algorithm for mending control\nstrategies to realize tasks after the addition of goals, while avoiding global\nre-synthesis of the strategy. Experiments are presented for a planar\nsurveillance task in which new regions of interest are incrementally added.\nRun-times are empirically shown to be favorable compared to re-synthesizing from scratch. We also present an algorithm for mending control strategies for the removal of goals. While in this setting the original strategy is still\nfeasible, our algorithm provides a more satisfying solution by \"tightening\nloose ends.'' Both algorithms are shown to yield so-called reach annotations,\nand thus the control strategies are easily amenable to other algorithms\nconcerning incremental synthesis, e.g., as in previous work by the authors for\nnavigation in uncertain environments.", "publisher": "California Institute of Technology", "publication_date": "2014-09-22" }, { "id": "authors:5wjdk-gha54", "collection": "authors", "collection_id": "5wjdk-gha54", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20160513-141535201", "type": "monograph", "title": "Negative Feedback Facilitates Temperature Robustness in Biomolecular Circuit Dynamics", "author": [ { "family_name": "Sen", "given_name": "Shaunak", "orcid": "0000-0002-1412-8633", "clpid": "Sen-Shaunak" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "Temporal dynamics in many biomolecular circuits can change with temperature because\nof the temperature dependence of underlying reaction rate parameters. It is generally unclear what\ncircuit mechanisms can inherently facilitate robustness in the dynamics to variations in temperature.\nHere, we address this issue using a combination of mathematical models and experimental measurements\nin a cell-free transcription-translation system. We find that negative transcriptional feedback\ncan reduce the effect of temperature variation on circuit dynamics. Further, we find that effective\nnegative feedback due to first-order degradation mechanisms can also enable such a temperature\nrobustness effect. Finally, we estimate temperature dependence of key parameters mediating such\nnegative feedback mechanisms. These results should be useful in the design of temperature robust\ncircuit dynamics.", "doi": "10.1101/007385", "publication_date": "2014-07-22" }, { "id": "authors:tmd2n-8ka09", "collection": "authors", "collection_id": "tmd2n-8ka09", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20190213-141617926", "type": "monograph", "title": "Engineering Resilient Space Systems", "author": [ { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" }, { "family_name": "Day", "given_name": "John C.", "clpid": "Day-J-C" }, { "family_name": "Ingham", "given_name": "Michel D.", "clpid": "Ingham-M-D" }, { "family_name": "Reder", "given_name": "Leonard J.", "clpid": "Reder-L-J" }, { "family_name": "Williams", "given_name": "Brian C.", "clpid": "Williams-B-C" } ], "abstract": "Several distinct trends will influence space exploration missions in the next decade. Destinations are\nbecoming more remote and mysterious, science questions more sophisticated, and, as mission experience\naccumulates, the most accessible targets are visited, advancing the knowledge frontier to more difficult,\nharsh, and inaccessible environments. This leads to new challenges including: hazardous conditions that\nlimit mission lifetime, such as high radiation levels surrounding interesting destinations like Europa or\ntoxic atmospheres of planetary bodies like Venus; unconstrained environments with navigation hazards,\nsuch as free-floating active small bodies; multielement missions required to answer more sophisticated\nquestions, such as Mars Sample Return (MSR); and long-range missions, such as Kuiper belt exploration,\nthat must survive equipment failures over the span of decades. These missions will need to be successful\nwithout a priori knowledge of the most efficient data collection techniques for optimum science return.\nScience objectives will have to be revised 'on the fly', with new data collection and navigation decisions\non short timescales.\nYet, even as science objectives are becoming more ambitious, several critical resources remain\nunchanged. Since physics imposes insurmountable light-time delays, anticipated improvements to the\nDeep Space Network (DSN) will only marginally improve the bandwidth and communications cadence to\nremote spacecraft. Fiscal resources are increasingly limited, resulting in fewer flagship missions, smaller\nspacecraft, and less subsystem redundancy. As missions visit more distant and formidable locations, the\njob of the operations team becomes more challenging, seemingly inconsistent with the trend of shrinking\nmission budgets for operations support. How can we continue to explore challenging new locations\nwithout increasing risk or system complexity?\nThese challenges are present, to some degree, for the entire Decadal Survey mission portfolio, as\ndocumented in Vision and Voyages for Planetary Science in the Decade 2013\u20132022 (National Research\nCouncil, 2011), but are especially acute for the following mission examples, identified in our recently\ncompleted KISS Engineering Resilient Space Systems (ERSS) study:\n1. A Venus lander, designed to sample the atmosphere and surface of Venus, would have to perform\nscience operations as components and subsystems degrade and fail;\n2. A Trojan asteroid tour spacecraft would spend significant time cruising to its ultimate destination\n(essentially hibernating to save on operations costs), then upon arrival, would have to act as its\nown surveyor, finding new objects and targets of opportunity as it approaches each asteroid,\nrequiring response on short notice; and\n3. A MSR campaign would not only be required to perform fast reconnaissance over long distances\non the surface of Mars, interact with an unknown physical surface, and handle degradations and\nfaults, but would also contain multiple components (launch vehicle, cruise stage, entry and\nlanding vehicle, surface rover, ascent vehicle, orbiting cache, and Earth return vehicle) that\ndramatically increase the need for resilience to failure across the complex system.\nThe concept of resilience and its relevance and application in various domains was a focus during the\nstudy, with several definitions of resilience proposed and discussed. While there was substantial variation\nin the specifics, there was a common conceptual core that emerged\u2014adaptation in the presence of\nchanging circumstances. These changes were couched in various ways\u2014anomalies, disruptions,\ndiscoveries\u2014but they all ultimately had to do with changes in underlying assumptions. Invalid\nassumptions, whether due to unexpected changes in the environment, or an inadequate understanding of\ninteractions within the system, may cause unexpected or unintended system behavior. A system is\nresilient if it continues to perform the intended functions in the presence of invalid assumptions.\nOur study focused on areas of resilience that we felt needed additional exploration and integration,\nnamely system and software architectures and capabilities, and autonomy technologies. (While also an\nimportant consideration, resilience in hardware is being addressed in multiple other venues, including\n2\nother KISS studies.) The study consisted of two workshops, separated by a seven-month focused study\nperiod. The first workshop (Workshop #1) explored the 'problem space' as an organizing theme, and the\nsecond workshop (Workshop #2) explored the 'solution space'. In each workshop, focused discussions\nand exercises were interspersed with presentations from participants and invited speakers.\nThe study period between the two workshops was organized as part of the synthesis activity during the\nfirst workshop. The study participants, after spending the initial days of the first workshop discussing the\nnature of resilience and its impact on future science missions, decided to split into three focus groups,\neach with a particular thrust, to explore specific ideas further and develop material needed for the second\nworkshop. The three focus groups and areas of exploration were:\n1. Reference missions: address/refine the resilience needs by exploring a set of reference missions\n2. Capability survey: collect, document, and assess current efforts to develop capabilities and\ntechnology that could be used to address the documented needs, both inside and outside NASA\n3. Architecture: analyze the impact of architecture on system resilience, and provide principles and\nguidance for architecting greater resilience in our future systems\nThe key product of the second workshop was a set of capability roadmaps pertaining to the three\nreference missions selected for their representative coverage of the types of space missions envisioned for\nthe future. From these three roadmaps, we have extracted several common capability patterns that would\nbe appropriate targets for near-term technical development: one focused on graceful degradation of\nsystem functionality, a second focused on data understanding for science and engineering applications,\nand a third focused on hazard avoidance and environmental uncertainty. Continuing work is extending\nthese roadmaps to identify candidate enablers of the capabilities from the following three categories:\narchitecture solutions, technology solutions, and process solutions.\nThe KISS study allowed a collection of diverse and engaged engineers, researchers, and scientists to think\ndeeply about the theory, approaches, and technical issues involved in developing and applying resilience\ncapabilities. The conclusions summarize the varied and disparate discussions that occurred during the\nstudy, and include new insights about the nature of the challenge and potential solutions:\n1. There is a clear and definitive need for more resilient space systems. During our study period,\nthe key scientists/engineers we engaged to understand potential future missions confirmed the\nscientific and risk reduction value of greater resilience in the systems used to perform these\nmissions.\n2. Resilience can be quantified in measurable terms\u2014project cost, mission risk, and quality of\nscience return. In order to consider resilience properly in the set of engineering trades performed\nduring the design, integration, and operation of space systems, the benefits and costs of resilience\nneed to be quantified. We believe, based on the work done during the study, that appropriate\nmetrics to measure resilience must relate to risk, cost, and science quality/opportunity. Additional\nwork is required to explicitly tie design decisions to these first-order concerns.