Robust Parameter Estimation for Hybrid Dynamical Systems

We consider the problem of estimating a vector of unknown constant parameters for a class of hybrid dynamical systems -- that is, systems whose state variables exhibit both continuous (flow) and discrete (jump) evolution. Using a hybrid systems framework, we propose a hybrid estimation algorithm that can operate during both flows and jumps that, under a notion of hybrid persistence of excitation, guarantees convergence of the parameter estimate to the true value. Furthermore, we show that the parameter estimate is input-to-state stable with respect to a class of hybrid disturbances. Simulation results including a spacecraft application show the merits of our proposed approach

Plasticità delle cellule endocrine dell’isola del Langerhans di pazienti con diabete di tipo 2

L\u2019isola pancreatica mantiene, anche nell\u2019adulto, una incredibile plasticit\ue0 e capacit\ue0 di modificarsi in risposta ad una crescente richiesta metabolica o dopo un severo danneggiamento delle popolazioni endocrine, come avviene nel diabete di tipo 1 e di tipo 2 (DT2). Particolarmente interessante \ue8 il processo di transdifferenziamento che si osserva tra cellule endocrine pancreatiche. Consiste nella conversione da un tipo cellulare endocrino non-beta verso quello beta, attraverso un processo di riprogrammazione. E\u2019 stato chiaramente identificato in modelli animali di diabete ma la sua presenza nell\u2019uomo e i meccanismi alla base di questo processo devono ancora essere dimostratati. Obiettivo dello studio \ue8 stato quello di valutare modificazione nella composizione e nell\u2019architettura dell\u2019isola in pazienti con diabete di DT2 e di verificare l\u2019esistenza di un possibile processo di transdifferenziamento tra cellule endocrine pancreatiche umane. Lo studio \ue8 stato condotto su sezioni di pancreas di 12 soggetti controllo (7M/5F, et\ue0 69\ub17 anni) e 14 soggetti con DT2 (8M/ 6F; et\ue0 66.4\ub110.34 anni). Le sezioni sono state colorate con anticorpi diretti contro i diversi ormoni e analizzate mediante microscopia confocale e analisi morfometrica. I nostri dati mostrano che l\u2019isola del Langerhans, in pazienti con DT2, va incontro a un rimodellamento caratterizzato da un progressiva riduzione dell\u2019area e della densit\ue0 cellulare dell\u2019isola (riduzione del 27\ub15% e del 15\ub17.9%, rispettivamente. P<0.05) per aumentata apoptosi di cellule beta e delta e amiloidosi. Per quanto riguarda le diverse popolazioni dell\u2019isola abbiamo evidenziato una diminuzione significativa delle cellule beta e delta e un aumento delle cellule co-esprimenti insulina e glucagone (valutata mediante indice di colocalizzazione) suggerendo l\u2019esistenza di un processo di transdifferenziamento tra cellule endocrine dell\u2019isola. L\u2019indice di colocalizzazione correla in modo negativo con l\u2019area delle cellule beta e risulta essere particolarmente elevato in pazienti sotto terapia insulinica, suggerendo una severa disfunzione dell\u2019isola. La comprensione dei meccanismi molecolari alla base di questo processo di transdifferenziamento potrebbe essere di estrema importanza per lo sviluppo di terapie mirate al controllo della progressione del DT2

The LRRK2 G2385R variant is a partial loss-of-function mutation that affects synaptic vesicle trafficking through altered protein interactions.

Mutations in the Leucine-rich repeat kinase 2 gene (LRRK2) are associated with familial Parkinson's disease (PD). LRRK2 protein contains several functional domains, including protein-protein interaction domains at its N- and C-termini. In this study, we analyzed the functional features attributed to LRRK2 by its N- and C-terminal domains. We combined TIRF microscopy and synaptopHluorin assay to visualize synaptic vesicle trafficking. We found that N- and C-terminal domains have opposite impact on synaptic vesicle dynamics. Biochemical analysis demonstrated that different proteins are bound at the two extremities, namely \u3b23-Cav2.1 at N-terminus part and \u3b2-Actin and Synapsin I at C-terminus domain. A sequence variant (G2385R) harboured within the C-terminal WD40 domain increases the risk for PD. Complementary biochemical and imaging approaches revealed that the G2385R variant alters strength and quality of LRRK2 interactions and increases fusion of synaptic vesicles. Our data suggest that the G2385R variant behaves like a loss-of-function mutation that mimics activity-driven events. Impaired scaffolding capabilities of mutant LRRK2 resulting in perturbed vesicular trafficking may arise as a common pathophysiological denominator through which different LRRK2 pathological mutations cause diseas

