Near-Nash targeting strategies for heterogeneous teams of autonomous combat vehicles

NASA Astrophysics Data System (ADS)

Galati, David G.; Simaan, Marwan A.

2008-04-01

Military strategists are currently seeking methodologies to control large numbers of autonomous assets. Automated planners based upon the Nash equilibrium concept in non-zero sum games are one option. Because such planners inherently consider possible adversarial actions, assets are able to adapt to, and to some extent predict, potential enemy actions. However, these planners must function properly both in cases in which a pure Nash strategy does not exist and in scenarios possessing multiple Nash equilibria. Another issue that needs to be overcome is the scalability of the Nash equilibrium. That is, as the dimensionality of the problem increases, the Nash strategies become unfeasible to compute using traditional methodologies. In this paper we introduce the concept of near-Nash strategies as a mechanism to overcome these difficulties. We then illustrate this concept by deriving the near-Nash strategies and using these strategies as the basis for an intelligent battle plan for heterogeneous teams of autonomous combat air vehicles in the Multi-Team Dynamic Weapon Target Assignment model.

Games of age-dependent prevention of chronic infections by social distancing.

PubMed

Reluga, Timothy C; Li, Jing

2013-06-01

Epidemiological games combine epidemic modelling with game theory to assess strategic choices in response to risks from infectious diseases. In most epidemiological games studied thus-far, the strategies of an individual are represented with a single choice parameter. There are many natural situations where strategies can not be represented by a single dimension, including situations where individuals can change their behavior as they age. To better understand how age-dependent variations in behavior can help individuals deal with infection risks, we study an epidemiological game in an SI model with two life-history stages where social distancing behaviors that reduce exposure rates are age-dependent. When considering a special case of the general model, we show that there is a unique Nash equilibrium when the infection pressure is a monotone function of aggregate exposure rates, but non-monotone effects can appear even in our special case. The non-monotone effects sometimes result in three Nash equilibria, two of which have local invasion potential simultaneously. Returning to a general case, we also describe a game with continuous age-structure using partial-differential equations, numerically identify some Nash equilibria, and conjecture about uniqueness.

A Game Theoretical Model for Location of Terror Response Facilities under Capacitated Resources

PubMed Central

Kang, Qi; Xu, Weisheng; Wu, Qidi

2013-01-01

This paper is concerned with the effect of capacity constraints on the locations of terror response facilities. We assume that the state has limited resources, and multiple facilities may be involved in the response until the demand is satisfied consequently. We formulate a leader-follower game model between the state and the terrorist and prove the existence and uniqueness of the Nash equilibrium. An integer linear programming is proposed to obtain the equilibrium results when the facility number is fixed. The problem is demonstrated by a case study of the 19 districts of Shanghai, China. PMID:24459446

Symmetric Decomposition of Asymmetric Games.

PubMed

Tuyls, Karl; Pérolat, Julien; Lanctot, Marc; Ostrovski, Georg; Savani, Rahul; Leibo, Joel Z; Ord, Toby; Graepel, Thore; Legg, Shane

2018-01-17

We introduce new theoretical insights into two-population asymmetric games allowing for an elegant symmetric decomposition into two single population symmetric games. Specifically, we show how an asymmetric bimatrix game (A,B) can be decomposed into its symmetric counterparts by envisioning and investigating the payoff tables (A and B) that constitute the asymmetric game, as two independent, single population, symmetric games. We reveal several surprising formal relationships between an asymmetric two-population game and its symmetric single population counterparts, which facilitate a convenient analysis of the original asymmetric game due to the dimensionality reduction of the decomposition. The main finding reveals that if (x,y) is a Nash equilibrium of an asymmetric game (A,B), this implies that y is a Nash equilibrium of the symmetric counterpart game determined by payoff table A, and x is a Nash equilibrium of the symmetric counterpart game determined by payoff table B. Also the reverse holds and combinations of Nash equilibria of the counterpart games form Nash equilibria of the asymmetric game. We illustrate how these formal relationships aid in identifying and analysing the Nash structure of asymmetric games, by examining the evolutionary dynamics of the simpler counterpart games in several canonical examples.

Continuous-Time Public Good Contribution Under Uncertainty: A Stochastic Control Approach

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ferrari, Giorgio, E-mail: giorgio.ferrari@uni-bielefeld.de; Riedel, Frank, E-mail: frank.riedel@uni-bielefeld.de; Steg, Jan-Henrik, E-mail: jsteg@uni-bielefeld.de

In this paper we study continuous-time stochastic control problems with both monotone and classical controls motivated by the so-called public good contribution problem. That is the problem of n economic agents aiming to maximize their expected utility allocating initial wealth over a given time period between private consumption and irreversible contributions to increase the level of some public good. We investigate the corresponding social planner problem and the case of strategic interaction between the agents, i.e. the public good contribution game. We show existence and uniqueness of the social planner’s optimal policy, we characterize it by necessary and sufficient stochasticmore » Kuhn–Tucker conditions and we provide its expression in terms of the unique optional solution of a stochastic backward equation. Similar stochastic first order conditions prove to be very useful for studying any Nash equilibria of the public good contribution game. In the symmetric case they allow us to prove (qualitative) uniqueness of the Nash equilibrium, which we again construct as the unique optional solution of a stochastic backward equation. We finally also provide a detailed analysis of the so-called free rider effect.« less

Geometry of Cournot-Nash Equilibrium with Application to Commons and Anticommons

ERIC Educational Resources Information Center

D'Agata, Antonio

2010-01-01

The author develops a simple geometric analysis of Cournot-Nash equilibrium in the price-quantity space by exploiting the economic content of the first-order condition. The approach makes it clear that strategic interdependency in oligopoly originates from externalities among producers. This explains why cartels are unstable and casts oligopoly…

Le Chatelier's principle in replicator dynamics

NASA Astrophysics Data System (ADS)

Allahverdyan, Armen E.; Galstyan, Aram

2011-10-01

The Le Chatelier principle states that physical equilibria are not only stable, but they also resist external perturbations via short-time negative-feedback mechanisms: a perturbation induces processes tending to diminish its results. The principle has deep roots, e.g., in thermodynamics it is closely related to the second law and the positivity of the entropy production. Here we study the applicability of the Le Chatelier principle to evolutionary game theory, i.e., to perturbations of a Nash equilibrium within the replicator dynamics. We show that the principle can be reformulated as a majorization relation. This defines a stability notion that generalizes the concept of evolutionary stability. We determine criteria for a Nash equilibrium to satisfy the Le Chatelier principle and relate them to mutualistic interactions (game-theoretical anticoordination) showing in which sense mutualistic replicators can be more stable than (say) competing ones. There are globally stable Nash equilibria, where the Le Chatelier principle is violated even locally: in contrast to the thermodynamic equilibrium a Nash equilibrium can amplify small perturbations, though both types of equilibria satisfy the detailed balance condition.

Le Chatelier's principle in replicator dynamics.

PubMed

Allahverdyan, Armen E; Galstyan, Aram

2011-10-01

The Le Chatelier principle states that physical equilibria are not only stable, but they also resist external perturbations via short-time negative-feedback mechanisms: a perturbation induces processes tending to diminish its results. The principle has deep roots, e.g., in thermodynamics it is closely related to the second law and the positivity of the entropy production. Here we study the applicability of the Le Chatelier principle to evolutionary game theory, i.e., to perturbations of a Nash equilibrium within the replicator dynamics. We show that the principle can be reformulated as a majorization relation. This defines a stability notion that generalizes the concept of evolutionary stability. We determine criteria for a Nash equilibrium to satisfy the Le Chatelier principle and relate them to mutualistic interactions (game-theoretical anticoordination) showing in which sense mutualistic replicators can be more stable than (say) competing ones. There are globally stable Nash equilibria, where the Le Chatelier principle is violated even locally: in contrast to the thermodynamic equilibrium a Nash equilibrium can amplify small perturbations, though both types of equilibria satisfy the detailed balance condition.

Exacerbating the Tragedy of the Commons: Private Inefficient Outcomes and Peer Effect in Experimental Games with Fishing Communities

PubMed Central

2016-01-01

Economic Experimental Games have shown that individuals make decisions that deviate down from the suboptimal Nash equilibrium. However, few studies have analyzed the case when deviation is above the Nash equilibrium. Extracting from above the Nash equilibrium is inefficient not only socially but also privately and it would exacerbate the tragedy of the commons. That would be the case of a race to the fish when stocks are becoming depleted or driver behavior on a highly congested road. The objective of this study is to analyze private inefficient extraction behavior in experimental games and to associate the type of player and the type of player group with such inefficient outcomes. To do this, we carried out economic experimental games with local coastal fishermen in Colombia, using a setting where the scarcity of the resource allows for an interior Nash equilibrium and inefficient over-extraction is possible. The state of the resource, the type of player and the composition of the group explain, in part, this inefficient behavior. PMID:26863228

Power allocation for target detection in radar networks based on low probability of intercept: A cooperative game theoretical strategy

NASA Astrophysics Data System (ADS)

Shi, Chenguang; Salous, Sana; Wang, Fei; Zhou, Jianjiang

2017-08-01

Distributed radar network systems have been shown to have many unique features. Due to their advantage of signal and spatial diversities, radar networks are attractive for target detection. In practice, the netted radars in radar networks are supposed to maximize their transmit power to achieve better detection performance, which may be in contradiction with low probability of intercept (LPI). Therefore, this paper investigates the problem of adaptive power allocation for radar networks in a cooperative game-theoretic framework such that the LPI performance can be improved. Taking into consideration both the transmit power constraints and the minimum signal to interference plus noise ratio (SINR) requirement of each radar, a cooperative Nash bargaining power allocation game based on LPI is formulated, whose objective is to minimize the total transmit power by optimizing the power allocation in radar networks. First, a novel SINR-based network utility function is defined and utilized as a metric to evaluate power allocation. Then, with the well-designed network utility function, the existence and uniqueness of the Nash bargaining solution are proved analytically. Finally, an iterative Nash bargaining algorithm is developed that converges quickly to a Pareto optimal equilibrium for the cooperative game. Numerical simulations and theoretic analysis are provided to evaluate the effectiveness of the proposed algorithm.

Battle for Climate and Scarcity Rents: Beyond the Linear-Quadratic Case.

PubMed

Kagan, Mark; van der Ploeg, Frederick; Withagen, Cees

Industria imports oil, produces final goods and wishes to mitigate global warming. Oilrabia exports oil and buys final goods from the other country. Industria uses the carbon tax to impose an import tariff on oil and steal some of Oilrabia's scarcity rent. Conversely, Oilrabia has monopoly power and sets the oil price to steal some of Industria's climate rent. We analyze the relative speeds of oil extraction and carbon accumulation under these strategic interactions for various production function specifications and compare these with the efficient and competitive outcomes. We prove that for the class of HARA production functions, the oil price is initially higher and subsequently lower in the open-loop Nash equilibrium than in the efficient outcome. The oil extraction rate is thus initially too low and in later stages too high. The HARA class includes linear, loglinear and semi-loglinear demand functions as special cases. For non-HARA production functions, Oilrabia may in the open-loop Nash equilibrium initially price oil lower than the efficient level, thus resulting in more oil extraction and climate damages. We also contrast the open-loop Nash and efficient outcomes numerically with the feedback Nash outcomes. We find that the optimal carbon tax path in the feedback Nash equilibrium is flatter than in the open-loop Nash equilibrium. It turns out that for certain demand functions using the carbon tax as an import tariff may hurt consumers' welfare as the resulting user cost of oil is so high that the fall in welfare wipes out the gain from higher tariff revenues.

