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Determining feedback Nash equilibrium solutions of nonzero-sum dynamic games is generally challenging. In this article, we propose four different iterative algorithms to find Nash equilibrium strategies for discrete-time linear quadratic games. The strategy update laws are based on the solution of either Lyapunov or Riccati equations for each player. Local convergence criteria are discussed. Motivated by the fact that in many practical scenarios each player in the game may have access to different (incomplete) information, we also introduce purely data-driven implementations of the algorithms. This allows the players to reach a Nash equilibrium solution of the game via scheduled experiments and without knowledge of each other's performance criteria or of the system dynamics. The efficacy of the presented algorithms is illustrated via numerical examples and a practical example involving human–robot interaction.

In this article, a control design strategy to achieve modal consensus and synchronization in a multiagent system is envisioned. The proposed solution relies only on input/output data locally collected by each agent and does not require any a priori knowledge of the underlying dynamics. Furthermore, while agreement on a prescribed modal content can be achieved for any generic initial conditions of the agents, it is shown that the synchronization task requires instead to address the problem of transferring, in finite time, the state of a system from an initial state to a desired terminal state in a completely data-driven framework. This control problem, interesting per se, is therefore tackled and solved here. The above concepts are then illustrated by means of numerical case studies.

Consumption of sugar-sweetened beverages (SSBs) has been linked to several adverse health outcomes, thus many countries introduced taxation to reduce it.

BackgroundEvidence on the association between smoke-free policies and per-capita cigarette consumption and mortality due to acute myocardial infarction (AMI) in Europe is limited. Hence, we aimed to assess this association and to evaluate which factors influence it.MethodsWe performed an interrupted time series analysis, including 27 member states of the European Union and the UK, on per-capita cigarette consumption and AMI mortality.A multivariate meta-regression was used to assess the potential influence of other factors on the observed associations.ResultsAround half of the smoke-free policies introduced were associated with a level or slope change, or both, of per-capita cigarette consumption and AMI mortality (17 of 35). As for cigarette consumption, the strongest level reduction was observed for the smoking ban issued in 2010 in Poland (rate ratio (RR): 0.47; 95% CI: 0.41, 0.53). Instead, the largest level reduction of AMI mortality was observed for the intervention introduced in 2012 in Bulgaria (RR: 0.38; 95% CI: 0.34, 0.42).Policies issued more recently or by countries with a lower human development index were found to be associated with a larger decrease in per-capita cigarette consumption. In addition, smoking bans applying to bars had a stronger inverse association with both cigarette consumption and AMI mortality.ConclusionsThe results of our study suggest that smoke-free policies are effective at reducing per-capita cigarette consumption and AMI mortality. It is extremely important to monitor and register data on tobacco, its prevalence and consumption to be able to tackle its health effects with concerted efforts.

Within the framework of finite-horizon optimal control problems involving nonlinear, input-affine dynamics, a connection between the costate variable and generating functions of the annihilating codistribution of the underlying Hamiltonian vector field is established. It is shown that the inverse mapping of any collection of n, such generating functions coincide, for any time and for a certain constant vector, with the costate of the optimal process. In particular, the corresponding constant vector is determined by solving a parameterized boundary value problem in the state space of the original plant alone, rather than in the extended state/costate space of the Hamiltonian dynamics.

A class of finite-horizon optimal control problems, the solution of which relies on a time-varying change of coordinates that incorporates the transition matrix of the system linearized along the current estimate of the optimal process, is studied. The transformed dynamics exhibit a constant optimal costate. Differently from existing methods that hinge upon similar tools, the proposed strategy does not require at each step the (numerical) solution of a two-point boundary value problem or of a time-varying Riccati equation, and only the solution of a linear initial value problem is needed. The method is firstly illustrated in the setting of linear dynamics and quadratic cost for which the construction permits the identification of a class of problems in which the solution to the underlying (quadratic) Differential Riccati Equation exhibit a separation between homogeneous and particular contributions.

It is shown that strong convexity/concavity of a component of the vector field, as a function of the state variables, induces the same property on the corresponding component of the flow, as a function of the initial condition. Such an inherited property is then instrumental, for instance, for establishing several instability theorems, the proofs of which rely precisely on consequences of convexity/concavity of the flow with respect to the initial condition. Furthermore, the property of convexity/concavity permits the construction of a canonical Chetaev function to certify instability without explicitly resorting to the computation of the flow. Finally, necessary conditions for continuous stabilizability are derived, hence putting the properties of convexity/concavity of the vector field in relation to the well-known Brockett's theorem.

