Property:Abstract
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R
In vitro transcription and translation systems have been used to rapidly test and debug synthetic circuits, allowing for much faster design-build-test cycles. To demonstrate the power of in vitro prototyping, we designed 16 two-input logic gates using a library of 14 linear DNA constructs. We successfully implemented all 16 gates in an E. coli cell extract prototyping environment (TXTL), going from design to functionality in less than 3 months. In separate tests, each taking less than an hour to set up and less than 8 hours to run, we were able to quickly diagnose functionality of engineered parts, including quantification of promoter leakiness and promoter and repressor strength. In subsequent short tests we determined optimal circuit component ratios and investigated component interactions, including crosstalk and resource loading. To lower the entry barrier to in vitro testing, we also created a cellphone-based fluorescent imager that can be used to measure fluorescent output of paper-based TXTL reactions. We hope to establish in vitro testing as a rapid, easily accessible tool for engineering synthetic circuits in research and education. +
D
In vitro transcription-translation (TX-TL) can enable faster engineering of biological systems. This speed-up can be significant, especially in difficult-to-transform chassis. This work shows the successful development of TX-TL systems using three soil-derived wild-type Pseudomonads known to promote plant growth: Pseudomonas synxantha, Pseudomonas chlororaphis, and Pseudomonas aureofaciens. One, P. synxantha, was further characterized. A lysate test of P. synxantha showed a maximum protein yield of 2.5 μM at 125 proteins per DNA template and a maximum protein synthesis rate of 20 nM/min. A set of different constitutive promoters driving mNeonGreen expression were tested in TX-TL and integrated into the genome, showing similar normalized strengths for in vivo and in vitro fluorescence. This correspondence between the TX-TL derived promoter strength and the in vivo promoter strength indicates these lysate-based cell-free systems can be used to characterize and engineer biological parts without genome integration, enabling a faster designbuild-test cycle. +
F
Failure-Tolerant Contract-Based Design of an Automated Valet Parking System using a Directive-Response Architecture +
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. +
B
Insects exhibit incredibly robust closed loop flight dynamics in the face of uncertainties.
A fundamental principle contributing to this unparalleled behavior is rapid processing and
convergence of visual sensory information to flight motor commands via spatial wide-field
integration, accomplished by retinal motion pattern sensitive interneurons (LPTCs) in the
lobula plate portion of the visual ganglia. Within a control-theoretic framework, an inner
product model for wide-field integration of retinal image flow is developed, representing the
spatial decompositions performed by LPTCs in the insect visuomotor system. A rigorous
characterization of the information available from this visuomotor convergence technique
for motion within environments exhibiting non-omogeneous spatial distributions is performed, establishing the connection between retinal motion sensitivity shape and closed
loop behavior. The proposed output feedback methodology is shown to be sufficient to give
rise to experimentally observed insect navigational heuristics, including forward speed regulation, obstacle avoidance, hovering, and terrain following behaviors. Hence, extraction of
global retinal motion cues through computationally efficient wide-field integration process-
ing provides a novel and promising methodology for utilizing visual sensory information in
autonomous robotic navigation and flight control applications. +
S
Insects exhibit unparalleled and incredibly robust flight dynamics in
the face of uncertainties. A fundamental principle contributing to this amazing
behavior is rapid processing and convergence of visual sensory information to flight
motor commands via spatial wide-field integration. Within the control-theoretic
framework presented here, a model for wide-field integration of retinal image flow
is developed which explains how various image flow kernels correspond to feedback
terms that stabilize the different modes of planar fiight. It is also demonstrated that
the proposed output feedback methodology is su±cient to explain experimentally
observed navigational heuristics as the centering and forward speed regulation
responses exhibited by honeybees. +
A
Insects exhibit unparalleled and incredibly robust
flight dynamics in the face of uncertainties. A fundamental principle contributing to this amazing behavior is rapid processing
and convergence of visual sensory information to flight motor
commands via spatial wide-field integration, accomplished by
motion pattern sensitive interneurons in the lobula plate portion
of the visual ganglia. Within a control-theoretic framework, a
model for wide-field integration of retinal image flow is developed, establishing the connection between image flow kernels
(retinal motion pattern sensitivities) and the feedback terms
they represent. It is demonstrated that the proposed output
feedback methodology is sufficient to give rise to experimentally
observed navigational heuristics as the centering and forward
speed regulation responses exhibited by honeybees. +
G
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. +
A
A 65nm CMOS Living-Cell Dynamic Fluorescence Sensor with 1.05fA Sensitivity at 600/700nm Wavelengths +
Integrated, low-cost and miniaturized devices that can detect clinically relevant biomarkers are crucial for the growing field of precision medicine as they can enable point-of-care diagnosis, continuous health monitoring and closed-loop drug delivery. Fluorescence (FL) sensing is known to be one of the most reliable, sensitive, and widely adopted sensing modality for many biomarkers. However, detecting the weak FL signal requires complex optical setups, especially narrowband optical filters to block the strong excitation (EX) light. Prior efforts to miniaturize and implement FL sensing in CMOS technologies have been limited to on-chip high-pass filters using dense vertical waveguide arrays. More importantly, the reported wavelength range of 800nm in prior work is not compatible with most of the commonly used fluorescent proteins that work with living cells. Luminescence is another mechanism for detecting biomarkers that does not require an EX source and optical filtering. However, there are limited number of luminescence proteins, and it is not feasible to use them in a closed-loop system since they can interfere with optogenetic control integration. +
S