Congestion schemes and Nash equilibrium in complex networks

NASA Astrophysics Data System (ADS)

Almendral, Juan A.; López, Luis; Cholvi, Vicent; Sanjuán, Miguel A. F.

2005-09-01

Whenever a common resource is scarce, a set of rules are needed to share it in a fairly way. However, most control schemes assume that users will behave in a cooperative way, without taking care of guaranteeing that they will not act in a selfish manner. Then, a fundamental issue is to evaluate the impact of cheating. From the point of view of game theory, a Nash equilibrium implies that nobody can take advantage by unilaterally deviating from this stable state, even in the presence of selfish users. In this paper we prove that any efficient Nash equilibrium strongly depends on the number of users, if the control scheme policy does not record their previous behavior. Since this is a common pattern in real situations, this implies that the system would be always out of equilibrium. Consequently, this result proves that, in practice, oblivious control schemes must be improved to cope with selfish users.

On Nash Equilibrium and Evolutionarily Stable States That Are Not Characterised by the Folk Theorem

PubMed Central

Li, Jiawei; Kendall, Graham

2015-01-01

In evolutionary game theory, evolutionarily stable states are characterised by the folk theorem because exact solutions to the replicator equation are difficult to obtain. It is generally assumed that the folk theorem, which is the fundamental theory for non-cooperative games, defines all Nash equilibria in infinitely repeated games. Here, we prove that Nash equilibria that are not characterised by the folk theorem do exist. By adopting specific reactive strategies, a group of players can be better off by coordinating their actions in repeated games. We call it a type-k equilibrium when a group of k players coordinate their actions and they have no incentive to deviate from their strategies simultaneously. The existence and stability of the type-k equilibrium in general games is discussed. This study shows that the sets of Nash equilibria and evolutionarily stable states have greater cardinality than classic game theory has predicted in many repeated games. PMID:26288088

The Worst-Case Weighted Multi-Objective Game with an Application to Supply Chain Competitions.

PubMed

Qu, Shaojian; Ji, Ying

2016-01-01

In this paper, we propose a worst-case weighted approach to the multi-objective n-person non-zero sum game model where each player has more than one competing objective. Our "worst-case weighted multi-objective game" model supposes that each player has a set of weights to its objectives and wishes to minimize its maximum weighted sum objectives where the maximization is with respect to the set of weights. This new model gives rise to a new Pareto Nash equilibrium concept, which we call "robust-weighted Nash equilibrium". We prove that the robust-weighted Nash equilibria are guaranteed to exist even when the weight sets are unbounded. For the worst-case weighted multi-objective game with the weight sets of players all given as polytope, we show that a robust-weighted Nash equilibrium can be obtained by solving a mathematical program with equilibrium constraints (MPEC). For an application, we illustrate the usefulness of the worst-case weighted multi-objective game to a supply chain risk management problem under demand uncertainty. By the comparison with the existed weighted approach, we show that our method is more robust and can be more efficiently used for the real-world applications.

On Nash-Equilibria of Approximation-Stable Games

NASA Astrophysics Data System (ADS)

Awasthi, Pranjal; Balcan, Maria-Florina; Blum, Avrim; Sheffet, Or; Vempala, Santosh

One reason for wanting to compute an (approximate) Nash equilibrium of a game is to predict how players will play. However, if the game has multiple equilibria that are far apart, or ɛ-equilibria that are far in variation distance from the true Nash equilibrium strategies, then this prediction may not be possible even in principle. Motivated by this consideration, in this paper we define the notion of games that are approximation stable, meaning that all ɛ-approximate equilibria are contained inside a small ball of radius Δ around a true equilibrium, and investigate a number of their properties. Many natural small games such as matching pennies and rock-paper-scissors are indeed approximation stable. We show furthermore there exist 2-player n-by-n approximation-stable games in which the Nash equilibrium and all approximate equilibria have support Ω(log n). On the other hand, we show all (ɛ,Δ) approximation-stable games must have an ɛ-equilibrium of support O(Δ^{2-o(1)}/ɛ2{log n}), yielding an immediate n^{O(Δ^{2-o(1)}/ɛ^2log n)}-time algorithm, improving over the bound of [11] for games satisfying this condition. We in addition give a polynomial-time algorithm for the case that Δ and ɛ are sufficiently close together. We also consider an inverse property, namely that all non-approximate equilibria are far from some true equilibrium, and give an efficient algorithm for games satisfying that condition.

Bidding for Brains: Intellectual Property Rights and the International Migration of Knowledge Workers. NBER Working Paper No. 15486

ERIC Educational Resources Information Center

McAusland, Carol; Kuhn, Peter J.

2009-01-01

We introduce international mobility of knowledge workers into a model of Nash equilibrium IPR policy choice among countries. We show that governments have incentives to use IPRs in a bidding war for global talent, resulting in Nash equilibrium IPRs that can be too high, rather than too low, from a global welfare perspective. These incentives…

Analysis of the dynamics of multi-team Bertrand game with heterogeneous players

NASA Astrophysics Data System (ADS)

Ding, Zhanwen; Hang, Qinglan; Yang, Honglin

2011-06-01

In this article, we study the dynamics of a two-team Bertrand game with players having heterogeneous expectations. We study the equilibrium solutions and the conditions of their locally asymptotic stability. Numerical simulations are used to illustrate the complex behaviours of the proposed model of the Bertrand game. We demonstrate that some parameters of the model have great influence on the stability of Nash equilibrium and on the speed of convergence to Nash equilibrium. The chaotic behaviour of the model has been controlled by using feedback control method.

Computing Nash equilibria through computational intelligence methods

NASA Astrophysics Data System (ADS)

Pavlidis, N. G.; Parsopoulos, K. E.; Vrahatis, M. N.

2005-03-01

Nash equilibrium constitutes a central solution concept in game theory. The task of detecting the Nash equilibria of a finite strategic game remains a challenging problem up-to-date. This paper investigates the effectiveness of three computational intelligence techniques, namely, covariance matrix adaptation evolution strategies, particle swarm optimization, as well as, differential evolution, to compute Nash equilibria of finite strategic games, as global minima of a real-valued, nonnegative function. An issue of particular interest is to detect more than one Nash equilibria of a game. The performance of the considered computational intelligence methods on this problem is investigated using multistart and deflection.

Spontaneous Time Symmetry Breaking in System with Mixed Strategy Nash Equilibrium: Evidences in Experimental Economics Data

NASA Astrophysics Data System (ADS)

Wang, Zhijian; Xu, Bin; Zhejiang Collaboration

2011-03-01

In social science, laboratory experiment with human subjects' interaction is a standard test-bed for studying social processes in micro level. Usually, as in physics, the processes near equilibrium are suggested as stochastic processes with time-reversal symmetry (TRS). To the best of our knowledge, near equilibrium, the breaking time symmetry, as well as the existence of robust time anti-symmetry processes, has not been reported clearly in experimental economics till now. By employing Markov transition method to analysis the data from human subject 2x2 Games with wide parameters and mixed Nash equilibrium, we study the time symmetry of the social interaction process near Nash equilibrium. We find that, the time symmetry is broken, and there exists a robust time anti-symmetry processes. We also report the weight of the time anti-symmetry processes in the total processes of each the games. Evidences in laboratory marketing experiments, at the same time, are provided as one-dimension cases. In these cases, time anti-symmetry cycles can also be captured. The proposition of time anti-symmetry processes is small, but the cycles are distinguishable.

A heterogenous Cournot duopoly with delay dynamics: Hopf bifurcations and stability switching curves

NASA Astrophysics Data System (ADS)

Pecora, Nicolò; Sodini, Mauro

2018-05-01

This article considers a Cournot duopoly model in a continuous-time framework and analyze its dynamic behavior when the competitors are heterogeneous in determining their output decision. Specifically the model is expressed in the form of differential equations with discrete delays. The stability conditions of the unique Nash equilibrium of the system are determined and the emergence of Hopf bifurcations is shown. Applying some recent mathematical techniques (stability switching curves) and performing numerical simulations, the paper confirms how different time delays affect the stability of the economy.

A Differential Evolution Algorithm Based on Nikaido-Isoda Function for Solving Nash Equilibrium in Nonlinear Continuous Games

PubMed Central

He, Feng; Zhang, Wei; Zhang, Guoqiang

2016-01-01

A differential evolution algorithm for solving Nash equilibrium in nonlinear continuous games is presented in this paper, called NIDE (Nikaido-Isoda differential evolution). At each generation, parent and child strategy profiles are compared one by one pairwisely, adapting Nikaido-Isoda function as fitness function. In practice, the NE of nonlinear game model with cubic cost function and quadratic demand function is solved, and this method could also be applied to non-concave payoff functions. Moreover, the NIDE is compared with the existing Nash Domination Evolutionary Multiplayer Optimization (NDEMO), the result showed that NIDE was significantly better than NDEMO with less iterations and shorter running time. These numerical examples suggested that the NIDE method is potentially useful. PMID:27589229

From rationality to cooperativeness: The totally mixed Nash equilibrium in Markov strategies in the iterated Prisoner's Dilemma.

PubMed

Menshikov, Ivan S; Shklover, Alexsandr V; Babkina, Tatiana S; Myagkov, Mikhail G

2017-01-01

In this research, the social behavior of the participants in a Prisoner's Dilemma laboratory game is explained on the basis of the quantal response equilibrium concept and the representation of the game in Markov strategies. In previous research, we demonstrated that social interaction during the experiment has a positive influence on cooperation, trust, and gratefulness. This research shows that the quantal response equilibrium concept agrees only with the results of experiments on cooperation in Prisoner's Dilemma prior to social interaction. However, quantal response equilibrium does not explain of participants' behavior after social interaction. As an alternative theoretical approach, an examination was conducted of iterated Prisoner's Dilemma game in Markov strategies. We built a totally mixed Nash equilibrium in this game; the equilibrium agrees with the results of the experiments both before and after social interaction.

From rationality to cooperativeness: The totally mixed Nash equilibrium in Markov strategies in the iterated Prisoner’s Dilemma

PubMed Central

Myagkov, Mikhail G.

2017-01-01

In this research, the social behavior of the participants in a Prisoner's Dilemma laboratory game is explained on the basis of the quantal response equilibrium concept and the representation of the game in Markov strategies. In previous research, we demonstrated that social interaction during the experiment has a positive influence on cooperation, trust, and gratefulness. This research shows that the quantal response equilibrium concept agrees only with the results of experiments on cooperation in Prisoner’s Dilemma prior to social interaction. However, quantal response equilibrium does not explain of participants’ behavior after social interaction. As an alternative theoretical approach, an examination was conducted of iterated Prisoner's Dilemma game in Markov strategies. We built a totally mixed Nash equilibrium in this game; the equilibrium agrees with the results of the experiments both before and after social interaction. PMID:29190280

On a numerical solving of random generated hexamatrix games

NASA Astrophysics Data System (ADS)

Orlov, Andrei; Strekalovskiy, Alexander

2016-10-01

In this paper, we develop a global search method for finding a Nash equilibrium in a hexamatrix game (polymatrix game of three players). The method, on the one hand, is based on the equivalence theorem of the problem of finding a Nash equilibrium in the game and a special mathematical optimization problem, and, on the other hand, on the usage of Global Search Theory for solving the latter problem. The efficiency of this approach is demonstrated by the results of computational testing.