Purpose: This review aims to provide an overview of current knowledge and future perspectives on sentinel node biopsy in gynaecological cancers. Methods: Literature research in the PubMed/MEDLINE database was carried out to identify relevant studies on sentinel node biopsy in gynaecological cancers. We selected only original studies, published in the English language and including a minimum of nine patients. Results: The most relevant results on sentinel node biopsy in gynaecological cancers were summed up, focusing on clinical indications, technical aspects, preoperative and intraoperative procedures and the latest technological advances. Conclusion: Sentinel node biopsy has been widely validated in well-selected patients with early-stage vulvar, cervical and endometrial cancers. It is essential to standardise the acquisition protocol, including SPECT/CT imaging, for an improved surgical planning and a personalised approach. Recent technological advances, such as hybrid tracers and intraoperative tools, may efficiently guide gynaecological cancer surgery.

The objective of this article is to study and characterize the role and the importance of information in achieving a feedback (Nash) equilibrium strategy in linear quadratic (LQ) differential games whenever the underlying players are distributed over a (physical or logic) network. It is assumed that each player should achieve a desired goal, quantified by an individual cost functional, in a competitive dynamic environment—captured by an interconnection network—by relying only on the information and data exchanged with other players according to a prescribed information network: The objective of this article is to establish the value of such an information exchange pattern toward achieving a more favorable (social) equilibrium. Interestingly, it is not assumed that the interconnection network and the information network coincide. Moreover, since the ability to achieve a certain Nash equilibrium strategy may be lost even by removing a single communication link in the network—thus partially limiting the use of the metrics discussed above—in the second part of this article, we also consider the value of the information in forming approximate Nash equilibrium strategies, namely, the so-called $\varepsilon$-Nash equilibria. Finally, the newly defined metrics are corroborated—together with a few suggested constructive results to characterize such values—by means of numerical examples.

Infinite-horizon optimal control problems for nonlinear systems are considered. Due to the nonlinear and intrinsically infinite-dimensional nature of the task, solving such optimal control problems is challenging. In this article, an exact finite-dimensional characterization of the optimal solution over the entire horizon is proposed. This is obtained via the (static) minimization of a suitably defined function of (projected) trajectories of the underlying Hamiltonian dynamics on a hypersphere of fixed radius. The result is achieved in the spirit of the so-called shooting methods by introducing, via simultaneous forward/backward propagation, an intermediate shooting point much closer to the origin, regardless of the actual initial state. A modified strategy allows one to determine an arbitrarily accurate approximate solution by means of standard gradient-descent algorithms over compact domains. Finally, to further increase the robustness of the control law, a receding-horizon architecture is envisioned by designing a sequence of shrinking hyperspheres. These aspects are illustrated by means of a benchmark numerical simulation.

The design of optimal control laws for nonlinear systems is tackled without knowledge of the underlying plant and of a functional description of the cost function. The proposed data-driven method is based only on real-time measurements of the state of the plant and of the (instantaneous) value of the reward signal and relies on a combination of ideas borrowed from the theories of optimal and adaptive control problems. As a result, the architecture implements a policy iteration strategy in which, hinging on the use of neural networks, the policy evaluation step and the computation of the relevant information instrumental for the policy improvement step are performed in a purely continuous-time fashion. Furthermore, the desirable features of the design method, including convergence rate and robustness properties, are discussed. Finally, the theory is validated via two benchmark numerical simulations.

In this paper, we consider discrete-time, scalar, two-player, linear-quadratic dynamic games and study the coupled algebraic equations characterising feedback Nash equilibria. Using geometric arguments, we first analyse the possible number of distinct feedback Nash equilibrium solutions a game may admit and discuss properties of different solutions, before deriving conditions for the existence of no, one, two or three distinct feedback Nash equilibria. Finally, illustrative numerical simulations corroborate the theoretical findings.

Open-loop Nash equilibria for a class of noncooperative linear quadratic differential games are studied in this paper. We provide a closed-form solution to the set of coupled asymmetric Riccati differential equations arising in the considered class. The construction of the proposed solution hinges upon a time-varying change of coordinates, leading to constant optimal costate for each of the involved players.

In this paper the problem of dynamic control allocation for input redundant, continuous-time linear systems is studied in the context of optimal control theory. Providing a new framework for the subject and relying on a well-established theoretical setting, an equivalent problem formulation is given and its solution is determined and discussed, also highlighting its simpler structure with respect to the one provided by approaches purely in the context of control allocation alone.