Autoantibodies against the glial glutamate transporter GLT1/EAAT2 in Type 1 diabetes mellitus-Clues to novel immunological and non-immunological therapies

: Islet cell surface autoantibodies were previously found in subjects with type 1 diabetes mellitus (T1DM), but their target antigens and pathogenic mechanisms remain elusive. The glutamate transporter solute carrier family 1, member 2 (GLT1/EAAT2) is expressed on the membrane of pancreatic β-cells and physiologically controls extracellular glutamate concentrations thus preventing glutamate-induced β-cell death. We hypothesized that GLT1 could be an immunological target in T1DM and that autoantibodies against GLT1 could be pathogenic. Immunoprecipitation and ELISA experiments showed that sera from T1DM subjects recognized GLT1 expressed in brain, pancreatic islets, and GLT1-transfected COS7-cell extracts. We validated these findings in two cohorts of T1DM patients by quantitative immunofluorescence assays. Analysis of the combined data sets indicated the presence of autoantibodies against GLT1 in 32 of the 87 (37%) T1DM subjects and in none of healthy controls (n&nbsp;=&nbsp;64) (p&nbsp;&lt;&nbsp;0.0001). Exposure of pancreatic βTC3 cells and human islets to purified IgGs from anti-GLT1 positive sera supplemented with complement resulted in plasma membrane ruffling, cell lysis and death. The cytotoxic effect was prevented when sera were depleted from IgGs. Furthermore, in the absence of complement, 6 out of 16 (37%) anti-GLT1 positive sera markedly reduced GLT1 transport activity in βTC3 cells by inducing GLT1 internalization, also resulting in β-cell death. In conclusion, we provide evidence that GLT1 is a novel T1DM autoantigen and that anti-GLT1 autoantibodies cause β-cell death through complement-dependent and independent mechanisms. GLT1 seems an attractive novel therapeutic target for the prevention of β-cell death in individuals with diabetes and prediabetes

PCSK9 deficiency reduces insulin secretion and promotes glucose intolerance: the role of the low-density lipoprotein receptor

Aims PCSK9 loss of function genetic variants are associated with lower low-density lipoprotein cholesterol but also with higher plasma glucose levels and increased risk of Type 2 diabetes mellitus. Here, we investigated the molecular mechanisms underlying this association. Methods and results Pcsk9 KO, WT, Pcsk9/Ldlr double KO (DKO), Ldlr KO, albumin AlbCre+/Pcsk9LoxP/LoxP (liver-selective Pcsk9 knock-out mice), and AlbCre-/Pcsk9LoxP/LoxP mice were used. GTT, ITT, insulin and C-peptide plasma levels, pancreas morphology, and cholesterol accumulation in pancreatic islets were studied in the different animal models. Glucose clearance was significantly impaired in Pcsk9 KO mice fed with a standard or a high-fat diet for 20\u2009weeks compared with WT animals; insulin sensitivity, however, was not affected. A detailed analysis of pancreas morphology of Pcsk9 KO mice vs. controls revealed larger islets with increased accumulation of cholesteryl esters, paralleled by increased insulin intracellular levels and decreased plasma insulin, and C-peptide levels. This phenotype was completely reverted in Pcsk9/Ldlr DKO mice implying the low-density lipoprotein receptor (LDLR) as the proprotein convertase subtilisin/kexin Type 9 (PCSK9) target responsible for the phenotype observed. Further studies in albumin AlbCre+/Pcsk9LoxP/LoxP mice, which lack detectable circulating PCSK9, also showed a complete recovery of the phenotype, thus indicating that circulating, liver-derived PCSK9, the principal target of monoclonal antibodies, does not impact beta-cell function and insulin secretion. Conclusion PCSK9 critically controls LDLR expression in pancreas perhaps contributing to the maintenance of a proper physiological balance to limit cholesterol overload in beta cells. This effect is independent of circulating PCSK9 and is probably related to locally produced PCSK9