A research on service quality decision-making of Chinese communications industry based on quantum game

NASA Astrophysics Data System (ADS)

Zhang, Cuihua; Xing, Peng

2015-08-01

In recent years, Chinese service industry is developing rapidly. Compared with developed countries, service quality should be the bottleneck for Chinese service industry. On the background of three major telecommunications service providers in China, the functions of customer perceived utilities are established. With the goal of consumer's perceived utility maximization, the classic Nash equilibrium solution and quantum equilibrium solution are obtained. Then a numerical example is studied and the changing trend of service quality and customer perceived utility is further analyzed by the influence of the entanglement operator. Finally, it is proved that quantum game solution is better than Nash equilibrium solution.

The Worst-Case Weighted Multi-Objective Game with an Application to Supply Chain Competitions

PubMed Central

Qu, Shaojian; Ji, Ying

2016-01-01

In this paper, we propose a worst-case weighted approach to the multi-objective n-person non-zero sum game model where each player has more than one competing objective. Our “worst-case weighted multi-objective game” model supposes that each player has a set of weights to its objectives and wishes to minimize its maximum weighted sum objectives where the maximization is with respect to the set of weights. This new model gives rise to a new Pareto Nash equilibrium concept, which we call “robust-weighted Nash equilibrium”. We prove that the robust-weighted Nash equilibria are guaranteed to exist even when the weight sets are unbounded. For the worst-case weighted multi-objective game with the weight sets of players all given as polytope, we show that a robust-weighted Nash equilibrium can be obtained by solving a mathematical program with equilibrium constraints (MPEC). For an application, we illustrate the usefulness of the worst-case weighted multi-objective game to a supply chain risk management problem under demand uncertainty. By the comparison with the existed weighted approach, we show that our method is more robust and can be more efficiently used for the real-world applications. PMID:26820512

Two retailer-supplier supply chain models with default risk under trade credit policy.

PubMed

Wu, Chengfeng; Zhao, Qiuhong

2016-01-01

The purpose of the paper is to formulate two uncooperative replenishment models with demand and default risk which are the functions of the trade credit period, i.e., a Nash equilibrium model and a supplier-Stackelberg model. Firstly, we present the optimal results of decentralized decision and centralized decision without trade credit. Secondly, we derive the existence and uniqueness conditions of the optimal solutions under the two games, respectively. Moreover, we present a set of theorems and corollary to determine the optimal solutions. Finally, we provide an example and sensitivity analysis to illustrate the proposed strategy and optimal solutions. Sensitivity analysis reveals that the total profits of supply chain under the two games both are better than the results under the centralized decision only if the optimal trade credit period isn't too short. It also reveals that the size of trade credit period, demand, retailer's profit and supplier's profit have strong relationship with the increasing demand coefficient, wholesale price, default risk coefficient and production cost. The major contribution of the paper is that we comprehensively compare between the results of decentralized decision and centralized decision without trade credit, Nash equilibrium and supplier-Stackelberg models with trade credit, and obtain some interesting managerial insights and practical implications.

Bountiful health care and A Beautiful Mind.

PubMed

Flower, Joe

2002-01-01

The Nash Equilibrium (put forward by John Nash and celebrated in the film, A Beautiful Mind) mathematically describes multi-player, infinite games. It is a general description of large human transactions, such as health care. Learn how new inputs, new players or new resources can disrupt these transactions.

Dynamics, morphogenesis and convergence of evolutionary quantum Prisoner's Dilemma games on networks

PubMed Central

Yong, Xi

2016-01-01

The authors proposed a quantum Prisoner's Dilemma (PD) game as a natural extension of the classic PD game to resolve the dilemma. Here, we establish a new Nash equilibrium principle of the game, propose the notion of convergence and discover the convergence and phase-transition phenomena of the evolutionary games on networks. We investigate the many-body extension of the game or evolutionary games in networks. For homogeneous networks, we show that entanglement guarantees a quick convergence of super cooperation, that there is a phase transition from the convergence of defection to the convergence of super cooperation, and that the threshold for the phase transitions is principally determined by the Nash equilibrium principle of the game, with an accompanying perturbation by the variations of structures of networks. For heterogeneous networks, we show that the equilibrium frequencies of super-cooperators are divergent, that entanglement guarantees emergence of super-cooperation and that there is a phase transition of the emergence with the threshold determined by the Nash equilibrium principle, accompanied by a perturbation by the variations of structures of networks. Our results explore systematically, for the first time, the dynamics, morphogenesis and convergence of evolutionary games in interacting and competing systems. PMID:27118882

Quantum Prisoners' Dilemma in Fluctuating Massless Scalar Field

NASA Astrophysics Data System (ADS)

Huang, Zhiming

2017-12-01

Quantum systems are easily affected by external environment. In this paper, we investigate the influences of external massless scalar field to quantum Prisoners' Dilemma (QPD) game. We firstly derive the master equation that describes the system evolution with initial maximally entangled state. Then, we discuss the effects of a fluctuating massless scalar field on the game's properties such as payoff, Nash equilibrium, and symmetry. We find that for different game strategies, vacuum fluctuation has different effects on payoff. Nash equilibrium is broken but the symmetry of the game is not violated.

Iterative algorithms for computing the feedback Nash equilibrium point for positive systems

NASA Astrophysics Data System (ADS)

Ivanov, I.; Imsland, Lars; Bogdanova, B.

2017-03-01

The paper studies N-player linear quadratic differential games on an infinite time horizon with deterministic feedback information structure. It introduces two iterative methods (the Newton method as well as its accelerated modification) in order to compute the stabilising solution of a set of generalised algebraic Riccati equations. The latter is related to the Nash equilibrium point of the considered game model. Moreover, we derive the sufficient conditions for convergence of the proposed methods. Finally, we discuss two numerical examples so as to illustrate the performance of both of the algorithms.

Nash equilibrium and multi criterion aerodynamic optimization

NASA Astrophysics Data System (ADS)

Tang, Zhili; Zhang, Lianhe

2016-06-01

Game theory and its particular Nash Equilibrium (NE) are gaining importance in solving Multi Criterion Optimization (MCO) in engineering problems over the past decade. The solution of a MCO problem can be viewed as a NE under the concept of competitive games. This paper surveyed/proposed four efficient algorithms for calculating a NE of a MCO problem. Existence and equivalence of the solution are analyzed and proved in the paper based on fixed point theorem. Specific virtual symmetric Nash game is also presented to set up an optimization strategy for single objective optimization problems. Two numerical examples are presented to verify proposed algorithms. One is mathematical functions' optimization to illustrate detailed numerical procedures of algorithms, the other is aerodynamic drag reduction of civil transport wing fuselage configuration by using virtual game. The successful application validates efficiency of algorithms in solving complex aerodynamic optimization problem.

Imagine-Self Perspective-Taking and Rational Self-Interested Behavior in a Simple Experimental Normal-Form Game.

PubMed

Karbowski, Adam; Ramsza, Michał

2017-01-01

The purpose of this study is to explore the link between imagine-self perspective-taking and rational self-interested behavior in experimental normal-form games. Drawing on the concept of sympathy developed by Adam Smith and further literature on perspective-taking in games, we hypothesize that introduction of imagine-self perspective-taking by decision-makers promotes rational self-interested behavior in a simple experimental normal-form game. In our study, we examined behavior of 404 undergraduate students in the two-person game, in which the participant can suffer a monetary loss only if she plays her Nash equilibrium strategy and the opponent plays her dominated strategy. Results suggest that the threat of suffering monetary losses effectively discourages the participants from choosing Nash equilibrium strategy. In general, players may take into account that opponents choose dominated strategies due to specific not self-interested motivations or errors. However, adopting imagine-self perspective by the participants leads to more Nash equilibrium choices, perhaps by alleviating participants' attributions of susceptibility to errors or non-self-interested motivation to the opponents.

Imagine-Self Perspective-Taking and Rational Self-Interested Behavior in a Simple Experimental Normal-Form Game

PubMed Central

Karbowski, Adam; Ramsza, Michał

2017-01-01

The purpose of this study is to explore the link between imagine-self perspective-taking and rational self-interested behavior in experimental normal-form games. Drawing on the concept of sympathy developed by Adam Smith and further literature on perspective-taking in games, we hypothesize that introduction of imagine-self perspective-taking by decision-makers promotes rational self-interested behavior in a simple experimental normal-form game. In our study, we examined behavior of 404 undergraduate students in the two-person game, in which the participant can suffer a monetary loss only if she plays her Nash equilibrium strategy and the opponent plays her dominated strategy. Results suggest that the threat of suffering monetary losses effectively discourages the participants from choosing Nash equilibrium strategy. In general, players may take into account that opponents choose dominated strategies due to specific not self-interested motivations or errors. However, adopting imagine-self perspective by the participants leads to more Nash equilibrium choices, perhaps by alleviating participants’ attributions of susceptibility to errors or non-self-interested motivation to the opponents. PMID:28955276

Algorithmic mechanisms for reliable crowdsourcing computation under collusion.

PubMed

Fernández Anta, Antonio; Georgiou, Chryssis; Mosteiro, Miguel A; Pareja, Daniel

2015-01-01

We consider a computing system where a master processor assigns a task for execution to worker processors that may collude. We model the workers' decision of whether to comply (compute the task) or not (return a bogus result to save the computation cost) as a game among workers. That is, we assume that workers are rational in a game-theoretic sense. We identify analytically the parameter conditions for a unique Nash Equilibrium where the master obtains the correct result. We also evaluate experimentally mixed equilibria aiming to attain better reliability-profit trade-offs. For a wide range of parameter values that may be used in practice, our simulations show that, in fact, both master and workers are better off using a pure equilibrium where no worker cheats, even under collusion, and even for colluding behaviors that involve deviating from the game.

Algorithmic Mechanisms for Reliable Crowdsourcing Computation under Collusion

PubMed Central

Fernández Anta, Antonio; Georgiou, Chryssis; Mosteiro, Miguel A.; Pareja, Daniel

2015-01-01

We consider a computing system where a master processor assigns a task for execution to worker processors that may collude. We model the workers’ decision of whether to comply (compute the task) or not (return a bogus result to save the computation cost) as a game among workers. That is, we assume that workers are rational in a game-theoretic sense. We identify analytically the parameter conditions for a unique Nash Equilibrium where the master obtains the correct result. We also evaluate experimentally mixed equilibria aiming to attain better reliability-profit trade-offs. For a wide range of parameter values that may be used in practice, our simulations show that, in fact, both master and workers are better off using a pure equilibrium where no worker cheats, even under collusion, and even for colluding behaviors that involve deviating from the game. PMID:25793524

Self-Coexistence among IEEE 802.22 Networks: Distributed Allocation of Power and Channel

PubMed Central

Sakin, Sayef Azad; Alamri, Atif; Tran, Nguyen H.