Two data-driven strategies for value iteration in linear quadratic optimal control problems over an infinite horizon are proposed. The two architectures share common features, since they both consist of a purely continuous-time control architecture and are based on the forward integration of the differential Riccati equation (DRE). They profoundly differ, instead, in the estimation mechanism of the vector field of the underlying DRE from collected data: The first relies on a characterization of properties of the advantage function associated to the problem, whereas the second is inspired by tools from adaptive control theory and ensures semi-global exponential convergence to the optimal solution. Advantages and drawbacks of the architectures are discussed, while the performance is validated via a benchmark numerical example.

The infinite-horizon optimal control problem for nonlinear systems is studied. In the context of model-based, iterative learning strategies we propose an alternative definition and construction of the temporal difference error arising in policy iteration strategies. In such architectures, the error is computed via the evolution of the Hamiltonian function (or, possibly, of its integral) along the trajectories of the closed-loop system. Herein the temporal difference error is instead obtained via two subsequent steps: first the dynamics of the underlying costate variable in the Hamiltonian system is steered by means of a (virtual) control input in such a way that the stable invariant manifold becomes externally attractive. Then, the distance-from-invariance of the manifold, induced by approximate solutions, yields a natural candidate measure for the policy evaluation step. The policy improvement phase is then performed by means of standard gradient descent methods that allows us to correctly update the weights of the underlying functional approximator. The above-mentioned architecture then yields an iterative (episodic) learning scheme based on a scalar, constant reward at each iteration, the value of which is insensitive to the length of the episode, as in the original spirit of reinforcement learning strategies for discrete-time systems. Finally, the theory is validated by means of a numerical simulation involving an automatic flight control problem.

This paper addresses the problem of dynamic input allocation in the presence of plant uncertainties. The current state of the art shows how to design an Allocator as the cascade of an Optimizer and an Annihilator to achieve steady-state input optimality and output invisibility simultaneously. This work proposes a novel algorithm based on polynomial factorization to design a dynamic Annihilator. The critical aspect of this approach lies in the assumption of the perfect plant knowledge, making the Annihilator not robust to uncertainties. A robustification process is introduced by optimizing its design parameters. This approach is formulated as a model-matching problem aiming to reduce the output mismatch induced by the allocation scheme while maintaining steady-state optimality. As the numerical simulations highlight, this method applies to linear and nonlinear allocation problems.

Supplemental Digital Content is available in the text.Electronic cigarettes (e-cigarettes) are battery powered electronic nicotine delivery systems that use a propylene glycol/vegetable glycerin base to deliver vaporized nicotine and flavorings to the body. E-cigarettes became commercially available without evidence regarding their risks, long-term safety, or utility in smoking cessation. Recent clinical trials suggest that e-cigarette use with counseling may be effective in reducing cigarette use but not nicotine dependence. However, meta-analyses of observational studies demonstrate that e-cigarette use is not associated with smoking cessation. Cardiovascular studies reported sympathetic activation, vascular stiffening, and endothelial dysfunction, which are associated with adverse cardiovascular events. The majority of pulmonary clinical trials in e-cigarette users included standard spirometry as the primary outcome measure, reporting no change in lung function. However, studies reported increased biomarkers of pulmonary disease in e-cigarette users. These studies were conducted in adults, but >30% of high school–age adolescents reported e-cigarette use. The effects of e-cigarette use on cardiopulmonary endpoints in adolescents and young adults remain unstudied. Because of adverse clinical findings and associations between e-cigarette use and increased incidence of respiratory diseases in people who have never smoked, large longitudinal studies are needed to understand the risk profile of e-cigarettes. Consistent with the Centers for Disease Control and Prevention recommendations, clinicians should monitor the health risks of e-cigarette use, discourage nonsmokers and adolescents from using e-cigarettes, and discourage smokers from engaging in dual use without cigarette reduction or cessation.

Bus bunching is one of the main issues encountered in bus service operations. The headway (i.e., time between two successive buses) of high-frequency services operating on congested routes can be subject to significant variability with two or more buses arriving at the same bus stop and at the same time (bus bunching). This affects the reliability of bus services and causes user frustration with the travel experience. Although public transport is encouraged as the most environment-friendly mass transit solution, bus bunching is undesirable given that it creates inefficiencies and can push passengers to use private transport.

The overexpression of PED/PEA15, the phosphoprotein enriched in diabetes/phosphoprotein enriched in the astrocytes 15 protein (here referred simply to as PED), observed in some forms of type II diabetes, reduces the transport of insulin-stimulated glucose by binding to the phospholipase D1 (PLD1). The inhibition of the PED/PLD1 interaction was shown to restore basal glucose transport, indicating PED as a pharmacological target for the development of drugs capable of improving insulin sensitivity and glucose tolerance. We here report the identification and selection of PED ligands by means of NMR screening of a library of small organic molecules, NMR characterization of the PED/PLD1 interaction in lysates of cells expressing PLD1, and modulation of such interactions using BPH03, the best selected ligand. Overall, we complement the available literature data by providing detailed information on the structural determinants of the PED/PLD1 interaction in a cellular lysate environment and indicate BPH03 as a precious scaffold for the development of novel compounds that are able to modulate such interactions with possible therapeutic applications in type II diabetes.