\n3. There are many existing basic technologies that can be applied to engineering resilient space\nsystems. Through the discussions during the study, we found many varied approaches and\nresearch that address the various facets of resilience, some within NASA, and many more\nbeyond. Examples from civil architecture, Department of Defense (DoD) / Defense Advanced\nResearch Projects Agency (DARPA) initiatives, 'smart' power grid control, cyber-physical\nsystems, software architecture, and application of formal verification methods for software were\nidentified and discussed. The variety and scope of related efforts is encouraging and presents\nmany opportunities for collaboration and development, and we expect many collaborative\nproposals and joint research as a result of the study.\n4. Use of principled architectural approaches is key to managing complexity and integrating\ndisparate technologies. The main challenge inherent in considering highly resilient space\nsystems is that the increase in capability can result in an increase in complexity with all of the\n3\nrisks and costs associated with more complex systems. What is needed is a better way of\nconceiving space systems that enables incorporation of capabilities without increasing\ncomplexity. We believe principled architecting approaches provide the needed means to convey a\nunified understanding of the system to primary stakeholders, thereby controlling complexity in\nthe conception and development of resilient systems, and enabling the integration of disparate\napproaches and technologies. A representative architectural example is included in Appendix F.\n5. Developing trusted resilience capabilities will require a diverse yet strategically directed\nresearch program. Despite the interest in, and benefits of, deploying resilience space systems, to\ndate, there has been a notable lack of meaningful demonstrated progress in systems capable of\nworking in hazardous uncertain situations. The roadmaps completed during the study, and\ndocumented in this report, provide the basis for a real funded plan that considers the required\nfundamental work and evolution of needed capabilities.\nExploring space is a challenging and difficult endeavor. Future space missions will require more\nresilience in order to perform the desired science in new environments under constraints of development\nand operations cost, acceptable risk, and communications delays. Development of space systems with\nresilient capabilities has the potential to expand the limits of possibility, revolutionizing space science by\nenabling as yet unforeseen missions and breakthrough science observations.\nOur KISS study provided an essential venue for the consideration of these challenges and goals.\nAdditional work and future steps are needed to realize the potential of resilient systems\u2014this study\nprovided the necessary catalyst to begin this process.", "doi": "10.26206/WDX7-K192", "publication_date": "2013-09-27" }, { "id": "authors:7yptp-9wj25", "collection": "authors", "collection_id": "7yptp-9wj25", "cite_using_url": "https://resolver.caltech.edu/CaltechCDSTR:2013.001", "type": "monograph", "title": "Optimal Control of Mixed Logical Dynamical Systems with Long-Term Temporal Logic Specifications", "author": [ { "family_name": "Wolff", "given_name": "Eric M.", "clpid": "Wolff-E-M" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "We present a mathematical programming-based method for control of large a class of nonlinear systems subject to temporal logic task specifications. We consider Mixed Logical Dynamical (MLD) systems, which include linear hybrid automata, constrained linear systems, and piecewise affine systems. We specify tasks using a fragment of linear temporal logic (LTL) that allows both finite- and infinite-horizon properties to be specified, including tasks such as surveillance, periodic walking, repeated assembly, and environmental monitoring. Our method directly encodes an LTL formula as mixed-integer linear constraints on the MLD system, instead of computing a finite abstraction. This approach is efficient; for common tasks the formulation may use significantly fewer binary variables than related approaches. In simulation, we solve non-trivial temporal logic motion planning tasks for high-dimensional continuous systems using our approach.", "publisher": "California Institute of Technology", "publication_date": "2013-06-24" }, { "id": "authors:qgpd8-25z64", "collection": "authors", "collection_id": "qgpd8-25z64", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130115-094546873", "type": "monograph", "title": "An Aircraft Electric Power Testbed for Validating Automatically Synthesized Reactive Control Protocols", "author": [ { "family_name": "Rogersten", "given_name": "Robert", "clpid": "Rogersten-R" }, { "family_name": "Xu", "given_name": "Huan", "clpid": "Xu-H" }, { "family_name": "Ozay", "given_name": "Necmiye", "clpid": "Ozay-N" }, { "family_name": "Topcu", "given_name": "Ufuk", "clpid": "Topcu-U" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "Modern aircraft increasingly rely on electric power for subsystems that have traditionally run on mechanical power. The complexity and safety-criticality of aircraft electric power systems have therefore increased, rendering the design of these systems more challenging. This work is motivated by the potential that correct-by-construction reactive controller synthesis tools may have in increasing the effectiveness of the electric power system design cycle. In particular, we have built an experimental hardware platform that captures some key elements of aircraft electric power systems within a simplified setting. We intend to use this platform for validating the applicability of theoretical advances in correct-by-construction control synthesis and for studying implementation-related challenges. We demonstrate a simple design workflow from formal specifications to auto-generated code that can run on software models and be used in hardware implementation. We show some preliminary results with different control architectures on the developed hardware testbed.", "publisher": "Caltech Library", "publication_date": "2013-01-15" }, { "id": "authors:43wc9-11598", "collection": "authors", "collection_id": "43wc9-11598", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20190410-120612586", "type": "monograph", "title": "Synthesis of Reactive Protocols for Vehicle-to-Vehicle Communication", "author": [ { "family_name": "Wiltsche", "given_name": "Clemens", "clpid": "Wiltsche-C" }, { "family_name": "Topcu", "given_name": "Ufuk", "clpid": "Topcu-U" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "We present a synthesis method for communication protocols for active safety applications that satisfy certain formal specifications on quality of service requirements. The protocols are developed to provide reliable communication services for automobile active safety applications. The synthesis method transforms a specification into a distributed implementation of senders and receivers that together satisfy the quality of service requirements by transmitting messages over an unreliable medium. We develop a specification language and an execution model for the implementations, and demonstrate the viability of our method by developing a protocol for a traffic scenario in which a car runs a red light at a busy intersection.", "doi": "10.48550/arXiv.1210.2035", "publisher": "arXiv", "publication_date": "2012-10-07" }, { "id": "authors:gz1wr-jzx39", "collection": "authors", "collection_id": "gz1wr-jzx39", "cite_using_url": "https://resolver.caltech.edu/CaltechCDSTR:2012.004", "type": "monograph", "title": "Motion planning in observations space with learned diffeomorphism models", "author": [ { "family_name": "Censi", "given_name": "Andrea", "orcid": "0000-0001-5162-0398", "clpid": "Censi-A" }, { "family_name": "Nilsson", "given_name": "Adam", "clpid": "Nilsson-A" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "We consider the problem of planning motions in observations\n space, based on learned models of the dynamics that\n associate to each action a diffeomorphism of the\n observations domain. For an arbitrary set of\n diffeomorphisms, this problem must be formulated as a\n generic search problem. We adapt established algorithms of\n the graph search family. In this scenario, node expansion\n is very costly, as each node in the graph is associated to\n an uncertain diffeomorphism and corresponding predicted\n observations. We describe several improvements that\n ameliorate performance: the introduction of better image\n similarities to use as heuristics; a method to reduce the\n number of expanded nodes by preliminarily identifying\n redundant plans; and a method to pre-compute composite\n actions that make the search efficient in all directions.", "publisher": "Caltech Library", "publication_date": "2012-09-27" }, { "id": "authors:4ced0-apw23", "collection": "authors", "collection_id": "4ced0-apw23", "cite_using_url": "https://resolver.caltech.edu/CaltechCDSTR:2012.003", "type": "monograph", "title": "Patching task-level robot controllers based on a local \u00b5-calculus formula", "author": [ { "family_name": "Livingston", "given_name": "Scott C.", "clpid": "Livingston-S-C" }, { "family_name": "Prabhakar", "given_name": "Pavithra", "clpid": "Prabhakar-P" }, { "family_name": "Jose", "given_name": "Alex B.", "clpid": "Jose-A-B" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "We present a method for mending strategies for\nGR(1) specifications. Given the addition or removal of edges\nfrom the game graph describing a problem (essentially transition\nrules in a GR(1) specification), we apply a \u00b5-calculus\nformula to a neighborhood of states to obtain a \"local strategy\"\nthat navigates around the invalidated parts of an original\nsynthesized strategy. Our method may thus avoid global resynthesis\nwhile recovering correctness with respect to the new\nspecification. We illustrate the results both in simulation and\non physical hardware for a planar robot surveillance task.", "publisher": "Caltech Library", "publication_date": "2012-09-20" }, { "id": "authors:wyqv1-6c387", "collection": "authors", "collection_id": "wyqv1-6c387", "cite_using_url": "https://resolver.caltech.edu/CaltechCDSTR:2011.008", "type": "monograph", "title": "Robust Control of Uncertain Markov Decision Processes with Temporal Logic Specifications", "author": [ { "family_name": "Wolff", "given_name": "Eric M.", "clpid": "Wolff-E-M" }, { "family_name": "Topcu", "given_name": "Ufuk", "clpid": "Topcu-U" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "We present a method for designing robust controllers for dynamical systems with linear temporal logic specifications. We abstract the original system by a finite Markov Decision Process (MDP) that has transition probabilities in a specified uncertainty set. A robust control policy for the MDP is generated that maximizes the worst-case probability of satisfying the specification over all transition probabilities in the uncertainty set. To do this, we use a procedure from probabilistic model checking to combine the system model with an automaton representing the specification. This new MDP is then transformed into an equivalent form that satisfies assumptions for stochastic shortest path dynamic programming. A robust version of dynamic programming allows us to solve for a $\\epsilon$-suboptimal robust control policy with time complexity $O(\\log 1/\\epsilon)$ times that for the non-robust case. We then implement this control policy on the original dynamical system.", "publisher": "California Institute of Technology", "publication_date": "2011-09-25" }, { "id": "authors:wwb40-h3k92", "collection": "authors", "collection_id": "wwb40-h3k92", "cite_using_url": "https://resolver.caltech.edu/CaltechCDSTR:2011.006", "type": "monograph", "title": "Synthesis of Switching Protocols from Temporal Logic Specifications", "author": [ { "family_name": "Liu", "given_name": "Jun", "clpid": "Liu-Jun" }, { "family_name": "Ozay", "given_name": "Necmiye", "clpid": "Ozay-N" }, { "family_name": "Topcu", "given_name": "Ufuk", "clpid": "Topcu-U" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "We propose formal means for synthesizing switching protocols that determine the sequence in which the modes of a switched system are activated to satisfy certain high-level specifications in linear temporal logic. The synthesized protocols are robust against exogenous disturbances on the continuous dynamics. Two types of finite transition systems, namely under- and over-approximations, that abstract the behavior of the underlying continuous dynamics are defined. In particular, we show that the discrete synthesis problem for an under-approximation can be formulated as a model checking problem, whereas that for an over-approximation can be transformed into a two-player game. Both of these formulations are amenable to efficient, off-the-shelf software tools. By construction, existence of a discrete switching strategy for the discrete synthesis problem guarantees the existence of a continuous switching protocol for the continuous synthesis problem, which can be implemented at the continuous level to ensure the correctness of the nonlinear switched system. Moreover, the proposed framework can be straightforwardly extended to accommodate specifications that require reacting to possibly adversarial external events. Finally, these results are illustrated using three examples from different application domains.", "publisher": "California Institute of Technology", "publication_date": "2011-09-16" }, { "id": "authors:r4rgt-jkx31", "collection": "authors", "collection_id": "r4rgt-jkx31", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20190410-120609095", "type": "monograph", "title": "Extremal Properties of Complex Networks", "author": [ { "family_name": "Barmpoutis", "given_name": "Dionysios", "clpid": "Barmpoutis-D" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "We describe the structure of connected graphs with the minimum and maximum average distance, radius, diameter, betweenness centrality, efficiency and resistance distance, given their order and size. We find tight bounds on these graph qualities for any arbitrary number of nodes and edges and analytically derive the form and properties of such networks.", "doi": "10.48550/arXiv.1104.5532", "publisher": "arXiv", "publication_date": "2011-04-29" }, { "id": "authors:r3tvy-yjv64", "collection": "authors", "collection_id": "r3tvy-yjv64", "cite_using_url": "https://resolver.caltech.edu/CaltechCDSTR:2011.004", "type": "monograph", "title": "Bootstrapping, uncertain semantics, and invariance", "author": [ { "family_name": "Censi", "given_name": "Andrea", "orcid": "0000-0001-5162-0398", "clpid": "Censi-A" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "In the problem of bootstrapping, an agent learns to use an unknown body, in an unknown world, starting from zero information about the models involved. This is a fascinating problem, which so far has not been given a proper formalization. In this paper, we give a rigorous definition of what it means for an agent to be able to use \"uninterpreted\" observations and commands: there are some disturbances, represented by group actions, that modify what we call \"semantic maps\". The range of disturbances tolerated by an agent indirectly encode the assumptions needed by the agent. We argue that the behavior of agent which claims optimality (in any sense) must actually be invariant to such disturbances, and we discuss several design principles which allow to obtain this invariance for observations nuisances.", "publisher": "Caltech", "publication_date": "2011-04" }, { "id": "authors:ehtwx-efc37", "collection": "authors", "collection_id": "ehtwx-efc37", "cite_using_url": "https://resolver.caltech.edu/CaltechCDSTR:2011.005", "type": "monograph", "title": "A group-theoretic approach to formalizing bootstrapping problems", "author": [ { "family_name": "Censi", "given_name": "Andrea", "orcid": "0000-0001-5162-0398", "clpid": "Censi-A" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "The bootstrapping problem consists in designing agents that learn a model of themselves and the world, and utilize it to achieve useful tasks. It is different from other learning problems as the agent starts with uninterpreted observations and commands, and with minimal prior information about the world. In this paper, we give a mathematical formalization of this aspect of the problem. We argue that the vague constraint of having \"no prior information\" can be recast as a precise algebraic condition on the agent: that its behavior is invariant to particular classes of nuisances on the world, which we show can be well represented by actions of groups (diffeomorphisms, permutations, linear transformations) on observations and commands. We then introduce the class of bilinear gradient dynamics sensors (BGDS) as a candidate for learning generic robotic sensorimotor cascades. We show how framing the problem as rejection of group nuisances allows a compact and modular analysis of typical preprocessing stages, such as learning the topology of the sensors. We demonstrate learning and using such models on real-world range-finder and camera data from publicly available datasets.", "publisher": "Caltech", "publication_date": "2011-04" }, { "id": "authors:detxd-fy181", "collection": "authors", "collection_id": "detxd-fy181", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20190410-120605649", "type": "monograph", "title": "Quantification and Minimization of Crosstalk Sensitivity in Networks", "author": [ { "family_name": "Barmpoutis", "given_name": "Dionysios", "clpid": "Barmpoutis-D" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "Crosstalk is defined as the set of unwanted interactions among the different entities of a network. Crosstalk is present in various degrees in every system where information is transmitted through a means that is accessible by all the individual units of the network. Using concepts from graph theory, we introduce a quantifiable measure for sensitivity to crosstalk, and analytically derive the structure of the networks in which it is minimized. It is shown that networks with an inhomogeneous degree distribution are more robust to crosstalk than corresponding homogeneous networks. We provide a method to construct the graph with the minimum possible sensitivity to crosstalk, given its order and size. Finally, for networks with a fixed degree sequence, we present an algorithm to find the optimal interconnection structure among their vertices.", "doi": "10.48550/arXiv.1012.0606", "publisher": "arXiv", "publication_date": "2010-12-02" }, { "id": "authors:zrbdx-3es81", "collection": "authors", "collection_id": "zrbdx-3es81", "cite_using_url": "https://resolver.caltech.edu/CaltechCDSTR:2010.003a", "type": "monograph", "title": "Bootstrapping bilinear models of robotic sensorimotor cascades", "author": [ { "family_name": "Censi", "given_name": "Andrea", "orcid": "0000-0001-5162-0398", "clpid": "Censi-A" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "We consider the bootstrapping problem, which consists in learning a model of the agent's sensors and actuators starting from zero prior information, and we take the problem of servoing as a cross-modal task to validate the learned models. We study the class of bilinear dynamics sensors, in which the derivative of the observations are a bilinear form of the control commands and the observations themselves. This class of models is simple yet general enough to represent the main phenomena of three representative robotics sensors (field sampler, camera, and range-finder), apparently very different from one another. It also allows a bootstrapping algorithm based on hebbian learning, and that leads to a simple and bioplausible control strategy. The convergence properties of learning and control are demonstrated with extensive simulations and by analytical arguments.", "publisher": "California Institute of Technology", "publication_date": "2010-07-15" }, { "id": "authors:ex3fk-5kt19", "collection": "authors", "collection_id": "ex3fk-5kt19", "cite_using_url": "https://resolver.caltech.edu/CaltechCDSTR:2010.002", "type": "monograph", "title": "Delay-Based Controller Design for Continuous-Time and Hybrid Applications", "author": [ { "family_name": "Lavaei", "given_name": "Javad", "clpid": "Lavaei-J" }, { "family_name": "Sojoudi", "given_name": "Somayeh", "clpid": "Sojoudi-S" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "Motivated by the availability of different types of delays in embedded systems and biological circuits, the objective of this work is to study the benefits that delay can provide in simplifying the implementation of controllers for continuous-time systems. Given a continuous-time linear time-invariant (LTI) controller, we propose three methods to approximate this controller arbitrarily precisely by a simple controller composed of delay blocks, a few integrators and possibly a unity feedback. Different problems associated with the approximation procedures, such as finding the optimal number of delay blocks or studying the robustness of the designed controller with