2017-01-01

Ensuring self-coexistence among IEEE 802.22 networks is a challenging problem owing to opportunistic access of incumbent-free radio resources by users in co-located networks. In this study, we propose a fully-distributed non-cooperative approach to ensure self-coexistence in downlink channels of IEEE 802.22 networks. We formulate the self-coexistence problem as a mixed-integer non-linear optimization problem for maximizing the network data rate, which is an NP-hard one. This work explores a sub-optimal solution by dividing the optimization problem into downlink channel allocation and power assignment sub-problems. Considering fairness, quality of service and minimum interference for customer-premises-equipment, we also develop a greedy algorithm for channel allocation and a non-cooperative game-theoretic framework for near-optimal power allocation. The base stations of networks are treated as players in a game, where they try to increase spectrum utilization by controlling power and reaching a Nash equilibrium point. We further develop a utility function for the game to increase the data rate by minimizing the transmission power and, subsequently, the interference from neighboring networks. A theoretical proof of the uniqueness and existence of the Nash equilibrium has been presented. Performance improvements in terms of data-rate with a degree of fairness compared to a cooperative branch-and-bound-based algorithm and a non-cooperative greedy approach have been shown through simulation studies. PMID:29215591

Self-Coexistence among IEEE 802.22 Networks: Distributed Allocation of Power and Channel.

PubMed

Sakin, Sayef Azad; Razzaque, Md Abdur; Hassan, Mohammad Mehedi; Alamri, Atif; Tran, Nguyen H; Fortino, Giancarlo

2017-12-07

Ensuring self-coexistence among IEEE 802.22 networks is a challenging problem owing to opportunistic access of incumbent-free radio resources by users in co-located networks. In this study, we propose a fully-distributed non-cooperative approach to ensure self-coexistence in downlink channels of IEEE 802.22 networks. We formulate the self-coexistence problem as a mixed-integer non-linear optimization problem for maximizing the network data rate, which is an NP-hard one. This work explores a sub-optimal solution by dividing the optimization problem into downlink channel allocation and power assignment sub-problems. Considering fairness, quality of service and minimum interference for customer-premises-equipment, we also develop a greedy algorithm for channel allocation and a non-cooperative game-theoretic framework for near-optimal power allocation. The base stations of networks are treated as players in a game, where they try to increase spectrum utilization by controlling power and reaching a Nash equilibrium point. We further develop a utility function for the game to increase the data rate by minimizing the transmission power and, subsequently, the interference from neighboring networks. A theoretical proof of the uniqueness and existence of the Nash equilibrium has been presented. Performance improvements in terms of data-rate with a degree of fairness compared to a cooperative branch-and-bound-based algorithm and a non-cooperative greedy approach have been shown through simulation studies.

General stochastic variational formulation for the oligopolistic market equilibrium problem with excesses

NASA Astrophysics Data System (ADS)

Barbagallo, Annamaria; Di Meglio, Guglielmo; Mauro, Paolo

2017-07-01

The aim of the paper is to study, in a Hilbert space setting, a general random oligopolistic market equilibrium problem in presence of both production and demand excesses and to characterize the random Cournot-Nash equilibrium principle by means of a stochastic variational inequality. Some existence results are presented.

Symmetry warrants rational cooperation by co-action in Social Dilemmas.

PubMed

Sasidevan, V; Sinha, Sitabhra

2015-08-12

Is it rational for selfish individuals to cooperate? The conventional answer based on analysis of games such as the Prisoners Dilemma (PD) is that it is not, even though mutual cooperation results in a better outcome for all. This incompatibility between individual rationality and collective benefit lies at the heart of questions about the evolution of cooperation, as illustrated by PD and similar games. Here, we argue that this apparent incompatibility is due to an inconsistency in the standard Nash framework for analyzing non-cooperative games and propose a new paradigm, that of the co-action equilibrium. As in the Nash solution, agents know that others are just as rational as them and taking this into account lead them to realize that others will independently adopt the same strategy, in contrast to the idea of unilateral deviation central to Nash equilibrium thinking. Co-action equilibrium results in better collective outcomes for games representing social dilemmas, with relatively "nicer" strategies being chosen by rational selfish individuals. In particular, the dilemma of PD gets resolved within this framework, suggesting that cooperation can evolve in nature as the rational outcome even for selfish agents, without having to take recourse to additional mechanisms for promoting it.

Nanoscale molecular communication networks: a game-theoretic perspective

NASA Astrophysics Data System (ADS)

Jiang, Chunxiao; Chen, Yan; Ray Liu, K. J.

2015-12-01

Currently, communication between nanomachines is an important topic for the development of novel devices. To implement a nanocommunication system, diffusion-based molecular communication is considered as a promising bio-inspired approach. Various technical issues about molecular communications, including channel capacity, noise and interference, and modulation and coding, have been studied in the literature, while the resource allocation problem among multiple nanomachines has not been well investigated, which is a very important issue since all the nanomachines share the same propagation medium. Considering the limited computation capability of nanomachines and the expensive information exchange cost among them, in this paper, we propose a game-theoretic framework for distributed resource allocation in nanoscale molecular communication systems. We first analyze the inter-symbol and inter-user interference, as well as bit error rate performance, in the molecular communication system. Based on the interference analysis, we formulate the resource allocation problem as a non-cooperative molecule emission control game, where the Nash equilibrium is found and proved to be unique. In order to improve the system efficiency while guaranteeing fairness, we further model the resource allocation problem using a cooperative game based on the Nash bargaining solution, which is proved to be proportionally fair. Simulation results show that the Nash bargaining solution can effectively ensure fairness among multiple nanomachines while achieving comparable social welfare performance with the centralized scheme.

Nash Equilibria in Noncooperative Predator-Prey Games

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ramos, Angel Manuel; Roubicek, Tomas

2007-09-15

A noncooperative game governed by a distributed-parameter predator-prey system is considered, assuming that two players control initial conditions for predator and prey, respectively. Existence of a Nash equilibrium is shown under the condition that the desired population profiles and the environmental carrying capacity for the prey are sufficiently small. A conceptual approximation algorithm is proposed and analyzed. Finally, numerical simulations are performed, too.

Individual welfare maximization in electricity markets including consumer and full transmission system modeling

NASA Astrophysics Data System (ADS)

Weber, James Daniel

1999-11-01

This dissertation presents a new algorithm that allows a market participant to maximize its individual welfare in the electricity spot market. The use of such an algorithm in determining market equilibrium points, called Nash equilibria, is also demonstrated. The start of the algorithm is a spot market model that uses the optimal power flow (OPF), with a full representation of the transmission system. The OPF is also extended to model consumer behavior, and a thorough mathematical justification for the inclusion of the consumer model in the OPF is presented. The algorithm utilizes price and dispatch sensitivities, available from the Hessian matrix of the OPF, to help determine an optimal change in an individual's bid. The algorithm is shown to be successful in determining local welfare maxima, and the prospects for scaling the algorithm up to realistically sized systems are very good. Assuming a market in which all participants maximize their individual welfare, economic equilibrium points, called Nash equilibria, are investigated. This is done by iteratively solving the individual welfare maximization algorithm for each participant until a point is reached where all individuals stop modifying their bids. It is shown that these Nash equilibria can be located in this manner. However, it is also demonstrated that equilibria do not always exist, and are not always unique when they do exist. It is also shown that individual welfare is a highly nonconcave function resulting in many local maxima. As a result, a more global optimization technique, using a genetic algorithm (GA), is investigated. The genetic algorithm is successfully demonstrated on several systems. It is also shown that a GA can be developed using special niche methods, which allow a GA to converge to several local optima at once. Finally, the last chapter of this dissertation covers the development of a new computer visualization routine for power system analysis: contouring. The contouring algorithm is demonstrated to be useful in visualizing bus-based and transmission line-based quantities.

Emergence of scale-free characteristics in socio-ecological systems with bounded rationality

PubMed Central

Kasthurirathna, Dharshana; Piraveenan, Mahendra

2015-01-01

Socio–ecological systems are increasingly modelled by games played on complex networks. While the concept of Nash equilibrium assumes perfect rationality, in reality players display heterogeneous bounded rationality. Here we present a topological model of bounded rationality in socio-ecological systems, using the rationality parameter of the Quantal Response Equilibrium. We argue that system rationality could be measured by the average Kullback–-Leibler divergence between Nash and Quantal Response Equilibria, and that the convergence towards Nash equilibria on average corresponds to increased system rationality. Using this model, we show that when a randomly connected socio-ecological system is topologically optimised to converge towards Nash equilibria, scale-free and small world features emerge. Therefore, optimising system rationality is an evolutionary reason for the emergence of scale-free and small-world features in socio-ecological systems. Further, we show that in games where multiple equilibria are possible, the correlation between the scale-freeness of the system and the fraction of links with multiple equilibria goes through a rapid transition when the average system rationality increases. Our results explain the influence of the topological structure of socio–ecological systems in shaping their collective cognitive behaviour, and provide an explanation for the prevalence of scale-free and small-world characteristics in such systems. PMID:26065713

Emergence of scale-free characteristics in socio-ecological systems with bounded rationality.

PubMed

Kasthurirathna, Dharshana; Piraveenan, Mahendra

2015-06-11

Socio-ecological systems are increasingly modelled by games played on complex networks. While the concept of Nash equilibrium assumes perfect rationality, in reality players display heterogeneous bounded rationality. Here we present a topological model of bounded rationality in socio-ecological systems, using the rationality parameter of the Quantal Response Equilibrium. We argue that system rationality could be measured by the average Kullback--Leibler divergence between Nash and Quantal Response Equilibria, and that the convergence towards Nash equilibria on average corresponds to increased system rationality. Using this model, we show that when a randomly connected socio-ecological system is topologically optimised to converge towards Nash equilibria, scale-free and small world features emerge. Therefore, optimising system rationality is an evolutionary reason for the emergence of scale-free and small-world features in socio-ecological systems. Further, we show that in games where multiple equilibria are possible, the correlation between the scale-freeness of the system and the fraction of links with multiple equilibria goes through a rapid transition when the average system rationality increases. Our results explain the influence of the topological structure of socio-ecological systems in shaping their collective cognitive behaviour, and provide an explanation for the prevalence of scale-free and small-world characteristics in such systems.

Distribution strategy of energy supply chain based on corporate social responsibility

NASA Astrophysics Data System (ADS)

Song, Qiaona

2018-02-01

From corporate social responsibilities influence on the consumer`s preferences, applying the basic Idea of game theory, the study on tactics of profit distribution of the one-period game between manufacturer and vendor in energy supply chain,then the repetitive game results of the two partners are discussed. The results show that alliance pricing is the unique nash equilibrium of the one-period game between manufacturer and vendor,and the expect profit of both manufacturer and vendor will increase after cooperation in the range of agreed value of the profit distribution factor. It`s optimal for manufacturer and vendor to insist on alliance pricing for their long-term benefits in energy supply chain.

Smarter than others? Conjectures in lowest unique bid auctions.