Background: Adverse drug reactions are a common cause of potentially avoidable harm, particularly in older adults. Aims: To evaluate the feasibility and efficacy of a pilot multifactorial intervention to reduce potentially inappropriate medication (PIM) use in older adults. Methods: We conducted a phase 2, feasibility, open-label study in the ambulatory setting of an integrated healthcare network in Buenos Aires, Argentina. We recruited primary care physicians (PCPs) and measured PIM use in a sample of their patients (65 years or older). Educational workshops for PCPs were organized with the involvement of clinician champions. Practical deprescribing algorithms were designed based on Beers criteria. Automatic email alerts based on specific PIMs recorded in each patient’s electronic health record were used as a reminder tool. PCPs were responsible for deprescribing decisions. We randomly sampled 879 patients taking PIMs from eight of the most commonly used drug classes at our institution and compared basal (6 months prior to the intervention) and final (12 months after) prevalence of PIM use using a test of proportions. Results: There was a significant reduction (p< 0.05) in all drug classes evaluated. Non-Steroidal Anti-Inflammatory Drugs (basal prevalence 5.92%; final 1.59%); benzodiazepines (10.13%; 6.94%); histamine antagonists (7.74%; 3.07%); opioids (2.16%; 1.25%); tricyclic antidepressants (8.08%; 4.10%); muscle relaxants (7.74%; 3.41%), anti-hypertensives (3.53%; 1.82%) and oxybutynin (2.96%; 1.82%). The absolute reduction in the overall prevalence was 8.5 percentage points (relative reduction of 51.4%). Conclusion: This multifactorial intervention is feasible and effective in reducing the use of potentially inappropriate medication in all drug classes evaluated.

The asymptotic output tracking problem is studied for a class of non-minimum phase nonlinear systems without requiring the a prioriknowledge, or even the existence, of a finite-dimensional exosystem that generates the prescribed periodic reference signal. The design strategy is illustrated in two steps. First, it is shown that the knowledge of a solution to a certain two-point boundary value problem involving the underlying zero-dynamics of the plant is instrumental and sufficient to construct a state feedback regulator that achieves boundedness of the trajectories and (exact) asymptotic tracking, hence completely circumventing the need for solving partial differential equations. Then, since the computation of the latter solution may be affected by numerical errors that are particularly detrimental in the presence of unstable zero-dynamics, the above architecture is robustifiedby means of an additional hybrid feedback loop whose trajectories converge to a solution of the two-point boundary value problem. Once the latter scheme has been established and discussed, the extension to the case of output feedback is presented, firstly in the specially structured case in which the input vector field depends only on the measured output and then extended to the generic case. The theory is then corroborated by means of a physically motivated numerical example involving an inverted pendulum on a cart. Interestingly, it is also shown that the solution provided by the hybrid scheme above coincides with the limiting solution of a suitably defined cheapoptimal control problem.

By relying on the recently introduced notion of transfer function for linear hybrid systems with periodic jumps, herein we extend, for the first time, frequency-domainanalysis tools – well-known and extensively used in the context of purely continuous or discrete time systems – to such a class of hybrid systems. In fact, knowledge of the transfer function allows for the frequency-domain definition of the notion of 0-th momentof the underlying hybrid system, which is instrumental, e.g. for the solution to model reduction or input-output system identification problems. It is shown, in addition, that the notion of moment based on the hybrid transfer function possesses an interesting time-domain counterpart, hence extending the results obtained for purely continuous-time systems. To further substantiate the theoretical claims, the paper is concluded by the frequency-domain robustness analysis of the classical consensus protocolin the presence of sampledmeasurements.

Mitochondria-associated membranes (MAMs) are central microdomains that fine-tune bioenergetics by the local transfer of calcium from the endoplasmic reticulum to the mitochondrial matrix. Here, we report an unexpected function of the endoplasmic reticulum stress transducer IRE1α as a structural determinant of MAMs that controls mitochondrial calcium uptake. IRE1α deficiency resulted in marked alterations in mitochondrial physiology and energy metabolism under resting conditions. IRE1α determined the distribution of inositol-1,4,5-trisphosphate receptors at MAMs by operating as a scaffold. Using mutagenesis analysis, we separated the housekeeping activity of IRE1α at MAMs from its canonical role in the unfolded protein response. These observations were validated in vivo in the liver of IRE1α conditional knockout mice, revealing broad implications for cellular metabolism. Our results support an alternative function of IRE1α in orchestrating the communication between the endoplasmic reticulum and mitochondria to sustain bioenergetics. Carreras-Sureda et al. uncover a non-canonical role for IRE1α as a scaffold that stabilizes InsP3Rs at MAMs to control calcium uptake, fine-tunes ER–mitochondrial communication and regulates energy metabolism via AMPK.

