The pseudokinase mixed lineage kinase domain-like protein (MLKL) is a key component of tumor necrosis factor (TNF)-induced necroptosis and plays a crucial role in necroptosis execution. However, the mechanisms that control MLKL activity are not completely understood. Here, we identify the molecular chaperone Hsp90 as a novel MLKL-interacting protein. We show that Hsp90 associates with MLKL and is required for MLKL stability. Moreover, we find that Hsp90 also regulates the stability of the upstream RIP3 kinase. Interference with Hsp90 function with the 17AAG inhibitor destabilizes MLKL and RIP3, resulting in their degradation by the proteasome pathway. Furthermore, we find that Hsp90 is required for TNF-stimulated necrosome assembly. Disruption of Hsp90 function prevents necrosome formation and strongly reduces MLKL phosphorylation and inhibits TNF-induced necroptosis. Consistent with a positive role of Hsp90 in necroptosis, coexpression of Hsp90 increases MLKL oligomerization and plasma membrane translocation and enhances MLKL-mediated necroptosis. Our findings demonstrate that an efficient necrotic response requires a functional Hsp90.

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Abstract-Most prior work on supervisory control of discrete event systems is for achieving deterministic specifications, expressed as formal languages. In this paper we study supervisory control for achieving nondeterministic specifications. Such specifications are useful when designing a system at a higher level of abstraction so that lower level details of system and its specification are omitted to obtain higher level models that may be nondeterministic. Nondeterministic specifications are also meaningful when the system to be controlled has a nondeterministic model due to the lack of information (caused for example by partial observation or unmodeled dynamics). Language equivalence is not an adequate notion of behavioral equivalence for nondeterministic systems, and instead we use the finest known notion of equivalence, namely the bisimulation equivalence. Choice of bisimulation equivalence is also supported by the fact that bisimulation equivalence specification is equivalent to a specification in the temporal logic of -calculus that subsumes the complete branching-time logic CTL*. Given nondeterministic models of system and its specification, we study the design of a supervisor (possibly nondeterministic) such that the controlled system is bisimilar to the specification. We obtain a small model theorem showing that a supervisor exists if and only if it exists over a certain finite state space, namely the power set of Cartesian product of system and specification state spaces. Also, the notion of state-controllability is introduced as part of a necessary and sufficient condition for the existence of a supervisor. In the special case of deterministic systems, we provide an existence condition that can be verified polynomially in both system and specification states, when the existence condition holds.

The decentralized supervisory control problem of discrete event systems under partial observation is studied in this paper. The main result of the paper is a necessary and sufficient condition for the existence of decentralized supervisors for ensuring. That the controlled behavior of the system lies in a given range. The contribution of the paper is (1) our setting of decentralized control generalizes the prior ones; (2) we present an alternative approach for solving the decentralized control problem, which leads to computational saving for concurrent systems and certain other systems; and (3) our generalized formulation and its solution lets us extend several of the existing results reported previously. The results of our paper are illustrated by an example of a simple manufacturing system.

The supervisory control problem of discrete event systems with temporal logic specifications is studied. The full branching time logic of CTL* is used for expressing specifications of discrete event systems. The control problem of CTL* is reduced to the decision problem of CTL*. A small model theorem for the control of CTL* is obtained. It is shown that the control problem of CTL* (resp., CTL) is complete for deterministic double (resp., single) exponential time. A sound and complete supervisor synthesis algorithm for the control of CTL* is provided. Special cases of the control of computation tree logic (CTL) and linear-time temporal logic are also studied. Introduction.Discrete event systems (DESs) involve discrete-valued quantities that evolve in response to certain discrete qualitative changes, called events. Examples of events include arrival of a customer in a queue, termination of an algorithm in a computer program, loss of a message packet in a communication network, and breakdown of a machine in a manufacturing system. The theory of supervisory control of DESs was introduced by Ramadge and Wonham [28] for designing controllers so that the controlled system satisfies certain desired qualitative constraints, such as a buffer in a manufacturing system should never overflow, or a message sequence in a communication network must be received in the same order as it was transmitted. Many extensions of the basic supervisory control problem such as control with partial observations, decentralized control, modular control, control of nondeterministic systems, and control of infinite behaviors represented by ω-languages, have been studied [16].In the supervisory control framework for discrete-event systems, an uncontrolled discrete event system, called plant, is modeled as a state machine, the event set of which is finite and is partitioned into the set of controllable and uncontrollable events. The language generated by such a state machine is used to describe the behavior of the plant at the logical level. The control task is formulated as that of the synthesis of a controller, called a supervisor, which exercises control over the plant by dynamically disabling some of the controllable events so that the plant achieves a certain desired behavior, called a specification, which is typically expressed as a formal language. * In this paper, we consider temporal logic [6,12] as a means to express the control specification.Temporal logic was studied initially to investigate the manner in which temporal operators are used in natural language arguments [11]. It provided a formal way of qualitatively describing and reasoning about how the truth values of assertions change over time. In [27], Pnueli first argued that temporal logic is appropriate for reasoning about nonterminating concurrent programs such as operating systems and network communication protocols. Now temporal logic is a widely active area of research and has been used in all aspects of concurrent program design, including specification, verification, and me...