respect to delay values, are then investigated. We also study the design of an LTI continuous-time controller satisfying given control objectives whose delay-based implementation needs the least number of delay blocks. A direct application of this work is in the sampled-data control of a real-time embedded system, where the sampling frequency is relatively high and/or the output of the system is sampled irregularly. Based on our results on delay-based controller design, we propose a digital-control scheme that can implement every continuous-time stabilizing (LTI)\ncontroller. Unlike a typical sampled-data controller, the hybrid controller introduced here -\u2014 consisting of an ideal sampler, a digital controller, a number of modified second-order holds and possibly a unity feedback -\u2014 is robust to sampling jitter and can operate at arbitrarily high sampling frequencies without requiring expensive, high-precision computation.", "publisher": "California Institute of Technology", "publication_date": "2010-06-12" }, { "id": "authors:0as71-fjz76", "collection": "authors", "collection_id": "0as71-fjz76", "cite_using_url": "https://resolver.caltech.edu/CaltechCDSTR:2010.001", "type": "monograph", "title": "A bio-plausible design for visual pose stabilization", "author": [ { "family_name": "Han", "given_name": "Shuo", "clpid": "Han-S" }, { "family_name": "Censi", "given_name": "Andrea", "orcid": "0000-0001-5162-0398", "clpid": "Censi-A" }, { "family_name": "Straw", "given_name": "Andrew D.", "orcid": "0000-0001-8381-0858", "clpid": "Straw-A-D" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "We consider the problem of purely visual pose stabilization (also known as servoing) of a second-order rigid-body system with six degrees of freedom: how to choose forces and torques, based on the current view and a memorized goal image, to steer the pose towards a desired one. Emphasis has been given to the bio-plausibility of the computation, in the sense that the control laws could be in principle implemented on the neural substrate of simple insects. We show that stabilizing laws can be realized by bilinear/quadratic operations on the visual input. This particular computational structure has several numerically favorable characteristics (sparse, local, and parallel), and thus permits an efficient engineering implementation. We show results of the control law tested on an indoor helicopter platform.", "publisher": "California Institute of Technology", "publication_date": "2010-03-10" }, { "id": "authors:rvc0y-vad65", "collection": "authors", "collection_id": "rvc0y-vad65", "cite_using_url": "https://resolver.caltech.edu/CaltechCDSTR:2009.001", "type": "monograph", "title": "Limits on the Network Sensitivity Function for Multi-Agent Systems on a Graph", "author": [ { "family_name": "Tonetti", "given_name": "Stefania", "clpid": "Tonetti-S" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "This report explores the tradeoffs and limits of performance in feedback control of interconnected multi-agent systems, focused on the network sensitivity functions. We consider the interaction topology described by a directed graph and we prove that the sensitivity transfer functions between every pair of agents, arbitrarily connected, can be derived using a version of the Mason's Direct Rule. Explicit forms for special types of graphs are presented. An analysis of the role of cycles points out that these structures influence and limit considerably the performance of the system. The more the cycles are equally distributed among the formation, the better performance the system can achieve, but they are always worse than the single agent case. We also prove the networked version of Bode's integral formula, showing that it still holds for multi-agent systems.", "publisher": "California Institute of Technology", "publication_date": "2009-09" }, { "id": "authors:p6779-0mp04", "collection": "authors", "collection_id": "p6779-0mp04", "cite_using_url": "https://resolver.caltech.edu/CaltechCDSTR:2008.003", "type": "monograph", "title": "Periodically Controlled Hybrid Systems: Verifying A Controller for An Autonomous Vehicle", "author": [ { "family_name": "Wongpiromsarn", "given_name": "Tichakorn", "clpid": "Wongpiromsarn-T" }, { "family_name": "Mitra", "given_name": "Sayan", "clpid": "Mitra-S" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" }, { "family_name": "Lamperski", "given_name": "Andrew", "clpid": "Lamperski-A" } ], "abstract": "This paper introduces Periodically Controlled Hybrid Automata (PCHA) for describing a class of hybrid control systems. In a PCHA, control actions occur roughly periodically while internal and input actions, may occur in the interim changing the discrete-state or the setpoint. Based on periodicity and subtangential conditions, a new sufficient condition for verifying invariance of PCHAs is presented. This technique is used in verifying safety of the planner-controller subsystem of an autonomous ground vehicle, and in deriving geometric properties of planner generated paths that can be followed safely by the controller under environmental uncertainties.", "publisher": "California Institute of Technology", "publication_date": "2008-10-17" }, { "id": "authors:yk813-ckb60", "collection": "authors", "collection_id": "yk813-ckb60", "cite_using_url": "https://resolver.caltech.edu/CaltechCDSTR:2007.001", "type": "monograph", "title": "Conversion and verification procedure for goal-based control programs", "author": [ { "family_name": "Braman", "given_name": "J. M. B.", "clpid": "Braman-J-M-B" }, { "family_name": "Murray", "given_name": "R. M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "Fault tolerance and safety verification of control systems are essential for the success of autonomous robotic systems. A control architecture called Mission Data System, developed at the Jet Propulsion Laboratory, takes a goal-based control approach. In this paper, a method for converting goal network control programs into linear hybrid systems is developed. The linear hybrid system can then be verified for safety in the presence of failures using existing symbolic model checkers. An example task is developed and successfully verified using HyTech, a symbolic model checking software for linear hybrid systems.", "publisher": "California Institute of Technology", "publication_date": "2007-08-17" }, { "id": "authors:27qye-ckm71", "collection": "authors", "collection_id": "27qye-ckm71", "cite_using_url": "https://resolver.caltech.edu/CaltechCDSTR:2004.008", "type": "monograph", "title": "On a stochastic sensor selection algorithm with applications in sensor scheduling and sensor coverage", "author": [ { "family_name": "Gupta", "given_name": "Vijay", "clpid": "Gupta-V" }, { "family_name": "Chung", "given_name": "Timothy H.", "clpid": "Chung-Timothy-H" }, { "family_name": "Hassibi", "given_name": "Babak", "orcid": "0000-0002-1375-5838", "clpid": "Hassibi-B" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "In this note we consider the following problem. Suppose a set of sensors is jointly trying to estimate a process. One sensor takes a measurement at every time step and the measurements are then exchanged among all the sensors. What is the sensor schedule that results in the minimum error covariance? We describe a stochastic sensor selection strategy that is easy to implement and is computationally tractable. The problem described above comes up in many domains out of which we discuss two. In the sensor selection problem, there are multliple sensors that cannot operate simultaneously (e.g., sonars in the same frequency band). Thus measurements need to be scheduled. In the sensor coverage problem, a geographical area needs to be covered by mobile sensors each with limited range. Thus from every position, the sensors obtain a different view-point of the area and the sensors need to optimize their positions. The algorithm is applied to these problems and illustrated through simple examples.", "publisher": "California Institute of Technology", "publication_date": "2004-10-10" }, { "id": "authors:s9j8v-mpz83", "collection": "authors", "collection_id": "s9j8v-mpz83", "cite_using_url": "https://resolver.caltech.edu/CaltechCDSTR:2004.007", "type": "monograph", "title": "Optimal LQG Control Across a Packet-Dropping Link", "author": [ { "family_name": "Gupta", "given_name": "Vijay", "clpid": "Gupta-V" }, { "family_name": "Spanos", "given_name": "Demetri", "clpid": "Spanos-D" }, { "family_name": "Hassibi", "given_name": "Babak", "orcid": "0000-0002-1375-5838", "clpid": "Hassibi-B" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "We examine optimal Linear Quadratic Gaussian control for a system in which communication between the sensor (output of the plant) and the controller occurs across a packet-dropping link. We extend the familiar LQG separation principle to this problem that allows us to solve this problem using a standard LQR state-feedback design, along with an optimal algorithm for propagating and using the information across the unreliable link. We present one such optimal algorithm, which consists of a Kalman Filter at the sensor side of the link, and a switched linear filter at the controller side. Our design does not assume any statistical model of the packet drop events, and is thus optimal for an arbitrary packet drop pattern. Further, the solution is appealing from a practical point of view because it can be implemented as a small modification of an existing LQG control design.", "publisher": "California Institute of Technology", "publication_date": "2004-08" }, { "id": "authors:4978t-yv173", "collection": "authors", "collection_id": "4978t-yv173", "cite_using_url": "https://resolver.caltech.edu/CaltechCDSTR:2004.006", "type": "monograph", "title": "A Sub-optimal Algorithm to Synthesize Control Laws for a Network of Dynamic Agents", "author": [ { "family_name": "Gupta", "given_name": "Vijay", "clpid": "Gupta-V" }, { "family_name": "Hassibi", "given_name": "Babak", "orcid": "0000-0002-1375-5838", "clpid": "Hassibi-B" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "We study the synthesis problem of an LQR controller when the matrix describing the control law is constrained to lie in a particular vector space. Our motivation is the use of such control laws to stabilize networks of autonomous agents in a decentralized fashion; with the information flow being dictated by the constraints of a pre-specified topology. In this paper, we consider the finite-horizon version of the problem and provide both a computationally intensive optimal solution and a sub-optimal solution that is computationally more tractable. Then we apply the