Biological and advanced cyber-physical control systems often have limited, sparse, uncertain, and distributed communication and computing in addition to sensing and actuation. Fortunately, the ...corresponding plants and performance requirements are also sparse and structured, and this must be exploited to make constrained controller design feasible and tractable. We introduce a new "system level" (SL) approach involving three complementary SL elements. SL parameterizations (SLPs) provide an alternative to the Youla parameterization of all stabilizing controllers and the responses they achieve, and combine with SL constraints (SLCs) to parameterize the largest known class of constrained stabilizing controllers that admit a convex characterization, generalizing quadratic invariance. SLPs also lead to a generalization of detectability and stabilizability, suggesting the existence of a rich separation structure, that when combined with SLCs is naturally applicable to structurally constrained controllers and systems. We further provide a catalog of useful SLCs, most importantly including sparsity, delay, and locality constraints on both communication and computing internal to the controller, and external system performance. Finally, we formulate SL synthesis problems, which define the broadest known class of constrained optimal control problems that can be solved using convex programming.
A major challenge faced in the design of large-scale cyber-physical systems, such as power systems, the Internet of Things or intelligent transportation systems, is that traditional distributed ...optimal control methods do not scale gracefully, neither in controller synthesis nor in controller implementation, to systems composed of a large number (e.g., on the order of billions) of interacting subsystems. This paper shows that this challenge can now be addressed by leveraging the recently introduced system-level approach (SLA) to controller synthesis. In particular, in the context of the SLA, we define suitable notions of separability for control objective functions and system constraints such that the global optimization problem (or iterate update problems of a distributed optimization algorithm) can be decomposed into parallel subproblems. We then further show that if additional locality (i.e., sparsity) constraints are imposed, then these subproblems can be solved using local models and local decision variables. The SLA is essential to maintain the convexity of the aforementioned problems under locality constraints. As a consequence, the resulting synthesis methods have <inline-formula><tex-math notation="LaTeX">O(1)</tex-math></inline-formula> complexity relative to the size of the global system. We further show that many optimal control problems of interest, such as (localized) LQR and LQG, <inline-formula><tex-math notation="LaTeX">\mathcal {H}_2</tex-math> </inline-formula> optimal control with joint actuator and sensor regularization, and (localized) mixed <inline-formula> <tex-math notation="LaTeX">\mathcal {H}_2/\mathcal {L}_1</tex-math></inline-formula> optimal control problems, satisfy these notions of separability, and use these problems to explore tradeoffs in performance, actuator, and sensing density, and average versus worst-case performance for a large-scale power inspired system.
Impairment of the circadian clock has been associated with numerous disorders, including metabolic disease. Although small molecules that modulate clock function might offer therapeutic approaches to ...such diseases, only a few compounds have been identified that selectively target core clock proteins. From an unbiased cell-based circadian phenotypic screen, we identified KL001, a small molecule that specifically interacts with cryptochrome (CRY). KL001 prevented ubiquitin-dependent degradation of CRY, resulting in lengthening of the circadian period. In combination with mathematical modeling, our studies using KL001 revealed that CRY1 and CRY2 share a similar functional role in the period regulation. Furthermore, KL001-mediated CRY stabilization inhibited glucagon-induced gluconeogenesis in primary hepatocytes. KL001 thus provides a tool to study the regulation of CRY-dependent physiology and aid development of clock-based therapeutics of diabetes.
Architecture, constraints, and behavior Doyle, John C; Csete, Marie
Proceedings of the National Academy of Sciences - PNAS,
09/2011, Letnik:
108, Številka:
Supplement 3
Journal Article
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This paper aims to bridge progress in neuroscience involving sophisticated quantitative analysis of behavior, including the use of robust control, with other relevant conceptual and theoretical ...frameworks from systems engineering, systems biology, and mathematics. Familiar and accessible case studies are used to illustrate concepts of robustness, organization, and architecture (modularity and protocols) that are central to understanding complex networks. These essential organizational features are hidden during normal function of a system but are fundamental for understanding the nature, design, and function of complex biologic and technologic systems.
Infants at higher risk of bronchopulmonary dysplasia had increased rates of survival free of cerebral palsy after postnatal corticosteroid treatment in a previous metaregression of data from 14 ...randomized controlled trials. The relationship persists and is stronger in an updated analysis with data from 20 randomized controlled trials.
In the mammalian suprachiasmatic nucleus (SCN), noisy cellular oscillators communicate within a neuronal network to generate precise system-wide circadian rhythms. Although the intracellular genetic ...oscillator and intercellular biochemical coupling mechanisms have been examined previously, the network topology driving synchronization of the SCN has not been elucidated. This network has been particularly challenging to probe, due to its oscillatory components and slow coupling timescale. In this work, we investigated the SCN network at a single-cell resolution through a chemically induced desynchronization. We then inferred functional connections in the SCN by applying the maximal information coefficient statistic to bioluminescence reporter data from individual neurons while they resynchronized their circadian cycling. Our results demonstrate that the functional network of circadian cells associated with resynchronization has small-world characteristics, with a node degree distribution that is exponential. We show that hubs of this small-world network are preferentially located in the central SCN, with sparsely connected shells surrounding these cores. Finally, we used two computational models of circadian neurons to validate our predictions of network structure.