Evolutionary-game-based dynamical tuning for multi-objective model predictive control

Model predictive control (MPC) is one of the most used optimization-based control strategies for large-scale systems, since this strategy allows to consider a large number of states and multi-objective cost functions in a straightforward way. One of the main issues in the design of multi-objective MPC controllers, which is the tuning of the weights associated to each objective in the cost function, is treated in this work. All the possible combinations of weights within the cost function affect the optimal result in a given Pareto front. Furthermore, when the system has time-varying parameters, e.g., periodic disturbances, the appropriate weight tuning might also vary over time. Moreover, taking into account the computational burden and the selected sampling time in the MPC controller design, the computation time to find a suitable tuning is limited. In this regard, the development of strategies to perform a dynamical tuning in function of the system conditions potentially improves the closed-loop performance. In order to adapt in a dynamical way the weights in the MPC multi-objective cost function, an evolutionary-game approach is proposed. This approach allows to vary the prioritization weights in the proper direction taking as a reference a desired region within the Pareto front. The proper direction for the prioritization is computed by only using the current system values, i.e., the current optimal control action and the measurement of the current states, which establish the system cost function over a certain point in the Pareto front. Finally, some simulations of a multi-objective MPC for a real multi-variable case study show a comparison between the system performance obtained with static and dynamical tuning.Peer ReviewedPostprint (author's final draft

Exenatide regulates pancreatic islet integrity and insulin sensitivity in the nonhuman primate baboon Papio hamadryas.

The glucagon-like peptide-1 receptor agonist exenatide improves glycemic control by several and not completely understood mechanisms. Herein, we examined the effects of chronic intravenous exenatide infusion on insulin sensitivity, β cell and α cell function and relative volumes, and islet cell apoptosis and replication in nondiabetic nonhuman primates (baboons). At baseline, baboons received a 2-step hyperglycemic clamp followed by an l-arginine bolus (HC/A). After HC/A, baboons underwent a partial pancreatectomy (tail removal) and received a continuous exenatide (n = 12) or saline (n = 12) infusion for 13 weeks. At the end of treatment, HC/A was repeated, and the remnant pancreas (head-body) was harvested. Insulin sensitivity increased dramatically after exenatide treatment and was accompanied by a decrease in insulin and C-peptide secretion, while the insulin secretion/insulin resistance (disposition) index increased by about 2-fold. β, α, and δ cell relative volumes in exenatide-treated baboons were significantly increased compared with saline-treated controls, primarily as the result of increased islet cell replication. Features of cellular stress and secretory dysfunction were present in islets of saline-treated baboons and absent in islets of exenatide-treated baboons. In conclusion, chronic administration of exenatide exerts proliferative and cytoprotective effects on β, α, and δ cells and produces a robust increase in insulin sensitivity in nonhuman primates

Vehicle optimal road departure prevention via model predictive control

This article addresses the problem of road departure prevention using integrated brake control. The scenario considered is when a high speed vehicle leaves the highway on a curve and enters the shoulder or another lane, due to excessive speed, or where the friction of the road drops due to adverse weather conditions. In such a scenario, the vehicle speed is too high for the available tyre-road friction and road departure is inevitable; however, its effect can be minimized with an optimal braking strategy. To achieve online implementation, the task is formulated as a receding horizon optimization problem and solved in a linear model predictive control (MPC) framework. In this formulation, a nonlinear tire model is adopted in order to work properly at the friction limits. The optimization results are close to those obtained previously using a particle model optimization, PPR, coupled to a control algorithm, MHA, specifically designed to operate at the vehicle friction limits. This shows the MPC formulation may equally be effective for vehicle control at the friction limits. The major difference here, compared to the earlier PPR/MHA control formulation, is that the proposed MPC strategy directly generates an optimal brake sequence, while PPR provides an optimal reference first, then MHA responds to the reference to give closed-loop actuator control. The presented MPC approach has the potential to be used in futur