technique to the decentralized vehicle formation control problem and show that the loss in performance due to the use of the sub-optimal solution is not huge; however the topology can have a large effect on performance.", "publisher": "California Institute of Technology", "publication_date": "2004-08" }, { "id": "authors:dggje-96y63", "collection": "authors", "collection_id": "dggje-96y63", "cite_using_url": "https://resolver.caltech.edu/CaltechCDSTR:2004.003", "type": "monograph", "title": "Distributed Receding Horizon Control with Application to Multi-Vehicle Formation Stabilization", "author": [ { "family_name": "Dunbar", "given_name": "William B.", "clpid": "Dunbar-W-B" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "We consider the control of interacting subsystems whose dynamics and constraints are uncoupled, but whose state vectors are coupled non-separably in a single centralized cost function of a finite horizon optimal control problem. For a given centralized cost structure, we generate distributed optimal control problems for each subsystem and establish that the distributed receding horizon implementation is asymptotically stabilizing. The communication requirements between subsystems with coupling in the cost function are that each subsystem obtain the previous optimal control trajectory of those subsystems at each receding horizon update. The key requirements for stability are that each distributed optimal control not deviate too far from the previous optimal control, and that the receding horizon updates happen sufficiently fast. The theory is applied in simulation for stabilization of a formation of vehicles.", "publisher": "California Institute of Technology", "publication_date": "2004-01-01" }, { "id": "authors:1phkj-1vd63", "collection": "authors", "collection_id": "1phkj-1vd63", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20150211-071040084", "type": "monograph", "title": "Scheduling for Distributed Sensor Networks", "author": [ { "family_name": "Gupta", "given_name": "Vijay", "clpid": "Gupta-V" }, { "family_name": "Chung", "given_name": "Timothy H.", "clpid": "Chung-Timothy-H" }, { "family_name": "Hassibi", "given_name": "Babak", "orcid": "0000-0002-1375-5838", "clpid": "Hassibi-B" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "We examine the problem of distributed estimation when only one sensor can take a measurement per time step. The measurements are then exchanged among the sensors. The problem is motivated by the use of sonar range-finders used by the vehicles on the Caltech Multi-Vehicle Wireless Testbed. We solve for the optimal recursive estimation algorithm when the sensor switching schedule is given. Then we investigate several approaches for determining an optimal sensor switching strategy. We see that this problem involves searching a tree in general and propose and analyze two strategies for pruning the tree to keep the computation limited. The first is a sliding window strategy motivated by the Viterbi algorithm, and the second one uses thresholding. We also study a technique that employs choosing the sensors randomly from a probability distribution which can then be optimized. The performance of the algorithms are illustrated with the help of numerical examples.", "publisher": "Caltech Library", "publication_date": "2004" }, { "id": "authors:rgqvm-ad468", "collection": "authors", "collection_id": "rgqvm-ad468", "cite_using_url": "https://resolver.caltech.edu/CaltechCDSTR:2003.012", "type": "monograph", "title": "Information Flow and Cooperative Control of Vehicle Formations", "author": [ { "family_name": "Fax", "given_name": "J. Alexander", "clpid": "Fax-J-A" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "We consider the problem of cooperation among a collection of vehicles performing a shared\ntask using intervehicle communication to coordinate their actions. We apply tools from graph theory to relate the topology of the communication network to formation stability. We prove a Nyquist criterion that uses the eigenvalues of the graph Laplacian matrix to determine the effect\nof the graph on formation stability. We also propose a method for decentralized information\nexchange between vehicles. This approach realizes a dynamical system that supplies each vehicle\nwith a common reference to be used for cooperative motion. We prove a separation principle\nthat states that formation stability is achieved if the information flow is stable for the given\ngraph and if the local controller stabilizes the vehicle. The information flow can be rendered\nhighly robust to changes in the graph, thus enabling tight formation control despite limitations\nin intervehicle communication capability.", "publisher": "California Institute of Technology", "publication_date": "2003-01-01" }, { "id": "authors:necme-9ea48", "collection": "authors", "collection_id": "necme-9ea48", "cite_using_url": "https://resolver.caltech.edu/CaltechCDSTR:2003.008", "type": "monograph", "title": "Flat systems, equivalence and trajectory generation", "author": [ { "family_name": "Martin", "given_name": "Phillipe", "clpid": "Martin-P" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" }, { "family_name": "Rouchon", "given_name": "Pierre", "clpid": "Rouchon-P" } ], "abstract": "Flat systems, an important subclass of nonlinear control systems introduced\nvia differential-algebraic methods, are defined in a differential\ngeometric framework. We utilize the infinite dimensional geometry developed\nby Vinogradov and coworkers: a control system is a diffiety, or more\nprecisely, an ordinary diffiety, i.e. a smooth infinite-dimensional manifold\nequipped with a privileged vector field. After recalling the definition of\na Lie-Backlund mapping, we say that two systems are equivalent if they\nare related by a Lie-Backlund isomorphism. Flat systems are those systems\nwhich are equivalent to a controllable linear one. The interest of\nsuch an abstract setting relies mainly on the fact that the above system\nequivalence is interpreted in terms of endogenous dynamic feedback. The\npresentation is as elementary as possible and illustrated by the VTOL\naircraft.", "publisher": "California Institute of Technology", "publication_date": "2003-01-01" }, { "id": "authors:vdwtz-5xz08", "collection": "authors", "collection_id": "vdwtz-5xz08", "cite_using_url": "https://resolver.caltech.edu/CaltechCDSTR:2003.005", "type": "monograph", "title": "Agreement Problems in Networks with Directed Graphs and Switching Topology", "author": [ { "family_name": "Olfati-Saber", "given_name": "Reza", "clpid": "Olfati-Saber-R" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "In this paper, we provide tools for convergence and performance analysis of an agreement protocol for a network of integrator agents with directed information flow. Moreover, we analyze algorithmic robustness of this consensus protocol for the case of a network with mobile nodes and switching topology. We establish a connection between the Fiedler eigenvalue of the graph Laplacian and the performance of this agreement protocol. We demostrate that a class of directed graphs, called balanced graphs, have a crucial role in solving average-consensus problems. Based on the properties of balanced graphs, a group disagreement function (i.e. Lyapunov function) is proposed for convergence analysis of this agreement protocol for networks with directed graphs. This group disagreement function is later used for convergence analysis for the agreement problem in networks with switching topology. We provide simulation results that are consistent with our theoretical results and demonstrate the effectiveness of the proposed analytical tools.", "publisher": "California Institute of Technology", "publication_date": "2003-01-01" }, { "id": "authors:fnn3t-hae17", "collection": "authors", "collection_id": "fnn3t-hae17", "cite_using_url": "https://resolver.caltech.edu/CaltechCDSTR:2001.01-007", "type": "monograph", "title": "Graph Laplacians and Stabilization of Vehicle Formations", "author": [ { "family_name": "Fax", "given_name": "J. Alexander", "clpid": "Fax-J-A" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "Control of vehicle formations has emerged as a topic of significant interest to the controls community. In this paper, we merge tools from graph theory and control theory to derive stability criteria for formation stabilization. The interconnection between vehicles (i.e., which vehicles are sensed by other vehicles) is modeled as a graph, and the eigenvalues of the Laplacian matrix of the graph are used in stating a Nyquist-like stability criterion for vehicle formations. The location of the Laplacian eigenvalues can be correlated to the graph structure, and therefore used to identify desirable and undesirable formation interconnection topologies.", "publisher": "California Institute of Technology", "publication_date": "2001-01-01" }, { "id": "authors:5r9fz-1q467", "collection": "authors", "collection_id": "5r9fz-1q467", "cite_using_url": "https://resolver.caltech.edu/CaltechCDSTR:1999.CIT-CDS-99-001", "type": "monograph", "title": "Geometric Approaches to Control in the Presence of Magnitude and Rate Saturations", "author": [ { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "This paper gives a survey of some recent results on control of systems with magnitude and rate limits, motivated by problems in real-time trajectory generation and tracking for unmanned aerial vehicles. Two problems are considered: stabilization using ``nonlinear wrappers'' to rescale a given control law and real-time trajectory generation using differential flatness. For both problems, simplified versions of the general problem are studied using tools from differential geometry and nonlinear control to give insights into the limitations imposed by magnitude and rate limits and provide insights into constructive solutions to the trajectory generation and tracking problems.", "publisher": "California Institute of Technology", "publication_date": "1999-01-01" }, { "id": "authors:jgtcd-pbg29", "collection": "authors", "collection_id": "jgtcd-pbg29", "cite_using_url": "https://resolver.caltech.edu/CaltechCDSTR:1998.CIT-CDS-98-009", "type": "monograph", "title": "Discrete Function Approximation: Numerical Tools for Nonlinear Control", "author": [ { "family_name": "Muruhan", "given_name": "Rathinam", "clpid": "Muruhan-R" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "We describe a method for discrete representation of continuous functions and show how this may be used for typical computations in nonlinear control desi gn. The method involves representing functions by their values and finitely many derivatives