ABSTRACTDynamic optimisation, with a particular focus on optimal control and nonzero-sum differential games, is considered. For nonlinear systems solutions sought via the dynamic programming strategy are inevitably characterised by partial differential equations (PDEs) which are often difficult to solve. A detailed overview of a control design framework which enables the systematic construction of approximate solutions for optimal control problems and differential games withoutrequiring the explicitsolution of any PDE is provided along with a novel design of a nonlinear control gain aimed at improving the ‘level of approximation’ achieved. Multi-agent systems are considered as a possible application of the theory.

The spread of information and communications technologies (ICT) and mobile devices is changing the relationship among citizenship and urban spaces. The use of the internet allows communities - either real or virtual ones - to produce an increasing amount of data about cities and their life. These assumptions were the basement for the "Urban Laboratory in Innovation", a workshop held in Potenza (Southern Italy), in which experts and researchers asked a group of volunteers to analyse life in public spaces of a neighbourhood and point out insights for its regeneration. This experience shows how social network and VGI are useful tools for the development of innovative policies, e-democracy and participation to decision-making processes. Nevertheless, even when specific tools are implemented to favour the inclusion of citizens into the policy-making processes, traditional participatory and design approaches are still a valuable instrument to synthesise their requirements and effectively support the development of site-specific urban planning tools.

In this paper, the output tracking problem for linear and nonlinear systems in normal form is revisited in the case of non-minimum phase dynamics and in the absence of any model for the exosystem generating the periodic reference signal. The asymptotic output tracking is obtained by replacing the classical stability condition for the zero dynamics driven by the reference signal with the existence of a solution to a two-point boundary value problem. The latter solution allows to generate the ideal steady-state evolution of the zero dynamics. This strategy allows to retain two interesting features of standard tracking and regulation approaches, namely, i) the use of a simple linear feedback structure and without the need of solving any partial differential equation (as in tracking) and ii) avoiding minimum phase requirements (as in output regulation). Since the same kind of two-point boundary value problem usually arises in the application of the Pontryagin Minimum Principle in optimal control, a natural question to ask is whether there is an underlying connection; hence, in the linear case, further insights are achieved by comparison with an alternative solution based on optimal control problem formulated for an auxiliary affine system.

CC–chemokine receptor 7 (CCR7) is a G protein–coupled receptor expressed on a variety of immune cells. CCR7 plays a critical role in the migration of lymphocytes into secondary lymphoid tissues. CCR7 expression, however, has been linked to numerous disease states. Due to its therapeutic relevance and absence of available CCR7 inhibitors, we undertook a high-throughput screen (HTS) to identify small-molecule antagonists of the receptor. Here, we describe a robust HTS approach using a commercially available β-galactosidase enzyme fragment complementation system and confirmatory transwell chemotaxis assays. This work resulted in the identification of several compounds with activity against CCR7. The most potent of these was subsequently determined to be cosalane, a cholesterol derivative previously designed as a therapeutic for human immunodeficiency virus. Cosalane inhibited both human and murine CCR7 in response to both CCL19 and CCL21 agonists at physiologic concentrations. Furthermore, cosalane produced durable inhibition of the receptor following a cellular incubation period with subsequent washout. Overall, our work describes the development of an HTS-compatible assay, completion of a large HTS campaign, and demonstration for the first time that cosalane is a validated CCR7 antagonist. These efforts could pave the way for new approaches to address CCR7-associated disease processes.

CC–chemokine receptor 7 (CCR7) is a G protein–coupled receptor expressed on a variety of immune cells. CCR7 plays a critical role in the migration of lymphocytes into secondary lymphoid tissues. CCR7 expression, however, has been linked to numerous disease states. Due to its therapeutic relevance and absence of available CCR7 inhibitors, we undertook a high-throughput screen (HTS) to identify small-molecule antagonists of the receptor. Here, we describe a robust HTS approach using a commercially available β-galactosidase enzyme fragment complementation system and confirmatory transwell chemotaxis assays. This work resulted in the identification of several compounds with activity against CCR7. The most potent of these was subsequently determined to be cosalane, a cholesterol derivative previously designed as a therapeutic for human immunodeficiency virus. Cosalane inhibited both human and murine CCR7 in response to both CCL19 and CCL21 agonists at physiologic concentrations. Furthermore, cosalane produced durable inhibition of the receptor following a cellular incubation period with subsequent washout. Overall, our work describes the development of an HTS-compatible assay, completion of a large HTS campaign, and demonstration for the first time that cosalane is a validated CCR7 antagonist. These efforts could pave the way for new approaches to address CCR7-associated disease processes.