Nervous systems sense, communicate, compute, and actuate movement using distributed components with severe trade-offs in speed, accuracy, sparsity, noise, and saturation. Nevertheless, brains achieve ...remarkably fast, accurate, and robust control performance due to a highly effective layered control architecture. Here, we introduce a driving task to study how a mountain biker mitigates the immediate disturbance of trail bumps and responds to changes in trail direction. We manipulated the time delays and accuracy of the control input from the wheel as a surrogate for manipulating the characteristics of neurons in the control loop. The observed speed-accuracy trade-offs motivated a theoretical framework consisting of two layers of control loops-a fast, but inaccurate, reflexive layer that corrects for bumps and a slow, but accurate, planning layer that computes the trajectory to follow-each with components having diverse speeds and accuracies within each physical level, such as nerve bundles containing axons with a wide range of sizes. Our model explains why the errors from two control loops are additive and shows how the errors in each control loop can be decomposed into the errors caused by the limited speeds and accuracies of the components. These results demonstrate that an appropriate diversity in the properties of neurons across layers helps to create "diversity-enabled sweet spots," so that both fast and accurate control is achieved using slow or inaccurate components.
Glycolytic Oscillations and Limits on Robust Efficiency Chandra, Fiona A.; Buzi, Gentian; Doyle, John C.
Science (American Association for the Advancement of Science),
07/2011, Letnik:
333, Številka:
6039
Journal Article
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Both engineering and evolution are constrained by trade-offs between efficiency and robustness, but theory that formalizes this fact is limited. For a simple two-state model of glycolysis, we ...explicitly derive analytic equations for hard trade-offs between robustness and efficiency with oscillations as an inevitable side effect. The model describes how the trade-offs arise from individual parameters, including the interplay of feedback control with autocatalysis of network products necessary to power and catalyze intermediate reactions. We then use control theory to prove that the essential features of these hard trade-off "laws" are universal and fundamental, in that they depend minimally on the details of this system and generalize to the robust efficiency of any autocatalytic network. The theory also suggests worst-case conditions that are consistent with initial experiments.
Stochastic noise at the cellular level has been shown to play a fundamental role in circadian oscillations, influencing how groups of cells entrain to external cues and likely serving as the ...mechanism by which cell-autonomous rhythms are generated. Despite this importance, few studies have investigated how clock perturbations affect stochastic noise-even as increasing numbers of high-throughput screens categorize how gene knockdowns or small molecules can change clock period and amplitude. This absence is likely due to the difficulty associated with measuring cell-autonomous stochastic noise directly, which currently requires the careful collection and processing of single-cell data. In this study, we show that the damping rate of population-level bioluminescence recordings can serve as an accurate measure of overall stochastic noise, and one that can be applied to future and existing high-throughput circadian screens. Using cell-autonomous fibroblast data, we first show directly that higher noise at the single-cell results in faster damping at the population level. Next, we show that the damping rate of cultured cells can be changed in a dose-dependent fashion by small molecule modulators, and confirm that such a change can be explained by single-cell noise using a mathematical model. We further demonstrate the insights that can be gained by applying our method to a genome-wide siRNA screen, revealing that stochastic noise is altered independently from period, amplitude, and phase. Finally, we hypothesize that the unperturbed clock is highly optimized for robust rhythms, as very few gene perturbations are capable of simultaneously increasing amplitude and lowering stochastic noise. Ultimately, this study demonstrates the importance of considering the effect of circadian perturbations on stochastic noise, particularly with regard to the development of small-molecule circadian therapeutics.
Posttranslational regulation of clock proteins is an essential part of mammalian circadian rhythms, conferring sensitivity to metabolic state and offering promising targets for pharmacological ...control. Two such regulators, casein kinase 1 (CKI) and F-box and leucine-rich repeat protein 3 (FBXL3), modulate the stability of closely linked core clock proteins period (PER) and cryptochrome (CRY), respectively. Inhibition of either CKI or FBXL3 leads to longer periods, and their effects are independent despite targeting proteins with similar roles in clock function. A mechanistic understanding of this independence, however, has remained elusive. Our analysis of cellular circadian clock gene reporters further differentiated between the actions of CKI and FBXL3 by revealing opposite amplitude responses from each manipulation. To understand the functional relationship between the CKI-PER and FBXL3-CRY pathways, we generated robust mechanistic predictions by applying a bootstrap uncertainty analysis to multiple mathematical circadian models. Our results indicate that CKI primarily regulates the accumulating phase of the PER-CRY repressive complex by controlling the nuclear import rate, whereas FBXL3 separately regulates the duration of transcriptional repression in the nucleus. Dynamic simulations confirmed that this spatiotemporal separation is able to reproduce the independence of the two regulators in period regulation, as well as their opposite amplitude effect. As a result, this study provides further insight into the molecular clock machinery responsible for maintaining robust circadian rhythms.
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