PubMed

Zhou, Cancan; Dong, Hongguang; Hu, Rui; Chen, Qinghua

2015-01-01

Research concerning various types of auctions, such as English auctions, Dutch auctions, highest-price sealed-bid auctions, and second-price sealed-bid auctions, is always a topic of considerable interest in interdisciplinary fields. The type of auction, known as a lowest unique bid auction (LUBA), has also attracted significant attention. Various models have been proposed, but they often fail to explain satisfactorily the real bid-distribution characteristics. This paper discusses LUBA bid-distribution characteristics, including the inverted-J shape and the exponential decrease in the upper region. The authors note that this type of distribution, which initially increases and later decreases, cannot be derived from the symmetric Nash equilibrium framework based on perfect information that has previously been used. A novel optimization model based on non-perfect information is presented. The kernel of this model is the premise that agents make decisions to achieve maximum profit based on imaginary information or assumptions regarding the behavior of others.

Auction-based Security Game for Multiuser Cooperative Networks

NASA Astrophysics Data System (ADS)

Wang, An; Cai, Yueming; Yang, Wendong; Cheng, Yunpeng

2013-04-01

In this paper, we develop an auction-based algorithm to allocate the relay power efficiently to improve the system secrecy rate in a cooperative network, where several source-destination pairs and one cooperative relay are involved. On the one hand, the cooperative relay assists these pairs to transmit under a peak power constraint. On the other hand, the relay is untrusty and is also a passive eavesdropper. The whole auction process is completely distributed and no instantaneous channel state information exchange is needed. We also prove the existence and uniqueness of the Nash Equilibrium (NE) for the proposed power auction game. Moreover, the Pareto optimality is also validated. Simulation results show that our proposed auction-based algorithm can effectively improve the system secrecy rate. Besides, the proposed auction-based algorithm can converge to the unique NE point within a finite number of iterations. More interestingly, we also find that the proposed power auction mechanism is cheat-proof.

Directional learning and the provisioning of public goods.

PubMed

Nax, Heinrich H; Perc, Matjaž

2015-01-26

We consider an environment where players are involved in a public goods game and must decide repeatedly whether to make an individual contribution or not. However, players lack strategically relevant information about the game and about the other players in the population. The resulting behavior of players is completely uncoupled from such information, and the individual strategy adjustment dynamics are driven only by reinforcement feedbacks from each player's own past. We show that the resulting "directional learning" is sufficient to explain cooperative deviations away from the Nash equilibrium. We introduce the concept of k-strong equilibria, which nest both the Nash equilibrium and the Aumann-strong equilibrium as two special cases, and we show that, together with the parameters of the learning model, the maximal k-strength of equilibrium determines the stationary distribution. The provisioning of public goods can be secured even under adverse conditions, as long as players are sufficiently responsive to the changes in their own payoffs and adjust their actions accordingly. Substantial levels of public cooperation can thus be explained without arguments involving selflessness or social preferences, solely on the basis of uncoordinated directional (mis)learning.

Statistical physics of the spatial Prisoner's Dilemma with memory-aware agents

NASA Astrophysics Data System (ADS)

Javarone, Marco Alberto

2016-02-01

We introduce an analytical model to study the evolution towards equilibrium in spatial games, with `memory-aware' agents, i.e., agents that accumulate their payoff over time. In particular, we focus our attention on the spatial Prisoner's Dilemma, as it constitutes an emblematic example of a game whose Nash equilibrium is defection. Previous investigations showed that, under opportune conditions, it is possible to reach, in the evolutionary Prisoner's Dilemma, an equilibrium of cooperation. Notably, it seems that mechanisms like motion may lead a population to become cooperative. In the proposed model, we map agents to particles of a gas so that, on varying the system temperature, they randomly move. In doing so, we are able to identify a relation between the temperature and the final equilibrium of the population, explaining how it is possible to break the classical Nash equilibrium in the spatial Prisoner's Dilemma when considering agents able to increase their payoff over time. Moreover, we introduce a formalism to study order-disorder phase transitions in these dynamics. As result, we highlight that the proposed model allows to explain analytically how a population, whose interactions are based on the Prisoner's Dilemma, can reach an equilibrium far from the expected one; opening also the way to define a direct link between evolutionary game theory and statistical physics.

Experimental oligopolies modeling: A dynamic approach based on heterogeneous behaviors

NASA Astrophysics Data System (ADS)

Cerboni Baiardi, Lorenzo; Naimzada, Ahmad K.

2018-05-01

In the rank of behavioral rules, imitation-based heuristics has received special attention in economics (see [14] and [12]). In particular, imitative behavior is considered in order to understand the evidences arising in experimental oligopolies which reveal that the Cournot-Nash equilibrium does not emerge as unique outcome and show that an important component of the production at the competitive level is observed (see e.g.[1,3,9] or [7,10]). By considering the pioneering groundbreaking approach of [2], we build a dynamical model of linear oligopolies where heterogeneous decision mechanisms of players are made explicit. In particular, we consider two different types of quantity setting players characterized by different decision mechanisms that coexist and operate simultaneously: agents that adaptively adjust their choices towards the direction that increases their profit are embedded with imitator agents. The latter ones use a particular form of proportional imitation rule that considers the awareness about the presence of strategic interactions. It is noteworthy that the Cournot-Nash outcome is a stationary state of our models. Our thesis is that the chaotic dynamics arousing from a dynamical model, where heterogeneous players are considered, are capable to qualitatively reproduce the outcomes of experimental oligopolies.

Price game and chaos control among three oligarchs with different rationalities in property insurance market.

PubMed

Ma, Junhai; Zhang, Junling

2012-12-01

Combining with the actual competition in Chinese property insurance market and assuming that the property insurance companies take the marginal utility maximization as the basis of decision-making when they play price games, we first established the price game model with three oligarchs who have different rationalities. Then, we discussed the existence and stability of equilibrium points. Third, we studied the theoretical value of Lyapunov exponent at Nash equilibrium point and its change process with the main parameters' changes though having numerical simulation for the system such as the bifurcation, chaos attractors, and so on. Finally, we analyzed the influences which the changes of different parameters have on the profits and utilities of oligarchs and their corresponding competition advantage. Based on this, we used the variable feedback control method to control the chaos of the system and stabilized the chaos state to Nash equilibrium point again. The results have significant theoretical and practical application value.

Price game and chaos control among three oligarchs with different rationalities in property insurance market

NASA Astrophysics Data System (ADS)

Ma, Junhai; Zhang, Junling

2012-12-01

Combining with the actual competition in Chinese property insurance market and assuming that the property insurance companies take the marginal utility maximization as the basis of decision-making when they play price games, we first established the price game model with three oligarchs who have different rationalities. Then, we discussed the existence and stability of equilibrium points. Third, we studied the theoretical value of Lyapunov exponent at Nash equilibrium point and its change process with the main parameters' changes though having numerical simulation for the system such as the bifurcation, chaos attractors, and so on. Finally, we analyzed the influences which the changes of different parameters have on the profits and utilities of oligarchs and their corresponding competition advantage. Based on this, we used the variable feedback control method to control the chaos of the system and stabilized the chaos state to Nash equilibrium point again. The results have significant theoretical and practical application value.

Quantum oligopoly

NASA Astrophysics Data System (ADS)

Lo, C. F.; Kiang, D.

2003-12-01

Based upon a modification of Li et al.'s "minimal" quantization rules (Phys. Lett. A306(2002) 73), we investigate the quantum version of the Cournot and Bertrand oligopoly. In the Cournot oligopoly, the profit of each of the N firms at the Nash equilibrium point rises monotonically with the measure of the quantum entanglement. Only at maximal entanglement, however, does the Nash equilibrium point coincide with the Pareto optimal point. In the Bertrand case, the Bertrand Paradox remains for finite entanglement (i.e., the perfectly competitive stage is reached for any N>=2), whereas with maximal entanglement each of the N firms will still have a non-zero shared profit. Hence, the Bertrand Paradox is completely resolved. Furthermore, a perfectly competitive market is reached asymptotically for N → ∞ in both the Cournot and Bertrand oligopoly.

Generation of Strategies for Environmental Deception in Two-Player Normal-Form Games

DTIC Science & Technology

2015-06-18

found in the literature is pre- sented by Kohlberg and Mertens [23]. A stable equilibrium by their definition is an equi- librium in an extensive-form...the equilibrium in this state provides them with an increased payoff. While interesting, Kohlberg and Mertens’ defi- 13 nition of equilibrium...stability used by Kohlberg and Mertens. Arsham’s work focuses on determining the amount by which a mixed-strategy Nash equilibrium’s payoff values can

Cournot competition between a non-profit firm and a for-profit firm with uncertainty

NASA Astrophysics Data System (ADS)

Ferreira, Fernanda A.

2010-03-01

In this paper, we consider a Cournot competition between a nonprofit firm and a for-profit firm in a homogeneous goods market, with uncertain demand. Given an asymmetric tax schedule, we compute explicitly the Bayesian-Nash equilibrium. Furthermore, we analyze the effects of the tax rate and the degree of altruistic preference on market equilibrium outcomes.

Directional learning and the provisioning of public goods

PubMed Central

Nax, Heinrich H.; Perc, Matjaž

2015-01-01

We consider an environment where players are involved in a public goods game and must decide repeatedly whether to make an individual contribution or not. However, players lack strategically relevant information about the game and about the other players in the population. The resulting behavior of players is completely uncoupled from such information, and the individual strategy adjustment dynamics are driven only by reinforcement feedbacks from each player's own past. We show that the resulting “directional learning” is sufficient to explain cooperative deviations away from the Nash equilibrium. We introduce the concept of k–strong equilibria, which nest both the Nash equilibrium and the Aumann-strong equilibrium as two special cases, and we show that, together with the parameters of the learning model, the maximal k–strength of equilibrium determines the stationary distribution. The provisioning of public goods can be secured even under adverse conditions, as long as players are sufficiently responsive to the changes in their own payoffs and adjust their actions accordingly. Substantial levels of public cooperation can thus be explained without arguments involving selflessness or social preferences, solely on the basis of uncoordinated directional (mis)learning. PMID:25619192

Mixed-strategy Nash equilibrium for a discontinuous symmetric N-player game

NASA Astrophysics Data System (ADS)

Hilhorst, H. J.; Appert-Rolland, C.

2018-03-01

We consider a game in which each player must find a compromise between more daring strategies that carry a high risk for him to be eliminated, and more cautious ones that, however, reduce his final score. For two symmetric players this game was originally formulated in 1961 by Dresher, who modeled a duel between two opponents. The game has also been of interest in the description of athletic competitions. We extend here the two-player game to an arbitrary number N of symmetric players. We show that there is a mixed-strategy Nash equilibrium and find its exact analytic expression, which we analyze in particular in the limit of large N, where mean-field behavior occurs. The original game with N  =  2 arises as a singular limit of the general case.