The hybrid output regulation problem in the presence of periodic jumps is approached in this paper for a class of nonlinear hybrid systems satisfying rather mild assumptions. We provide sufficient conditions that characterize steady-state trajectories achieving output regulation that are defined, mimicking the linear case, in terms of two equations: the first one describes the solution of a flow-onlyoutput regulation problem, while the second is associated to an auxiliary output regulation problem concerning the monodromyequivalent system of the flow zero-dynamics. Such conditions are then revisited and a receding-horizon, steady-state-less, solution to the (hybrid) output regulation problem is suggested, based on the solution of a sequence of two-point boundary value problems.

To investigate large library docking’s ability to find molecules with joint activity against on-targets and selectivity versus antitargets, the dopamine D2and serotonin 5-HT2Areceptors were targeted, seeking selectivity against the histamine H1receptor. In a second campaign, κ-opioid receptor ligands were sought with selectivity versus the μ-opioid receptor. While hit rates ranged from 40% to 63% against the on-targets, they were just as good against the antitargets, even though the molecules were selected for their putative lack of binding to the off-targets. Affinities, too, were often as good or better for the off-targets. Even though it was occasionally possible to find selective molecules, such as a mid-nanomolar D2/5-HT2Aligand with 21-fold selectivity versus the H1receptor, this was the exception. Whereas false-negatives are tolerable in docking screens against on-targets, they are intolerable against antitargets; addressing this problem may demand new strategies in the field.

A multi-agent system consisting of Nwheeled mobile robots is considered. The robots are modeled by unicycle dynamics and the multi-agent collision avoidance problem, which lies in steering each robot from its initial position to a desired target position while avoiding collisions with obstacles and other agents is considered. The problem is solved in two steps. First, exploiting a differential game formulation, collision-free trajectories are generated for virtual agentssatisfying single-integrator dynamics. Second, the previous step is used to construct dynamic feedback strategies for the wheeled mobile robots satisfying unicycle dynamics which ensure each of the robots reaches its target without collisions occurring. A numerical study of the proposed methodology is provided through a series of simulations.

In this paper, the problem of estimating the orbital positions of a swarm of satellites is considered under the assumption that two sources of information are available: i)GPS measurements, which are however affected by an unknown bias, and ii) exactrelative distances, which are obtained by means of antennas mounted on each satellite. First, it is shown that the task can be accurately approximated via an observer design problem for a multi-agent system consisting on minimally damped linear oscillators evolving on the underlying orbital plane. Then, a certain cost functional is proposed as a measure of information merging. In particular, the use of the latter index is twofold. In the first part, for fixed values of the relative weightings of all the available measurements, the readings of the GPS are dynamically corrected via a virtual signal that minimizes the cost functional point-wise in time along the orbit. The result is an observer which can be locally implemented by each individual agent, using only locally available information. In the second part, the index is instead employed as a tool for assessing the reliability of each sensor: the correction signal mentioned above is independently computed by means of a H∞formulation of the observer design problem and the (optimal) weights of the cost functional are in turn computed with the property that the output of the H∞regulator coincides, for any time, with the minimizer of the cost functional.

We provide evidence that the IFN-regulated member of the Schlafen (SLFN) family of proteins, SLFN5, promotes the malignant phenotype in glioblastoma multiforme (GBM). Our studies indicate that SLFN5 expression promotes motility and invasiveness of GBM cells, and that high levels of SLFN5 expression correlate with high-grade gliomas and shorter overall survival in patients suffering from GBM. In efforts to uncover the mechanism by which SLFN5 promotes GBM tumorigenesis, we found that this protein is a transcriptional co-repressor of STAT1. Type-I IFN treatment triggers the interaction of STAT1 with SLFN5, and the resulting complex negatively controls STAT1-mediated gene transcription via interferon stimulated response elements. Thus, SLFN5 is both an IFN-stimulated response gene and a repressor of IFN-gene transcription, suggesting the existence of a negative-feedback regulatory loop that may account for suppression of antitumor immune responses in glioblastoma.