Intercommunication of the microbiome-gut-brain axis occurs through various signaling pathways including the vagus nerve, immune system, endocrine/paracrine, and bacteria-derived metabolites. But how these pathways integrate to influence cognition remains undefined. In this paper, we create a systems level mathematical framework comprised of interconnected organ-level dynamical subsystems to increase conceptual understanding of how these subsystems contribute to cognitive performance. With this framework we propose that control of hippocampal long-term potentiation (hypothesized to correlate with cognitive performance) is influenced by inter- organ signaling with diet as the external control input. Specifically, diet can influence synaptic strength (LTP) homeostatic conditions necessary for learning. The proposed model provides new qualitative information about the functional relationship between diet and output cognitive performance. The results can give insight for optimization of cognitive performance via diet in experimental animal models. +
A
It has been shown that optimal controller synthesis for positive systems can be formulated as a linear program. Leveraging these results, we propose a scalable iterative algo- rithm for the systematic design of sparse, small gain feedback strategies that stabilize the evolutionary dynamics of a generic disease model. We achieve the desired feedback structure by augmenting the optimization problems with `1 and `2 regular- ization terms, and illustrate our method on an example inspired by an experimental study aimed at finding appropriate HIV neutralizing antibody therapy combinations in the presence of escape mutants. +
S
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 differ- ential 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. +
T
It is the general assumption that in estimation and control over wireless links, the receiver should drop any erroneous packets. While this approach is appropriate for non real-time data-network applications, it can result in instability and loss of performance in networked control systems. In this technical note we consider estimation of a multiple-input multiple-output dynamical system over a mobile fading communication channel using a Kalman filter. We show that the communication protocols suitable for other already-existing applications like data networks may not be entirely applicable for estimation and control of a rapidly changing dynamical system. We then develop new design paradigms in terms of handling noisy packets for such delay-sensitive applications. We reformulate the estimation problem to include the impact of stochastic communication noise in the erroneous packets. We prove that, in the absence of a permanent cross-layer information path, packet drop should be designed to balance information loss and communication noise in order to optimize the performance. +
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. +
C
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 but not on
velocity 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. +
L
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. +
B
Learning and adaptivity will play a large role in robotics in the future, as robots move from structured to unstructured environments that cannot be fully predicted or understood by the designer. Two questions that are open: 1) in principle, how much it is possible to learn; and, 2) in practice, how much we should learn. The bootstrapping scenario describes the extremum case where agents need to learn âeverythingâ from scratch, including a torque-to-pixels models for its robotic body. Systems with such capabilities will be advantaged in terms of being resilient to unforeseen changes and deviations from prior assumptions. This paper considers the bootstrapping problem for a subset of the set of all robots: the Vehicles, inspired by Braitenbergâs work, are idealization of mobile robots equipped with a set of âcanonicalâ exteroceptive sensors (camera; range- finder; field-sampler). Their sensel-level dynamics are derived and shown to be surprising close. We define the class of BDS models, which assume an instantaneous bilinear dynamics between observations and commands, and derive streaming-based bilinear strategies for them. We show in what sense the BDS dynamics approximates the set of Vehicles to guarantee success in the task of generalized servoing: driving the observations to a given goal snapshot. Simulations and experiments substantiate the theoretical results. This is the first instance of a bootstrapping agent that can learn the dynamics of a relatively large universe of systems, and use the models to solve well-defined tasks, with no parameter tuning or hand-designed features. +
D
Locomotion of microorganisms and tiny artificial swimmers is governed by low- Reynolds-number hydrodynamics, where viscous effects dominate and inertial effects are negligible. While the theory of low-Reynolds-number locomotion is well studied for unbounded fluid domains, the presence of a boundary has a significant influence on the swimmer's trajectories, and poses problems of dynamic stability of its motion. In this paper we consider a simple theoretical model of a micro-swimmer near a wall, study its dynamics, and analyze the stability of its motion. We highlight the underlying geometric structure of the dynamics, and establish a relation between the reversing symmetry of the system and existence and stability of periodic and steady solutions of motion near the wall. The results are demonstrated by numerical simulations and validated by motion experiments with robotic swimmer prototypes. +
E
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. +
G
Manipulation of particles suspended in fluids is crucial for many applications, such as precision machining, chemical processes, bio-engineering, and self-feeding of microorganisms. In this paper, we study the problem of particle manipulation by cyclic fluid boundary excitations from a geometric-control viewpoint. We focus on the simplified problem of manipulating a single particle by generating controlled cyclic motion of a circular rigid body in a two-dimensional perfect fluid. We show that the drift in the particle location after one cyclic motion of the body can be interpreted as the geometric phase of a connection induced by the system's hydrodynamics. We then formulate the problem as a control system, and derive a geometric criterion for its nonlinear controllability. Moreover, by exploiting the geometric structure of the system, we explicitly construct a feedback-based gait that results in attraction of the particle towards the rigid body. We argue that our gait is robust and model-independent, and demonstrate it in both perfect fluid and Stokes fluid. +
E
Many algorithms have been proposed in the literature for control of
multi-fingered robot hands. This paper compares the performance of
several of these algorithms, as well as some extensions of more
conventional manipulator control laws, in the case of planar grasping.
A brief introduction to the subject of robot hands and the notation
used in this paper is included. +