at discrete set of points on the domain. We propose a grid structure based on a hierarchy of rectangular boxes that provides flexibility in placing grid points densely in some regions and sparsely in the other. The grids possess enough structure to facilitate easy interpolation schemes based on piecewise polynomials. We illustrate the method using a simple example where we compute the feedback linearizing output of a system.", "publisher": "California Institute of Technology", "publication_date": "1998-01-01" }, { "id": "authors:sk5yt-68524", "collection": "authors", "collection_id": "sk5yt-68524", "cite_using_url": "https://resolver.caltech.edu/CaltechCDSTR:1998.CIT-CDS-98-001", "type": "monograph", "title": "Evaluation of Bleed Valve Rate Requirements in Nonlinear Control of Rotating Stall on Axial Flow Compressors", "author": [ { "family_name": "Yeung", "given_name": "S.", "clpid": "Yeung-S" }, { "family_name": "Wang", "given_name": "Y.", "clpid": "Wang-Y" }, { "family_name": "Murray", "given_name": "R. M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "In this paper we evaluate the actuator rate requirements for control of rotating stall using a bleed valve and provide tools for predicting these requirements. Modification of both the stable and unstable parts of the compressor characteristic via addition of continuous air injection serves to reduce the requirement of a bleed valve used for the purpose of rotating stall stabilization. Analytical tools based on low order models (2-3 states) and simulation tools based on a reduced order model (37 states) are described. A bleed actuator rate limit study is presented to compare the actuator requirements predicted by theory, simulation, and experiment. The comparisons show that the predictions obtained from theory and simulations share the same trend as the experiments, with increasing accuracy as the complexity of the underlying model increases. Some insights on the design of a bleed-compressor pair are given.", "publisher": "California Institute of Technology", "publication_date": "1998-01-01" }, { "id": "authors:v9wzx-40j87", "collection": "authors", "collection_id": "v9wzx-40j87", "cite_using_url": "https://resolver.caltech.edu/CaltechCDSTR:1997.014", "type": "monograph", "title": "Nonlinear Rescaling of Control Laws with Application to Stabilization in the Presence of Magnitude Saturation", "author": [ { "family_name": "Morin", "given_name": "Pascal", "clpid": "Morin-P" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" }, { "family_name": "Praly", "given_name": "L.", "clpid": "Praly-L" } ], "abstract": "Motivated by some recent results on the stabilization of homogeneous systems, we present a gain-scheduling approach for the stabilization of non-linear systems. Given\na one-parameter family of stabilizing feedbacks and associated Lyapunov functions, we show how the parameter can be rescaled as a function of the state to give a new\nstabilizing controller. In the case of homogeneous systems, we obtain generalizations of some existing results. We show that this approach can also be applied to nonhomogeneous\nsystems. In particular, the main application considered in this paper is to the problem of stabilization with magnitude limitations. For this problem, we develop a design method for single-input controllable systems with eigenvalues in the left closed plane.", "publisher": "California Institute of Technology", "publication_date": "1997-11" }, { "id": "authors:dp0rr-v2p13", "collection": "authors", "collection_id": "dp0rr-v2p13", "cite_using_url": "https://resolver.caltech.edu/CaltechCDSTR:1997.CIT-CDS-97-012", "type": "monograph", "title": "System Identification for Limit Cycling Systems: A Case Study for Combustion Instabilities", "author": [ { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" }, { "family_name": "Jacobsen", "given_name": "C.A.", "clpid": "Jacobsen-C-A" }, { "family_name": "Casas", "given_name": "R.", "clpid": "Casas-R" }, { "family_name": "Khibnik", "given_name": "A.I.", "clpid": "Khibnik-A-I" }, { "family_name": "Johnson", "given_name": "C.R. Jr.", "clpid": "Johnson-C-R-J" }, { "family_name": "Bitmead", "given_name": "R.", "clpid": "Bitmead-R" }, { "family_name": "Peracchio", "given_name": "A.A.", "clpid": "Peracchio-A-A" } ], "abstract": "This paper presents a case study in system identification for limit \ncycling systems. The focus of the paper is on (a) the use of model \nstructure derived from physcal considerations and (b) the use of algorithms \nfor the identification of component subsystems of this model structure. \nThe physical process used in this case study is that of a reduced order \nmodel for combustion instabilities for lean premixed systems. The \nidentification techniques applied in this paper are the use of linear system \nidentification tools (prediction error methods), time delay estimation (based on \nKalman filter harmonic estimation methods) and qualitative validation of \nmodel properties using harmonic balance and describing function methods. \nThe novelty of the paper, apart from its practical application, is that \nclosed loop limit cycle data is used together with a priori process \nstructural knowledge to identify both linear dynamic forward and nonlinear \nfeedback paths. Future work will address the refinement of the process \npresented in this paper, the use of alternative algorithms and also the use \nof control approachs for the validated model structure obtained from \nthis paper.", "publisher": "California Institute of Technology", "publication_date": "1997-01-01" }, { "id": "authors:vz43m-e3g52", "collection": "authors", "collection_id": "vz43m-e3g52", "cite_using_url": "https://resolver.caltech.edu/CaltechCDSTR:1997.CIT-CDS-96-017", "type": "monograph", "title": "Real Time Trajectory Generation for Differentially Flat Systems", "author": [ { "family_name": "van Nieuwstadt", "given_name": "Michiel J.", "clpid": "van-Nieuwstadt-M-J" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "This paper considers the problem of real time trajectory generation \nand tracking for nonlinear control systems. We employ a two degree of \nfreedom approach that separates the nonlinear tracking problem into real \ntime trajectory generation followed by local (gain-scheduled) \nstabilization. The central problem which we consider is how to generate, possibly \nwith some delay, a feasible state space and input trajectory in real \ntime from an output trajectory that is given online. We propose two \nalgorithms that solve the real time trajectory generation problem for \ndifferentially flat systems with (possibly non-minimum phase) zero dynamics. One \nis based on receding horizon point to point steering, the other allows \nadditional minimization of a cost function. Both algorithms explicitly address \nthe tradeoff between stability and performance and we prove convergence \nof the algorithms for a reasonable class of output trajectories. To \nillustrate the application of these techniques to physical systems, we present \nexperimental results using a vectored thrust flight control experiment built at \nCaltech. A brief introduction to differentially flat systems and its \nrelationship with feedback linearization is also included.", "publisher": "California Institute of Technology", "publication_date": "1997-01-01" }, { "id": "authors:qh0me-t9d81", "collection": "authors", "collection_id": "qh0me-t9d81", "cite_using_url": "https://resolver.caltech.edu/CaltechCDSTR:1997.CIT-CDS-97-003", "type": "monograph", "title": "Tracking for Fully Actuated Mechanical Systems: A Geometric Framework", "author": [ { "family_name": "Bullo", "given_name": "Francesco", "clpid": "Bullo-F" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "We present a general framework for the control of Lagrangian \nsystems with as many inputs as degrees of freedom. Relying on the geometry \nof mechanical systems on manifolds, we propose a design algorithm for \nthe tracking problem. The notion of error function and transport map \nlead to a proper definition of configuration and velocity error. These \nare the crucial ingredients in designing a proportional derivative \nfeedback and feedforward controller. The proposed approach includes as \nspecial cases a variety of results on control of manipulators, pointing \ndevices and autonomous vehicles. Our design provides particular insight \ninto both aerospace and underwater applications where the configuration \nmanifold is a Lie group.", "publisher": "California Institute of Technology", "publication_date": "1997-01-01" }, { "id": "authors:aez2d-10a90", "collection": "authors", "collection_id": "aez2d-10a90", "cite_using_url": "https://resolver.caltech.edu/CaltechCDSTR:1996.018", "type": "monograph", "title": "Configuration Flatness of Lagrangian Systems Underactuated by One Control", "author": [ { "family_name": "Rathinam", "given_name": "Muruhan", "clpid": "Rathinam-M" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "Lagrangian control systems that are differentially flat with flat outputs that only depend on configuration variables are said to be configuration flat. We provide a complete characterisation of configuration flatness for systems with n degrees of freedom and n - 1 controls whose range of control forces only depends on configuration and whose Lagrangian has the form of kinetic energy minus potential. The method presented allows us to determine if such a system is configuration flat and, if so provides a constructive method for finding all possible configuration flat outputs. Our characterisation relates configuration flatness to Riemannian geometry. We illustrate the method by two examples.", "publisher": "California Institute of Technology", "publication_date": "1996-09-27" }, { "id": "authors:3s283-kvz40", "collection": "authors", "collection_id": "3s283-kvz40", "cite_using_url": "https://resolver.caltech.edu/CaltechCDSTR:1996.CIT-CDS-95-029", "type": "monograph", "title": "Active Control of an Axial Flow Compressor via Pulsed Air Injection", "author": [ { "family_name": "D'Andrea", "given_name": "Raffaello", "clpid": "D'Andrea-R" }, { "family_name": "Behnken", "given_name": "Robert L.", "clpid": "Behnken-R-L" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "This paper presents the use of pulsed air injection \nto control the onset of rotating stall in a low-speed, axial flow \ncompressor. By measuring the unsteady pressures near the rotor face, a control \nalgorithm determines the magnitude and phase of the first mode of rotating \nstall and controls the injection of air in the front of the rotor face. \nExperimental results show that this technique slightly extends the stall