In this paper, the problems of (modal) consensus and formation control are tackled for a group of heterogeneous agents described by linear dynamics and communicating over a network with fixed topology. The classic approach to these problems prescribes that each agent is provided with its own complete internal model of the desired dynamics (which can be viewed as an exosystem). In this paper, the novel concept of Distributed Endogenous Internal Modelis introduced and discussed. Such internal model is characterized by two features: i) it is actually distributed over the network, i.e. no single agent is provided with a complete internal model; ii) it is endogenous, namely it is generated by exploiting the dynamics already available to the overall group of agents, through the local cooperation between each agent and its neighbors. As a consequence, each agent is capable of generating the desired steady-state distributed static control input by only exchanging information with its neighbors, without the need for additional dynamics anywhere in the network.

In this paper the problem of disturbance decoupling is tackled for linear hybrid systems in the presence of state-driven jumps, induced by multi-affine sets. Firstly it is shown that the definition of the control objective needs to be adapted to the hybrid setting, by distinguishing between weak and strong disturbance decoupling. In the former, the desired requirement consists in ensuring that the output of the plant is independent of the disturbance on each flowing subinterval followed by a single jump, while the latter requires that both the output trajectory and the corresponding, possibly perturbed, time domain are not affected by the disturbance. Then, easily verifiable geometric necessary and sufficient conditions to achieve weak or strong decoupling are presented and discussed. The paper is concluded by numerical simulations that corroborate the theoretical analysis.

In this paper, we propose a novel, data-driven approach to external model-based regulation for uncertain plant and known exosystem models. At the core of the method lies a technique for least-square estimation of the gains of the plant model at the frequency of excitation, which is adopted for the construction of a hybrid external model of an equivalent disturbance acting at the plant input. Interestingly, in spite of residual errors on the estimates (arising from the use of finite estimation intervals), the reset mechanism employed in the hybrid external model ensures asymptotic regulation, instead of practical regulation. Furthermore, the method does not require a priori knowledge of the transfer matrix of the plant, and takes advantage of an external approach to robust regulation, where the ensuing stabilization problem may be simpler than the ones typically found in internal model-based design.

Output regulation is typically enforced by the use of Internal Model based regulators, which guarantee that steady-state performance (asymptotic tracking and disturbance rejection) is achieved. However, although the overall performance of the regulated system is essentially linked to the properties of the transient responses of such regulators, only a limited attention has been devoted in the literature to such properties, especially in the MIMO case. In this paper, we address the problem of optimizing the transient responses of an already designed closed-loop system including an internal model based output regulation device, by the use of two mechanisms: the selection of an optimized feedforward gain, and the initialization of the states of the regulator. These two mechanisms can be employed both combined or separately, depending on the available information, the control objectives and other application-related constraints.

The approximate optimal control problem via measurement feedback for input-affine nonlinear systems is considered in this paper. In particular, a systematic method is provided for constructing stabilising output feedbacks that approximate - with the optimality loss explicitly quantifiable - the solution of the optimal control problem by requiring only the solution of algebraic equations. In fact, the combination of a classical state estimate with an additional dynamic extension permits the construction of a dynamic control law, without involving the solution of any partial differential equation or inequality. Moreover, provided a given sufficient condition is satisfied, the dynamic control law is guaranteed to be (locally) stabilising. A numerical example illustrating the method is provided.

This paper investigates, in a centralized manner, the motion planning problem for a team of unicycle-like mobile robots in a known environment. In particular, a multi-agent collision-free patrolling and formation control algorithm is presented, which combines outcomes of: (i) stability analysis of hybrid systems, (ii) algebraic geometry, and (iii) classical potential functions. The objective is achieved by designing a Lyapunov-based hybrid strategy that autonomously selects the navigation parameters. Tools borrowed from algebraic geometry are adopted to construct Lyapunov functions that guarantee the convergence to the desired formation and path, while classical potential functions are exploited to avoid collisions among agents and the fixed obstacles within the environment. The proposed navigation algorithm is tested in simulation and then validated by using the robots of a remote accessible robotic testbed.

Morphine is an alkaloid from the opium poppy used to treat pain. The potentially lethal side effects of morphine and related opioids—which include fatal respiratory depression—are thought to be mediated by μ-opioid-receptor (μOR) signalling through the β-arrestin pathway or by actions at other receptors. Conversely, G-protein μOR signalling is thought to confer analgesia. Here we computationally dock over 3 million molecules against the μOR structure and identify new scaffolds unrelated to known opioids. Structure-based optimization yields PZM21—a potent Giactivator with exceptional selectivity for μOR and minimal β-arrestin-2 recruitment. Unlike morphine, PZM21 is more efficacious for the affective component of analgesia versus the reflexive component and is devoid of both respiratory depression and morphine-like reinforcing activity in mice at equi-analgesic doses. PZM21 thus serves as both a probe to disentangle μOR signalling and a therapeutic lead that is devoid of many of the side effects of current opioids.