Using and comparing metaheuristic algorithms for optimizing bidding strategy viewpoint of profit maximization of generators

NASA Astrophysics Data System (ADS)

Mousavi, Seyed Hosein; Nazemi, Ali; Hafezalkotob, Ashkan

2015-03-01

With the formation of the competitive electricity markets in the world, optimization of bidding strategies has become one of the main discussions in studies related to market designing. Market design is challenged by multiple objectives that need to be satisfied. The solution of those multi-objective problems is searched often over the combined strategy space, and thus requires the simultaneous optimization of multiple parameters. The problem is formulated analytically using the Nash equilibrium concept for games composed of large numbers of players having discrete and large strategy spaces. The solution methodology is based on a characterization of Nash equilibrium in terms of minima of a function and relies on a metaheuristic optimization approach to find these minima. This paper presents some metaheuristic algorithms to simulate how generators bid in the spot electricity market viewpoint of their profit maximization according to the other generators' strategies, such as genetic algorithm (GA), simulated annealing (SA) and hybrid simulated annealing genetic algorithm (HSAGA) and compares their results. As both GA and SA are generic search methods, HSAGA is also a generic search method. The model based on the actual data is implemented in a peak hour of Tehran's wholesale spot market in 2012. The results of the simulations show that GA outperforms SA and HSAGA on computing time, number of function evaluation and computing stability, as well as the results of calculated Nash equilibriums by GA are less various and different from each other than the other algorithms.

Nonconvergence to Saddle Boundary Points under Perturbed Reinforcement Learning

DTIC Science & Technology

2012-12-07

of the ODE (12). Note that for some games not all stationary points of the ODE (12) are Nash equilibria. For example, if you consider the Typewriter ...B A 4, 4 2, 2 B 2, 2 3, 3 Table 1: The Typewriter Game. On the other hand, any stationary point in the interior of the probability simplex will... Typewriter Game of Table 1. We observe that it is possible for the process to converge to a pure strategy profile which is not a Nash equilibrium when Ri(α

Social dilemmas in multistrategy evolutionary potential games

NASA Astrophysics Data System (ADS)

Szabó, György; Bunth, Gergely

2018-01-01

The nature of social dilemmas is studied in n -strategy evolutionary potential games on a square lattice with nearest-neighbor interactions and the logit rule. For symmetric games with symmetric payoff matrices there are no dilemmas because of the coincidence of individual and common interests. The dilemmas are caused by the antisymmetric parts of the self- and cross-dependent payoff components if it modifies the preferred Nash equilibrium. The contentment of players and the emergence of dilemmas in the preferred Nash equilibria are illustrated on some two-dimensional cross sections of the parameter space.

Complexity analysis of dual-channel game model with different managers' business objectives

NASA Astrophysics Data System (ADS)

Li, Ting; Ma, Junhai

2015-01-01

This paper considers dual-channel game model with bounded rationality, using the theory of bifurcations of dynamical system. The business objectives of retailers are assumed to be different, which is closer to reality than previous studies. We study the local stable region of Nash equilibrium point and find that business objectives can expand the stable region and play an important role in price strategy. One interesting finding is that a fiercer competition tends to stabilize the Nash equilibrium. Simulation shows the complex behavior of two dimensional dynamic system, we find period doubling bifurcation and chaos phenomenon. We measure performances of the model in different period by using the index of average profit. The results show that unstable behavior in economic system is often an unfavorable outcome. So this paper discusses the application of adaptive adjustment mechanism when the model exhibits chaotic behavior and then allows the retailers to eliminate the negative effects.

A novel game theoretic approach for modeling competitive information diffusion in social networks with heterogeneous nodes

NASA Astrophysics Data System (ADS)

Agha Mohammad Ali Kermani, Mehrdad; Fatemi Ardestani, Seyed Farshad; Aliahmadi, Alireza; Barzinpour, Farnaz

2017-01-01

Influence maximization deals with identification of the most influential nodes in a social network given an influence model. In this paper, a game theoretic framework is developed that models a competitive influence maximization problem. A novel competitive influence model is additionally proposed that incorporates user heterogeneity, message content, and network structure. The proposed game-theoretic model is solved using Nash Equilibrium in a real-world dataset. It is shown that none of the well-known strategies are stable and at least one player has the incentive to deviate from the proposed strategy. Moreover, violation of Nash equilibrium strategy by each player leads to their reduced payoff. Contrary to previous works, our results demonstrate that graph topology, as well as the nodes' sociability and initial tendency measures have an effect on the determination of the influential node in the network.

A novel role of astrocyte elevated gene-1 (AEG-1) in regulating nonalcoholic steatohepatitis (NASH).

PubMed

Srivastava, Jyoti; Robertson, Chadia L; Ebeid, Kareem; Dozmorov, Mikhail; Rajasekaran, Devaraja; Mendoza, Rachel; Siddiq, Ayesha; Akiel, Maaged A; Jariwala, Nidhi; Shen, Xue-Ning; Windle, Jolene J; Subler, Mark A; Mukhopadhyay, Nitai D; Giashuddin, Shah; Ghosh, Shobha; Lai, Zhao; Chen, Yidong; Fisher, Paul B; Salem, Aliasger K; Sanyal, Arun J; Sarkar, Devanand

2017-08-01

Nonalcoholic steatohepatitis (NASH) is the most prevalent cause of chronic liver disease in the Western world. However, an optimum therapy for NASH is yet to be established, mandating more in-depth investigation into the molecular pathogenesis of NASH to identify novel regulatory molecules and develop targeted therapies. Here, we unravel a unique function of astrocyte elevated gene-1(AEG-1)/metadherin in NASH using a transgenic mouse with hepatocyte-specific overexpression of AEG-1 (Alb/AEG-1) and a conditional hepatocyte-specific AEG-1 knockout mouse (AEG-1 ΔHEP ). Alb/AEG-1 mice developed spontaneous NASH whereas AEG-1 ΔHEP mice were protected from high-fat diet (HFD)-induced NASH. Intriguingly, AEG-1 overexpression was observed in livers of NASH patients and wild-type (WT) mice that developed steatosis upon feeding HFD. In-depth molecular analysis unraveled that inhibition of peroxisome proliferator-activated receptor alpha activity resulting in decreased fatty acid β-oxidation, augmentation of translation of fatty acid synthase resulting in de novo lipogenesis, and increased nuclear factor kappa B-mediated inflammation act in concert to mediate AEG-1-induced NASH. Therapeutically, hepatocyte-specific nanoparticle-delivered AEG-1 small interfering RNA provided marked protection from HFD-induced NASH in WT mice. AEG-1 might be a key molecule regulating initiation and progression of NASH. AEG-1 inhibitory strategies might be developed as a potential therapeutic intervention in NASH patients. (Hepatology 2017;66:466-480). © 2017 by the American Association for the Study of Liver Diseases.

Bertrand and Cournot oligopolies when rivals' costs are unknown

NASA Astrophysics Data System (ADS)

Ferreira, Fernanda A.; Ferreira, Flávio

2010-10-01

We study Bertrand and Cournot oligopoly models with incomplete information about rivals' costs, where the uncertainty is given by a uniform distribution. We compute the Bayesian-Nash equilibrium of both games, the ex-ante expected profits and the ex-post profits of each firm. We see that, in the price competition, even though only one firm produces in equilibrium, all firms have a positive ex-ante expected profit.

Bounded rationality leads to equilibrium of public goods games.

PubMed

Xu, Zhaojin; Wang, Zhen; Zhang, Lianzhong

2009-12-01

In this work, we introduce a degree of rationality to the public goods games in which players can determine whether or not to participate, and with it a new mechanism has been established. Existence of the bounded rationality would lead to a new equilibrium which differs from the Nash equilibrium and qualitatively explains the fundamental role of loners' payoff for maintaining cooperation. Meanwhile, it is shown how the potential strategy influences the players' decision. Finally, we explicitly demonstrate a rock-scissors-paper dynamics which is a consequence of this model.

Bounded rationality leads to equilibrium of public goods games

NASA Astrophysics Data System (ADS)

Xu, Zhaojin; Wang, Zhen; Zhang, Lianzhong

2009-12-01

In this work, we introduce a degree of rationality to the public goods games in which players can determine whether or not to participate, and with it a new mechanism has been established. Existence of the bounded rationality would lead to a new equilibrium which differs from the Nash equilibrium and qualitatively explains the fundamental role of loners’ payoff for maintaining cooperation. Meanwhile, it is shown how the potential strategy influences the players’ decision. Finally, we explicitly demonstrate a rock-scissors-paper dynamics which is a consequence of this model.

Stochastic Games for Continuous-Time Jump Processes Under Finite-Horizon Payoff Criterion

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wei, Qingda, E-mail: weiqd@hqu.edu.cn; Chen, Xian, E-mail: chenxian@amss.ac.cn

In this paper we study two-person nonzero-sum games for continuous-time jump processes with the randomized history-dependent strategies under the finite-horizon payoff criterion. The state space is countable, and the transition rates and payoff functions are allowed to be unbounded from above and from below. Under the suitable conditions, we introduce a new topology for the set of all randomized Markov multi-strategies and establish its compactness and metrizability. Then by constructing the approximating sequences of the transition rates and payoff functions, we show that the optimal value function for each player is a unique solution to the corresponding optimality equation andmore » obtain the existence of a randomized Markov Nash equilibrium. Furthermore, we illustrate the applications of our main results with a controlled birth and death system.« less

Nonalcoholic fatty liver disease and liver transplantation - Where do we stand?

PubMed Central

Mikolasevic, Ivana; Filipec-Kanizaj, Tajana; Mijic, Maja; Jakopcic, Ivan; Milic, Sandra; Hrstic, Irena; Sobocan, Nikola; Stimac, Davor; Burra, Patrizia

2018-01-01

Nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH) is a challenging and multisystem disease that has a high socioeconomic impact. NAFLD/NASH is a main cause of macrovesicular steatosis and has multiple impacts on liver transplantation (LT), on patients on the waiting list for transplant, on post-transplant setting as well as on organ donors. Current data indicate new trends in the area of chronic liver disease. Due to the increased incidence of metabolic syndrome (MetS) and its components, NASH cirrhosis and hepatocellular carcinoma caused by NASH will soon become a major indication for LT. Furthermore, due to an increasing incidence of MetS and, consequently, NAFLD, there will be more steatotic donor livers and less high quality organs available for LT, in addition to a lack of available liver allografts. Patients who have NASH and are candidates for LT have multiple comorbidities and are unique LT candidates. Finally, we discuss long-term grafts and patient survival after LT, the recurrence of NASH and NASH appearing de novo after transplantation. In addition, we suggest topics and areas that require more research for improving the health care of this increasing patient population. PMID:29662288

Network formation: neighborhood structures, establishment costs, and distributed learning.

PubMed

Chasparis, Georgios C; Shamma, Jeff S

2013-12-01

We consider the problem of network formation in a distributed fashion. Network formation is modeled as a strategic-form game, where agents represent nodes that form and sever unidirectional links with other nodes and derive utilities from these links. Furthermore, agents can form links only with a limited set of neighbors. Agents trade off the benefit from links, which is determined by a distance-dependent reward function, and the cost of maintaining links. When each agent acts independently, trying to maximize its own utility function, we can characterize “stable” networks through the notion of Nash equilibrium. In fact, the introduced reward and cost functions lead to Nash equilibria (networks), which exhibit several desirable properties such as connectivity, bounded-hop diameter, and efficiency (i.e., minimum number of links). Since Nash networks may not necessarily be efficient, we also explore the possibility of “shaping” the set of Nash networks through the introduction of state-based utility functions. Such utility functions may represent dynamic phenomena such as establishment costs (either positive or negative). Finally, we show how Nash networks can be the outcome of a distributed learning process. In particular, we extend previous learning processes to so-called “state-based” weakly acyclic games, and we show that the proposed network formation games belong to this class of games.