point \nof the compressor and eliminates the hysteresis loop normally \nassociated with rotating stall. A parametric study is used to determine the \noptimal control parameters for suppression of stall. Analytic \nresults---using a low-dimensional model developed by Moore and Greitzer combined \nwith an unsteady shift in the compressor characteristic to model the \ninjectors---give further insights into the operation of the controller. Based on \nthis model, we show that the behavior of the experiment can be explained \nas a change in the bifurcation behavior of the system under nonlinear \nfeedback. A higher fidelity simulation model is then used to further verify \nsome of the specific performance characteristics that are observed in \nexperiments.", "publisher": "California Institute of Technology", "publication_date": "1996-01-01" }, { "id": "authors:nc5x7-9sp27", "collection": "authors", "collection_id": "nc5x7-9sp27", "cite_using_url": "https://resolver.caltech.edu/CaltechCDSTR:1996.CIT-CDS-96-006", "type": "monograph", "title": "Configuration Flatness of Lagrangian Systems Underactuated by One Control", "author": [ { "family_name": "Rathinam", "given_name": "Muruhan", "clpid": "Rathinam-M" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "Lagrangian control systems that are differentially flat with flat \noutputs that only depend on configuration variables are said to be \nconfiguration flat. We provide a complete characterisation of configuration \nflatness for systems with $n$ degrees of freedom and $n-1$ controls whose \nrange of control forces only depends on configuration and whose \nLagrangian has the form of kinetic energy minus potential. The method \npresented allows us to determine if such a system is configuration flat and, \nif so provides a constructive method for finding all possible \nconfiguration flat outputs. Our characterisation relates configuration flatness \nto Riemannian geometry. We illustrate the method by two examples.", "publisher": "California Institute of Technology", "publication_date": "1996-01-01" }, { "id": "authors:b81as-p1483", "collection": "authors", "collection_id": "b81as-p1483", "cite_using_url": "https://resolver.caltech.edu/CaltechCDSTR:1996.CIT-CDS-96-007", "type": "monograph", "title": "Decomposition for Control Systems on Manifolds with an Affine Connection", "author": [ { "family_name": "Lewis", "given_name": "Andrew D.", "clpid": "Lewis-A-D" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "In this letter we present a decomposition for control systems whose \ndrift vector field is the geodesic spray associated with an affine \nconnection. With the geometric insight gained with this decomposition, we are \nable to easily prove some special results for this class of control \nsystems. Examples illustrate the theory.", "publisher": "California Institute of Technology", "publication_date": "1996-01-01" }, { "id": "authors:atdba-tj579", "collection": "authors", "collection_id": "atdba-tj579", "cite_using_url": "https://resolver.caltech.edu/CaltechCDSTR:1996.CIT-CDS-96-015", "type": "monograph", "title": "An Experimental Comparison of Tradeoffs in Using Compliant Manipulators for Robotic Grasping Tasks", "author": [ { "family_name": "Sur", "given_name": "Sudipto", "clpid": "Sur-S" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "Controllers developed for control of flexible-link robots in hybrid\nforce-position control tasks by a new singular perturbation analysis\nof flexible manipulators are implemented on an experimental two-robot\ngrasping setup. Performance criteria are defined for the grasping\ntask. We present preliminary experimental data to show the tradeoffs\nbetween controller complexity and performance enhancement as we deal\nwith greater flexibility. Various performance criteria are set up and\nexperimental results are discussed within that setting. We conclude\nthat large flexibility can be controlled and can lead to reasonable\nperformances.", "publisher": "California Institute of Technology", "publication_date": "1996-01-01" }, { "id": "authors:seskv-grc42", "collection": "authors", "collection_id": "seskv-grc42", "cite_using_url": "https://resolver.caltech.edu/CaltechCDSTR:1995.CIT-CDS-94-006", "type": "monograph", "title": "Differential Flatness and Absolute Equivalence", "author": [ { "family_name": "van Nieuwstadt", "given_name": "Michiel", "clpid": "van-Nieuwstadt-M-J" }, { "family_name": "Rathinam", "given_name": "Muruhan", "clpid": "Rathinam-M" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "In this paper we give a formulation of differential flatness---a concept originally introduced by Fleiss, Levine, Martin, and Rouchon---in terms of absolute equivalence between exterior differential systems. Systems which are differentially flat have several useful properties which can be exploited to generate effective control strategies for nonlinear systems. The original definition of flatness was given in the context of differentiable algebra, and required that all mappings be meromorphic functions. Our formulation of flatness does not require any algebraic structure and allows one to use tools from exterior differential systems to help characterize differentially flat systems. In particular, we shown that in the case of single input control systems (i.e., codimension 2 Pfaffian systems), a system is differentially flat if and only if it is feedback linearizable via static state feedback. However, in higher codimensions feedback linearizability and flatness are *not* equivalent: one must be careful with the role of time as well the use of prolongations which may not be realizable as dynamic feedbacks in a control setting. Applications of differential flatness to nonlinear control systems and open questions will be discussed. Revised 14 Aug 95", "publisher": "California Institute of Technology", "publication_date": "1995-08-14" }, { "id": "authors:wgq2y-5kk21", "collection": "authors", "collection_id": "wgq2y-5kk21", "cite_using_url": "https://resolver.caltech.edu/CaltechCDSTR:1995.CIT-CDS-95-010", "type": "monograph", "title": "Proportional Derivative (PD) Control on the Euclidean Group", "author": [ { "family_name": "Bullo", "given_name": "Francesco", "clpid": "Bullo-F" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "In this paper we study the stabilization problem for control \nsystems defined on SE(3) (the special Euclidean group of rigid-body \nmotions) and its subgroups. Assuming one actuator is available for each \ndegree of freedom, we exploit geometric properties of Lie groups (and \ncorresponding Lie algebras) to generalize the classical proportional derivative \n(PD) control in a coordinate-free way. For the SO(3) case, the \ncompactness of the group gives rise to a natural metric structure and to a \nnatural choice of preferred control direction: an optimal (in the sense of \ngeodesic) solution is given to the attitude control problem. In the SE(3) \ncase, no natural metric is uniquely defined, so that more freedom is left \nin the control design. Different formulations of PD feedback can be \nadopted by extending the SO(3) approach to the whole of SE(3) or by \nbreaking the problem into a control problem on SO(3) x R^3. For the simple \nSE(2) case, simulations are reported to illustrate the behavior of the \ndifferent choices. We also discuss the trajectory tracking problem and show \nhow to reduce it to a stabilization problem, mimicking the usual \napproach in R^n. Finally, regarding the case of underactuated control \nsystems, we derive linear and homogeneous approximating vector fields for \nstandard systems on SO(3) and SE(3).", "publisher": "California Institute of Technology", "publication_date": "1995-01-01" }, { "id": "authors:dan54-2aa27", "collection": "authors", "collection_id": "dan54-2aa27", "cite_using_url": "https://resolver.caltech.edu/CaltechCDSTR:1995.CIT-CDS-95-015", "type": "monograph", "title": "Configuration Controllability of Simple Mechanical Control Systems", "author": [ { "family_name": "Lewis", "given_name": "Andrew D.", "clpid": "Lewis-A-D" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "In this paper we present a definition of \"configuration controllability\"\nfor mechanical systems whose Lagrangian is kinetic energy with\nrespect to a Riemannian metric minus potential energy. A computable\ntest for this new version of controllability is also derived. This \ncondition involves a new object which we call the {\\em symmetric\nproduct}. Of particular interest is a definition of \"equilibrium controllability\"\nfor which we are able to derive computable sufficient conditions.\nExamples illustrate the theory.", "publisher": "California Institute of Technology", "publication_date": "1995-01-01" }, { "id": "authors:s9dkh-10a09", "collection": "authors", "collection_id": "s9dkh-10a09", "cite_using_url": "https://resolver.caltech.edu/CaltechCDSTR:1995.CIT-CDS-95-025", "type": "monograph", "title": "A Homotopy Algorithm for Approximating Geometric Distributions by Integrable Systems", "author": [ { "family_name": "Sluis", "given_name": "Willem M.", "clpid": "Sluis-W-M" }, { "family_name": "Banaszuk", "given_name": "Andrzej", "clpid": "Banaszuk-A" }, { "family_name": "Hauser", "given_name": "John", "clpid": "Hauser-J" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "In the geometric theory of nonlinear control systems, the notion of a\ndistribution and the dual notion of codistribution play a central\nrole. Many results in nonlinear control theory require certain\ndistributions to be integrable. Distributions (and codistributions)\nare not generically integrable and, moreover, the integrability\nproperty is not likely to persist under small perturbations of the\nsystem. Therefore, it is natural to consider the problem of\napproximating a given codistribution by an integrable codistribution,\nand to determine to what extent such an approximation may be used for\nobtaining approximate solutions to various problems in control\ntheory. In this note, we concentrate on the purely mathematical\nproblem of approximating a given codistribution by an integrable\ncodistribution. We present an algorithm for approximating an\nm-dimensional nonintegrable codistribution by an integrable one using\na homotopy approach. The method yields an approximating codistribution\nthat agrees with the original codistribution on an m-dimensional\nsubmanifold E_0 of R^n.", "publisher": "California Institute of Technology", "publication_date": "1995-01-01" }, { "id": "authors:rawy5-knx49", "collection": "authors", "collection_id": "rawy5-knx49", "cite_using_url": "https://resolver.caltech.edu/CaltechCDSTR:1995.CIT-CDS-94-013", "type": "monograph", "title": "Nonholonomic