We study the supervisory control of discrete-event systems (DESs) under partial observation using nondeterministic supervisors. We formally define a nondeterministic control policy and also a control & observation compatible nondeterministic state machine and prove their equivalence. The control action of a nondeterministic supervisor is chosen online, nondeterministically from among a set of choices determined offline. Also, the control action can be changed online nondeterministically (prior to any new observation) in accordance with choices determined offline. The online choices, once made, can be used to affect the set of control action choices in future. We show that when control is exercised using a nondeterministic supervisor, the specification language is required to satisfy a weaker notion of observability, which we define in terms of recognizability and achievability. Achievability serves as necessary and sufficient condition for the existence of a nondeterministic supervisor, and it is weaker than controllability and observability combined. When all events are controllable, achievability reduces to recognizability. We show that both existence, and synthesis of nondeterministic supervisors can be determined polynomially. (For deterministic supervisors, only existence can be determined polynomially.) Both achievability and recognizability are preserved under union, and also under intersection (when restricted over prefix-closed languages). Using the intersection closure property we derive a necessary and sufficient condition for the range control problem for the prefix-closed case. Unlike the deterministic supervisory setting where the complexity of existence is exponential, our existence condition is polynomially verifiable, and also a supervisor can be polynomially synthesized.

Abstract. Gastric cancer (GC) is the third primary cause of cancer-related mortality and one of the most common type of malignant diseases worldwide. Despite remarkable progress in multimodality therapy, advanced GC with high aggressiveness always ends in treatment failure. Epithelialmesenchymal transition (EMT) has been widely recognized to be a key process associating with GC evolution, during which cancer cells go through phenotypic variations and acquire the capability of migration and invasion. Wnt/β-catenin pathway has established itself as an EMT regulative signaling due to its maintenance of epithelial integrity as well as tight adherens junctions while mutations of its components will lead to GC initiation and diffusion. The E-cadherin/β-catenin complex plays an important role in stabilizing β-catenin at cell membrane while disruption of this compound gives rise to nuclear translocation of β-catenin, which accounts for upregulation of EMT biomarkers and unfavorable prognosis. Additionally, several microRNAs positively or negatively modify EMT by reciprocally acting with certain target genes of Wnt/β-catenin pathway in GC. Thus, this review centers on the strong associations between Wnt/β-catenin pathway and microRNAs during alteration of EMT in GC, which may induce advantageous therapeutic strategies for human gastric cancer.

AK-toxin I caused plasma membrane modifications with plasma membrane-derived membrane fragments only in sensitive Japanese pear tissues. H 2 O 2 generation was abundant in both the membrane fragments and the plasma membranes of the toxin-treated sensitive tissues. Whether lipid peroxidation was induced in plasma membranes of the toxin-treated sensitive tissues was examined biochemically and histochemically. Lipid peroxidation was caused only in the toxin-treated sensitive tissues or the toxin-treated plasma membrane-enriched fractions from sensitive young pear fruits. The results indicated that the peroxidation was probably induced by reactive oxygen species in the modified plasma membranes by action of toxin, suggesting that peroxidation is closely associated with plasma membrane modifications.