DEVELOPING AND FIELD IMPLEMENTING A DYNAMIC ECO-ROUTING SYSTEM.

DOT National Transportation Integrated Search

2017-04-01

The study develops two different eco-routing systems and uses them to investigate and quantify the system-wide impacts of implementing an eco-routing system. The first one is basically a Nash Equilibrium feedback system, which uses the Ant Colony opt...

Optimization, Monotonicity and the Determination of Nash Equilibria — An Algorithmic Analysis

NASA Astrophysics Data System (ADS)

Lozovanu, D.; Pickl, S. W.; Weber, G.-W.

2004-08-01

This paper is concerned with the optimization of a nonlinear time-discrete model exploiting the special structure of the underlying cost game and the property of inverse matrices. The costs are interlinked by a system of linear inequalities. It is shown that, if the players cooperate, i.e., minimize the sum of all the costs, they achieve a Nash equilibrium. In order to determine Nash equilibria, the simplex method can be applied with respect to the dual problem. An introduction into the TEM model and its relationship to an economic Joint Implementation program is given. The equivalence problem is presented. The construction of the emission cost game and the allocation problem is explained. The assumption of inverse monotony for the matrices leads to a new result in the area of such allocation problems. A generalization of such problems is presented.

N-Player Quantum Games in an EPR Setting

PubMed Central

Chappell, James M.; Iqbal, Azhar; Abbott, Derek

2012-01-01

The -player quantum games are analyzed that use an Einstein-Podolsky-Rosen (EPR) experiment, as the underlying physical setup. In this setup, a player’s strategies are not unitary transformations as in alternate quantum game-theoretic frameworks, but a classical choice between two directions along which spin or polarization measurements are made. The players’ strategies thus remain identical to their strategies in the mixed-strategy version of the classical game. In the EPR setting the quantum game reduces itself to the corresponding classical game when the shared quantum state reaches zero entanglement. We find the relations for the probability distribution for -qubit GHZ and W-type states, subject to general measurement directions, from which the expressions for the players’ payoffs and mixed Nash equilibrium are determined. Players’ payoff matrices are then defined using linear functions so that common two-player games can be easily extended to the -player case and permit analytic expressions for the Nash equilibrium. As a specific example, we solve the Prisoners’ Dilemma game for general . We find a new property for the game that for an even number of players the payoffs at the Nash equilibrium are equal, whereas for an odd number of players the cooperating players receive higher payoffs. By dispensing with the standard unitary transformations on state vectors in Hilbert space and using instead rotors and multivectors, based on Clifford’s geometric algebra (GA), it is shown how the N-player case becomes tractable. The new mathematical approach presented here has wide implications in the areas of quantum information and quantum complexity, as it opens up a powerful way to tractably analyze N-partite qubit interactions. PMID:22606258

Bilevel formulation of a policy design problem considering multiple objectives and incomplete preferences

NASA Astrophysics Data System (ADS)

Hawthorne, Bryant; Panchal, Jitesh H.

2014-07-01

A bilevel optimization formulation of policy design problems considering multiple objectives and incomplete preferences of the stakeholders is presented. The formulation is presented for Feed-in-Tariff (FIT) policy design for decentralized energy infrastructure. The upper-level problem is the policy designer's problem and the lower-level problem is a Nash equilibrium problem resulting from market interactions. The policy designer has two objectives: maximizing the quantity of energy generated and minimizing policy cost. The stakeholders decide on quantities while maximizing net present value and minimizing capital investment. The Nash equilibrium problem in the presence of incomplete preferences is formulated as a stochastic linear complementarity problem and solved using expected value formulation, expected residual minimization formulation, and the Monte Carlo technique. The primary contributions in this article are the mathematical formulation of the FIT policy, the extension of computational policy design problems to multiple objectives, and the consideration of incomplete preferences of stakeholders for policy design problems.

Bertrand Model Under Incomplete Information

NASA Astrophysics Data System (ADS)

Ferreira, Fernanda A.; Pinto, Alberto A.

2008-09-01

We consider a Bertrand duopoly model with unknown costs. The firms' aim is to choose the price of its product according to the well-known concept of Bayesian Nash equilibrium. The chooses are made simultaneously by both firms. In this paper, we suppose that each firm has two different technologies, and uses one of them according to a certain probability distribution. The use of either one or the other technology affects the unitary production cost. We show that this game has exactly one Bayesian Nash equilibrium. We analyse the advantages, for firms and for consumers, of using the technology with highest production cost versus the one with cheapest production cost. We prove that the expected profit of each firm increases with the variance of its production costs. We also show that the expected price of each good increases with both expected production costs, being the effect of the expected production costs of the rival dominated by the effect of the own expected production costs.

Identifying protein complexes in PPI network using non-cooperative sequential game.

PubMed

Maulik, Ujjwal; Basu, Srinka; Ray, Sumanta

2017-08-21

Identifying protein complexes from protein-protein interaction (PPI) network is an important and challenging task in computational biology as it helps in better understanding of cellular mechanisms in various organisms. In this paper we propose a noncooperative sequential game based model for protein complex detection from PPI network. The key hypothesis is that protein complex formation is driven by mechanism that eventually optimizes the number of interactions within the complex leading to dense subgraph. The hypothesis is drawn from the observed network property named small world. The proposed multi-player game model translates the hypothesis into the game strategies. The Nash equilibrium of the game corresponds to a network partition where each protein either belong to a complex or form a singleton cluster. We further propose an algorithm to find the Nash equilibrium of the sequential game. The exhaustive experiment on synthetic benchmark and real life yeast networks evaluates the structural as well as biological significance of the network partitions.

How Many Formative Assessment Angels Can Dance on the Head of a Meta-Analytic Pin: 0.2

ERIC Educational Resources Information Center

Kingston, Neal; Nash, Brooke

2012-01-01

In their critique of Kingston and Nash (2011), Briggs, Ruiz-Primo, Furtak, Shepard, and Yin (2012) make several major points. First, Kingston and Nash's conclusions about the state of research on the efficacy of formative assessment are similar to other researchers, "including some of the authors." Second, their research may be unique in that they…

Power allocation for SWIPT in K-user interference channels using game theory

NASA Astrophysics Data System (ADS)

Wen, Zhigang; Liu, Ying; Liu, Xiaoqing; Li, Shan; Chen, Xianya

2018-12-01

A simultaneous wireless information and power transfer system in interference channels of multi-users is considered. In this system, each transmitter sends one data stream to its targeted receiver, which causes interference to other receivers. Since all transmitter-receiver links want to maximize their own average transmission rate, a power allocation problem under the transmit power constraints and the energy-harvesting constraints is developed. To solve this problem, we propose a game theory framework. Then, we convert the game into a variational inequalities problem by establishing the connection between game theory and variational inequalities and solve the variational inequalities problem. Through theoretical analysis, the existence and uniqueness of Nash equilibrium are both guaranteed by the theory of variational inequalities. A distributed iterative alternating optimization water-filling algorithm is derived, which is proved to converge. Numerical results show that the proposed algorithm reaches fast convergence and achieves a higher sum rate than the unaided scheme.

Reinforcement Learning for Constrained Energy Trading Games With Incomplete Information.

PubMed

Wang, Huiwei; Huang, Tingwen; Liao, Xiaofeng; Abu-Rub, Haitham; Chen, Guo

2017-10-01

This paper considers the problem of designing adaptive learning algorithms to seek the Nash equilibrium (NE) of the constrained energy trading game among individually strategic players with incomplete information. In this game, each player uses the learning automaton scheme to generate the action probability distribution based on his/her private information for maximizing his own averaged utility. It is shown that if one of admissible mixed-strategies converges to the NE with probability one, then the averaged utility and trading quantity almost surely converge to their expected ones, respectively. For the given discontinuous pricing function, the utility function has already been proved to be upper semicontinuous and payoff secure which guarantee the existence of the mixed-strategy NE. By the strict diagonal concavity of the regularized Lagrange function, the uniqueness of NE is also guaranteed. Finally, an adaptive learning algorithm is provided to generate the strategy probability distribution for seeking the mixed-strategy NE.

Quantum Nash Equilibria and Quantum Computing

NASA Astrophysics Data System (ADS)

Fellman, Philip Vos; Post, Jonathan Vos

In 2004, At the Fifth International Conference on Complex Systems, we drew attention to some remarkable findings by researchers at the Santa Fe Institute (Sato, Farmer and Akiyama, 2001) about hitherto unsuspected complexity in the Nash Equilibrium. As we progressed from these findings about heteroclinic Hamiltonians and chaotic transients hidden within the learning patterns of the simple rock-paper-scissors game to some related findings on the theory of quantum computing, one of the arguments we put forward was just as in the late 1990's a number of new Nash equilibria were discovered in simple bi-matrix games (Shubik and Quint, 1996; Von Stengel, 1997, 2000; and McLennan and Park, 1999) we would begin to see new Nash equilibria discovered as the result of quantum computation. While actual quantum computers remain rather primitive (Toibman, 2004), and the theory of quantum computation seems to be advancing perhaps a bit more slowly than originally expected, there have, nonetheless, been a number of advances in computation and some more radical advances in an allied field, quantum game theory (Huberman and Hogg, 2004) which are quite significant. In the course of this paper we will review a few of these discoveries and illustrate some of the characteristics of these new "Quantum Nash Equilibria". The full text of this research can be found at http://necsi.org/events/iccs6/viewpaper.php?id-234

Budget Allocation in a Competitive Communication Spectrum Economy

NASA Astrophysics Data System (ADS)

Lin, Ming-Hua; Tsai, Jung-Fa; Ye, Yinyu

2009-12-01

This study discusses how to adjust "monetary budget" to meet each user's physical power demand, or balance all individual utilities in a competitive "spectrum market" of a communication system. In the market, multiple users share a common frequency or tone band and each of them uses the budget to purchase its own transmit power spectra (taking others as given) in maximizing its Shannon utility or pay-off function that includes the effect of interferences. A market equilibrium is a budget allocation, price spectrum, and tone power distribution that independently and simultaneously maximizes each user's utility. The equilibrium conditions of the market are formulated and analyzed, and the existence of an equilibrium is proved. Computational results and comparisons between the competitive equilibrium and Nash equilibrium solutions are also presented, which show that the competitive market equilibrium solution often provides more efficient power distribution.

Run-Reversal Equilibrium for Clinical Trial Randomization

PubMed Central

Grant, William C.