Mechanical Systems with Symmetry", "author": [ { "family_name": "Bloch", "given_name": "A. M.", "clpid": "Bloch-A-M" }, { "family_name": "Krishnaprasad", "given_name": "P. S.", "clpid": "Krishnaprasad-P-S" }, { "family_name": "Marsden", "given_name": "J. E.", "clpid": "Marsden-J-E" }, { "family_name": "Murray", "given_name": "R. M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "This work develops the geometry and dynamics of mechanical systems with nonholonomic constraints and symmetry from the perspective of Lagrangian mechanics and with a view to control theoretical applications. The basic methodology is that of geometric mechanics applied to the formulation of Lagrange d'Alembert, generalizing the use of connections and momentum maps associated with a given symmetry group to this case. We begin by formulating the mechanics of nonholonomic systems using an Ehresmann connection to model the constraints, and show how the curvature of this connection enters into Lagrange's equations. Unlike the situation with standard configuration space constraints, the presence of symmetries in the nonholonomic case may or may not lead to conservation laws. However, the momentum map determined by the symmetry group still satisfies a useful differential equation that decouples from the group variables. This momentum equation, which plays an important role in control problems, involves parallel transport operators and is computed explicitly in coordinates. An alternative description using a ``body reference frame'' relates part of the momentum equation to the components of the Euler-Poincar\\'{e} equations along those symmetry directions consistent with the constraints. One of the purposes of this paper is to derive this evolution equation for the momentum and to distinguish geometrically and mechanically the cases where it is conserved and those where it is not. An example of the former is a ball or vertical disk rolling on a flat plane and an example of the latter is the snakeboard, a modified version of the skateboard which uses momentum coupling for locomotion generation. We construct a synthesis of the mechanical connection and the Ehresmann connection defining the constraints, obtaining an important new object we call the nonholonomic connection. When the nonholonomic connection is a principal connection for the given symmetry group, we show how to perform Lagrangian reduction in the presence of nonholonomic constraints, generalizing previous results which only held in special cases. Several detailed examples are given to illustrate the theory. September 1994 Revised, March 1995 Revised, June 1995", "publisher": "California Institute of Technology", "publication_date": "1995-01-01" }, { "id": "authors:5fs0n-0vw05", "collection": "authors", "collection_id": "5fs0n-0vw05", "cite_using_url": "https://resolver.caltech.edu/CaltechCDSTR:1995.CIT-CDS-95-032", "type": "monograph", "title": "Numerically Efficient Robustness Analysis of Trajectory Tracking for Nonlinear Systems", "author": [ { "family_name": "Tierno", "given_name": "Jorge E.", "clpid": "Tierno-J-E" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" }, { "family_name": "Doyle", "given_name": "John C.", "orcid": "0000-0002-1828-2486", "clpid": "Doyle-J-C" }, { "family_name": "Gregory", "given_name": "Irene M.", "clpid": "Gregory-I-M" } ], "abstract": "A numerical algorithm for computing necessary conditions for \nperformance specifications is developed for nonlinear uncertain systems \nfollowing a prescribed trajectory. This algorithm provides a computational \nefficient means of evaluating the performance of a nonlinear system in the \npresence of noise, real parametric uncertainty, and unmodeled dynamics. The \nalgorithm is similar in nature and behavior to the power algorithm for the mu \nlower bound, and does not rely on a descent method. The algorithm is \napplied to two flight control examples.", "publisher": "California Institute of Technology", "publication_date": "1995-01-01" }, { "id": "authors:fjkqw-v1p46", "collection": "authors", "collection_id": "fjkqw-v1p46", "cite_using_url": "https://resolver.caltech.edu/CaltechCDSTR:1995.CIT-CDS-95-005", "type": "monograph", "title": "Control on the Sphere and Reduced Attitude Stabilization", "author": [ { "family_name": "Bullo", "given_name": "Francesco", "clpid": "Bullo-F" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" }, { "family_name": "Sarti", "given_name": "Augusto", "clpid": "Sarti-A" } ], "abstract": "This paper focuses on a new geometric approach to (fully actuated)\ncontrol systems on the sphere. Our control laws exploit the basic and\nintuitive notions of geodesic direction and of distance between\npoints, and generalize the classical proportional plus derivative\nfeedback (PD) without the need of arbitrary local coordinate charts.\nThe stability analysis relies on an appropriate Lyapunov function,\nwhere the notion of distance and its properties are exploited. This\nmethodology then applies to spin-axis stabilization of a spacecraft\nactuated by only two control torques: discarding the rotation about\nthe unactuated axis, a reduced system is considered, whose state is in\nfact defined on the sphere. For this reduced stabilization problem\nour approach allows us not only to deal optimally with the inevitable\nsingularity, but also to achieve simplicity, versatility and\n(coordinate independent) adaptive capabilities.", "publisher": "California Institute of Technology", "publication_date": "1995-01-01" }, { "id": "authors:czz6z-zm965", "collection": "authors", "collection_id": "czz6z-zm965", "cite_using_url": "https://resolver.caltech.edu/CaltechCDSTR:1995.CIT-CDS-95-012", "type": "monograph", "title": "Exponential Stabilization of Driftless Nonlinear Control Systems using Homogeneous Feedback", "author": [ { "family_name": "M'Closkey", "given_name": "Robert T.", "clpid": "M'Closkey-R-T" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "This paper focuses on the problem of exponential stabilization of\ncontrollable, driftless systems using time-varying, homogeneous\nfeedback. The analysis is performed with respect to a homogeneous\nnorm in a non-standard dilation that is compatible with the algebraic\nstructure of the control Lie algebra. Using this structure, we show\nthat any continuous, time-varying controller that achieves exponential\nstabilization relative to the Euclidean norm is necessarily\nnon-Lipschitz. Despite these restrictions, we provide a set of\nconstructive, sufficient conditions for extending smooth, asymptotic\nstabilizers to homogeneous, exponential stabilizers. The modified\nfeedbacks are everywhere continuous, smooth away from the origin, and\ncan be extended to a large class of systems with torque inputs. The\nfeedback laws are applied to an experimental mobile robot and show\nsignificant improvement in convergence rate over smooth stabilizers.", "publisher": "California Institute of Technology", "publication_date": "1995-01-01" }, { "id": "authors:2pdbe-k1104", "collection": "authors", "collection_id": "2pdbe-k1104", "cite_using_url": "https://resolver.caltech.edu/CaltechCDSTR:1994.CIT-CDS-94-016", "type": "monograph", "title": "Variational Principles for Constrained Systems: Theory and Experiment", "author": [ { "family_name": "Lewis", "given_name": "Andrew D.", "clpid": "Lewis-A-D" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "In this paper we present two methods, the nonholonomic method and the\nvakonomic method, for deriving equations of motion for a\nmechanical system with constraints. The resulting equations are compared.\nResults are also presented from an experiment for a model system: a ball\nrolling without sliding on a rotating table. Both sets of equations of\nmotion for the model system are compared with the experimental results. The\neffects of various forms of friction are considered in the nonholonomic\nequations. With appropriate friction terms, the nonholonomic equations of\nmotion for the model system give reasonable agreement with the experimental\nobservations.", "publisher": "California Institute of Technology", "publication_date": "1994-01-01" }, { "id": "authors:ssytx-z6q73", "collection": "authors", "collection_id": "ssytx-z6q73", "cite_using_url": "https://resolver.caltech.edu/CaltechCDSTR:1994.CIT-CDS-94-014", "type": "monograph", "title": "Geometric Phases and Robotic Locomotion", "author": [ { "family_name": "Kelly", "given_name": "Scott D.", "clpid": "Kelly-S-D" }, { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "Robotic locomotion is based in a variety of instances upon cyclic changes in the shape of a robot mechanism. Certain variations in shape exploit the constrained nature of a robot's interaction with its environment to generate net motion. This is true for legged robots, snakelike robots, and wheeled mobile robots undertaking maneuvers such as parallel parking. In this paper we explore the use of tools from differential geometry to model and analyze this class of locomotion mechanisms in a unified way. In particular, we describe locomotion in terms of the geometric phase associated with a connection on a principal bundle, and address issues such as controllability and choice of gait. We also provide an introduction to the basic mathematical concepts which we require and apply the theory to numerous example systems.", "publisher": "California Institute of Technology", "publication_date": "1994-01-01" }, { "id": "authors:5t4mg-yfy72", "collection": "authors", "collection_id": "5t4mg-yfy72", "cite_using_url": "https://resolver.caltech.edu/CaltechCDSTR:1992.002", "type": "monograph", "title": "Nilpotent Bases for a Class of Non-Integrable Distributions with Applications to Trajectory Generation for Nonholonomic Systems", "author": [ { "family_name": "Murray", "given_name": "Richard M.", "orcid": "0000-0002-5785-7481", "clpid": "Murray-R-M" } ], "abstract": "This paper develops a constructive method for finding a nilpotent basis for a special class of smooth nonholonomic distributions. The main tool is the use of the Goursat normal form theorem which arises in the study of exterior differential systems. The results are applied to the problem of finding a set of nilpotent input vector fields for a nonholonomic control system, which can then used to construct explicit trajectories to drive the system between any two points. A kinematic model of a rolling penny is used to illustrate this approach. The methods presented here extend previous work using \"chained form\" and cast that work into a coordinate-free setting.", "publisher": "California Institute of Technology", "publication_date": "1992-10-14" } ]