A scheme is proposed to induce optimal input allocation of dynamically redundant nonlinear actuators with first-order dynamics that satisfies suitable regularity and stability assumptions. The allocation scheme is parametrized by a cost function associated with the most desirable actuator configuration, and guarantees convergence to the desired set point as well as to the minimum of the cost function. The overall scheme is also shown to reduce, in some special cases, to a nonlinear version of a PI type of control action.

Recent studies investigating chronic cerebrospinal venous insufficiency highlighted that intracranial venous return has not yet been routinely investigated by ultrasound in the normal population. This creates an absence of a reference standard and raises concerns that the approach introduces variations into the results. The primary objective of this study was to develop reference standards for the assessment of the internal jugular vein in a normal population. A prospective small-scale study was conducted. Internal jugular veins of 31 normal candidates were examined using B-Mode and PW Doppler. Measurements at proximal and mid-point internal jugular vein were taken in sitting (90°) and supine (0°) positions. Area measurements were taken during passive respiration in cm2. Time average velocity measurements were taken during passive respiration over a 3-second period. Reflux measurements were taken after apnoea and reflux was recorded from any reversed flow. Measurements were taken three times; an average was calculated and statically analysed. Of the 31 participants, one was excluded from the study and 30 were suitable. The Mann-Whitney Utest was used to analyse the results; all results (area, time average velocity and reflux) showed that there was a significant difference between the two positions with p< 0.05 (two-tailed). This pilot study does suggest that there is a significant difference in area, time average velocity and reflux measurements of the internal jugular vein when taken in the sitting and supine position, which could affect the outcome of chronic cerebrospinal venous insufficiency. A further large-scale study is required to validate and standardise the assessment of the internal jugular vein.

The aim of this study was to test our approach based on the use of calvarial graft and extraoral approach, in treatment of severe mandibular atrophies with implant surgery and prosthetic rehabilitation.

In this paper the output regulation problem for a class of hybrid linear systems in the presence of uncertain time domain is considered. Uncertainty is modeled by assuming that the time domain is not known to the controller and by allowing for arbitrarily close, even simultaneous, jumps. Considering the full information setting, the geometric characterization of the relevant regulation manifolds is given. Finally, the theory is illustrated and validated by means of numerical examples.

A new robust error-feedback regulator is proposed for a class of uncertain hybrid systems with periodic jumps, using a hybrid extension of the classical internal model principle. The plant need not be minimum phase, square nor SISO. The proposed regulator contains an internal model composed by two main units, a flow internal modelproviding the correct input to achieve regulation during flows, and a jump internal modelresetting the state of the regulator at each period. Such a structure reminds internal model design for ripple-free regulation of sampled-data systems; an important difference is that here the jump internal model must contain more copies of the relevant dynamics of the exosystem with respect to the flow internal model.

A prospective, large library virtual screen against an activated β2-adrenergic receptor (β2AR) structure returned potent agonists to the exclusion of inverse-agonists, providing the first complement to the previous virtual screening campaigns against inverse-agonist-bound G protein coupled receptor (GPCR) structures, which predicted only inverse-agonists. In addition, two hits recapitulated the signaling profile of the co-crystal ligand with respect to the G protein and arrestin mediated signaling. This functional fidelity has important implications in drug design, as the ability to predict ligands with predefined signaling properties is highly desirable. However, the agonist-bound state provides an uncertain template for modeling the activated conformation of other GPCRs, as a dopamine D2 receptor (DRD2) activated model templated on the activated β2AR structure returned few hits of only marginal potency.

Arsenic Trioxide (As2O3) is one of the most effective agents in the treatment of acute promyelocytic leukemia (APL), but has no significant efficacy in other forms of AML. The mechanisms of relative resistance of non-APL cells are not well understood, but emerging evidence suggests that activation of negative feedback regulatory loops and pathways contributes to such resistance. We provide evidence that a signaling cascade involving the kinase RSK1 is engaged in a negative feedback manner during arsenic-treatment of cells and exhibits regulatory effects on growth and survival of AML cells in response to treatment with As2O3. Our data demonstrate that pharmacological inhibition or molecular disruption of expression of RSK1 enhances As2O3-dependent apoptosis and/or growth inhibition of AML cells. Importantly, combination of a pharmacological inhibitor of RSK and As2O3results in enhanced suppression of primary AML leukemic progenitors. Altogether, our findings suggest an important regulatory role for RSK1 in the generation of the effects of As2O3in AML cells. They also raise the potential of RSK1 targeting in combination with As2O3as a novel approach to promote antileukemic responses.