2015-01-01

In this paper, we describe a new restricted randomization method called run-reversal equilibrium (RRE), which is a Nash equilibrium of a game where (1) the clinical trial statistician chooses a sequence of medical treatments, and (2) clinical investigators make treatment predictions. RRE randomization counteracts how each investigator could observe treatment histories in order to forecast upcoming treatments. Computation of a run-reversal equilibrium reflects how the treatment history at a particular site is imperfectly correlated with the treatment imbalance for the overall trial. An attractive feature of RRE randomization is that treatment imbalance follows a random walk at each site, while treatment balance is tightly constrained and regularly restored for the overall trial. Less predictable and therefore more scientifically valid experiments can be facilitated by run-reversal equilibrium for multi-site clinical trials. PMID:26079608

Pigeons ("Columba Livia") Approach Nash Equilibrium in Experimental Matching Pennies Competitions

ERIC Educational Resources Information Center

Sanabria, Federico; Thrailkill, Eric

2009-01-01

The game of Matching Pennies (MP), a simplified version of the more popular Rock, Papers, Scissors, schematically represents competitions between organisms with incentives to predict each other's behavior. Optimal performance in iterated MP competitions involves the production of random choice patterns and the detection of nonrandomness in the…

Selfish Routing

DTIC Science & Technology

2002-05-01

traffic models , thereby identifying types of networks for which the cost of routing selfishly is mild. The inefficiency inherent in an uncoordinated outcome...17 1.6 Bibliographic Notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 2 Preliminaries 18 2.1 The Model ...to Other Models 68 4.1 Flows at Approximate Nash Equilibrium . . . . . . . . . . . . . . . . 69 4.2 Finitely Many Users: Splittable Flow

Modeling Misbehavior in Cooperative Diversity: A Dynamic Game Approach

NASA Astrophysics Data System (ADS)

Dehnie, Sintayehu; Memon, Nasir

2009-12-01

Cooperative diversity protocols are designed with the assumption that terminals always help each other in a socially efficient manner. This assumption may not be valid in commercial wireless networks where terminals may misbehave for selfish or malicious intentions. The presence of misbehaving terminals creates a social-dilemma where terminals exhibit uncertainty about the cooperative behavior of other terminals in the network. Cooperation in social-dilemma is characterized by a suboptimal Nash equilibrium where wireless terminals opt out of cooperation. Hence, without establishing a mechanism to detect and mitigate effects of misbehavior, it is difficult to maintain a socially optimal cooperation. In this paper, we first examine effects of misbehavior assuming static game model and show that cooperation under existing cooperative protocols is characterized by a noncooperative Nash equilibrium. Using evolutionary game dynamics we show that a small number of mutants can successfully invade a population of cooperators, which indicates that misbehavior is an evolutionary stable strategy (ESS). Our main goal is to design a mechanism that would enable wireless terminals to select reliable partners in the presence of uncertainty. To this end, we formulate cooperative diversity as a dynamic game with incomplete information. We show that the proposed dynamic game formulation satisfied the conditions for the existence of perfect Bayesian equilibrium.

Algorithmic Mechanism Design of Evolutionary Computation.

PubMed

Pei, Yan

2015-01-01

We consider algorithmic design, enhancement, and improvement of evolutionary computation as a mechanism design problem. All individuals or several groups of individuals can be considered as self-interested agents. The individuals in evolutionary computation can manipulate parameter settings and operations by satisfying their own preferences, which are defined by an evolutionary computation algorithm designer, rather than by following a fixed algorithm rule. Evolutionary computation algorithm designers or self-adaptive methods should construct proper rules and mechanisms for all agents (individuals) to conduct their evolution behaviour correctly in order to definitely achieve the desired and preset objective(s). As a case study, we propose a formal framework on parameter setting, strategy selection, and algorithmic design of evolutionary computation by considering the Nash strategy equilibrium of a mechanism design in the search process. The evaluation results present the efficiency of the framework. This primary principle can be implemented in any evolutionary computation algorithm that needs to consider strategy selection issues in its optimization process. The final objective of our work is to solve evolutionary computation design as an algorithmic mechanism design problem and establish its fundamental aspect by taking this perspective. This paper is the first step towards achieving this objective by implementing a strategy equilibrium solution (such as Nash equilibrium) in evolutionary computation algorithm.

Algorithmic Mechanism Design of Evolutionary Computation

PubMed Central

2015-01-01

We consider algorithmic design, enhancement, and improvement of evolutionary computation as a mechanism design problem. All individuals or several groups of individuals can be considered as self-interested agents. The individuals in evolutionary computation can manipulate parameter settings and operations by satisfying their own preferences, which are defined by an evolutionary computation algorithm designer, rather than by following a fixed algorithm rule. Evolutionary computation algorithm designers or self-adaptive methods should construct proper rules and mechanisms for all agents (individuals) to conduct their evolution behaviour correctly in order to definitely achieve the desired and preset objective(s). As a case study, we propose a formal framework on parameter setting, strategy selection, and algorithmic design of evolutionary computation by considering the Nash strategy equilibrium of a mechanism design in the search process. The evaluation results present the efficiency of the framework. This primary principle can be implemented in any evolutionary computation algorithm that needs to consider strategy selection issues in its optimization process. The final objective of our work is to solve evolutionary computation design as an algorithmic mechanism design problem and establish its fundamental aspect by taking this perspective. This paper is the first step towards achieving this objective by implementing a strategy equilibrium solution (such as Nash equilibrium) in evolutionary computation algorithm. PMID:26257777

Evolution of wealth in a non-conservative economy driven by local Nash equilibria.

PubMed

Degond, Pierre; Liu, Jian-Guo; Ringhofer, Christian

2014-11-13

We develop a model for the evolution of wealth in a non-conservative economic environment, extending a theory developed in Degond et al. (2014 J. Stat. Phys. 154, 751-780 (doi:10.1007/s10955-013-0888-4)). The model considers a system of rational agents interacting in a game-theoretical framework. This evolution drives the dynamics of the agents in both wealth and economic configuration variables. The cost function is chosen to represent a risk-averse strategy of each agent. That is, the agent is more likely to interact with the market, the more predictable the market, and therefore the smaller its individual risk. This yields a kinetic equation for an effective single particle agent density with a Nash equilibrium serving as the local thermodynamic equilibrium. We consider a regime of scale separation where the large-scale dynamics is given by a hydrodynamic closure with this local equilibrium. A class of generalized collision invariants is developed to overcome the difficulty of the non-conservative property in the hydrodynamic closure derivation of the large-scale dynamics for the evolution of wealth distribution. The result is a system of gas dynamics-type equations for the density and average wealth of the agents on large scales. We recover the inverse Gamma distribution, which has been previously considered in the literature, as a local equilibrium for particular choices of the cost function. © 2014 The Author(s) Published by the Royal Society. All rights reserved.

Quantum prisoners' dilemma under enhanced interrogation

NASA Astrophysics Data System (ADS)

Siopsis, George; Balu, Radhakrishnan; Solmeyer, Neal

2018-06-01

In the quantum version of prisoners' dilemma, each prisoner is equipped with a single qubit that the interrogator can entangle. We enlarge the available Hilbert space by introducing a third qubit that the interrogator can entangle with the other two. We discuss an enhanced interrogation technique based on tripartite entanglement and analyze Nash equilibria. We show that for tripartite entanglement approaching a W-state, we calculate the Nash equilibria numerically and show that they coincide with the Pareto-optimal choice where both prisoners cooperate. Upon continuous variation between a W-state and a pure bipartite entangled state, the game is shown to have a surprisingly rich structure. The role of bipartite and tripartite entanglement is explored to explain that structure. As an application, we consider an evolutionary game based on our quantum game with a network of agents on a square lattice with periodic boundary conditions and show that the strategy corresponding to Nash equilibrium completely dominates without placing any restrictions on the initial set of strategies.

Optimal vaccination strategies and rational behaviour in seasonal epidemics.

PubMed

Doutor, Paulo; Rodrigues, Paula; Soares, Maria do Céu; Chalub, Fabio A C C

2016-12-01

We consider a SIRS model with time dependent transmission rate. We assume time dependent vaccination which confers the same immunity as natural infection. We study two types of vaccination strategies: (i) optimal vaccination, in the sense that it minimizes the effort of vaccination in the set of vaccination strategies for which, for any sufficiently small perturbation of the disease free state, the number of infectious individuals is monotonically decreasing; (ii) Nash-equilibria strategies where all individuals simultaneously minimize the joint risk of vaccination versus the risk of the disease. The former case corresponds to an optimal solution for mandatory vaccinations, while the second corresponds to the equilibrium to be expected if vaccination is fully voluntary. We are able to show the existence of both optimal and Nash strategies in a general setting. In general, these strategies will not be functions but Radon measures. For specific forms of the transmission rate, we provide explicit formulas for the optimal and the Nash vaccination strategies.

Nash Equilibria in Theory of Reasoned Action

NASA Astrophysics Data System (ADS)

Almeida, Leando; Cruz, José; Ferreira, Helena; Pinto, Alberto Adrego

2009-08-01

Game theory and Decision Theory have been applied to many different areas such as Physics, Economics, Biology, etc. In its application to Psychology, we introduce, in the literature, a Game Theoretical Model of Planned Behavior or Reasoned Action by establishing an analogy between two specific theories. In this study we take in account that individual decision-making is an outcome of a process where group decisions can determine individual probabilistic behavior. Using Game Theory concepts, we describe how intentions can be transformed in behavior and according to the Nash Equilibrium, this process will correspond to the best individual decision/response taking in account the collective response. This analysis can be extended to several examples based in the Game Theoretical Model of Planned Behavior or Reasoned Action.

Game-theoretic equilibrium analysis applications to deregulated electricity markets

NASA Astrophysics Data System (ADS)

Joung, Manho

This dissertation examines game-theoretic equilibrium analysis applications to deregulated electricity markets. In particular, three specific applications are discussed: analyzing the competitive effects of ownership of financial transmission rights, developing a dynamic game model considering the ramp rate constraints of generators, and analyzing strategic behavior in electricity capacity markets. In the financial transmission right application, an investigation is made of how generators' ownership of financial transmission rights may influence the effects of the transmission lines on competition. In the second application, the ramp rate constraints of generators are explicitly modeled using a dynamic game framework, and the equilibrium is characterized as the Markov perfect equilibrium. Finally, the strategic behavior of market participants in electricity capacity markets is analyzed and it is shown that the market participants may exaggerate their available capacity in a Nash equilibrium. It is also shown that the more conservative the independent system operator's capacity procurement, the higher the risk of exaggerated capacity offers.

Power-efficient distributed resource allocation under goodput QoS constraints for heterogeneous networks

NASA Astrophysics Data System (ADS)

Andreotti, Riccardo; Del Fiorentino, Paolo; Giannetti, Filippo; Lottici, Vincenzo

2016-12-01

This work proposes a distributed resource allocation (RA) algorithm for packet bit-interleaved coded OFDM transmissions in the uplink of heterogeneous networks (HetNets), characterized by small cells deployed over a macrocell area and sharing the same band. Every user allocates its transmission resources, i.e., bits per active subcarrier, coding rate, and power per subcarrier, to minimize the power consumption while both guaranteeing a target quality of service (QoS) and accounting for the interference inflicted by other users transmitting over the same band. The QoS consists of the number of information bits delivered in error-free packets per unit of time, or goodput (GP), estimated at the transmitter by resorting to an efficient effective SNR mapping technique. First, the RA problem is solved in the point-to-point case, thus deriving an approximate yet accurate closed-form expression for the power allocation (PA). Then, the interference-limited HetNet case is examined, where the RA problem is described as a non-cooperative game, providing a solution in terms of generalized Nash equilibrium. Thanks to the closed-form of the PA, the solution analysis is based on the best response concept. Hence, sufficient conditions for existence and uniqueness of the solution are analytically derived, along with a distributed algorithm capable of reaching the game equilibrium.

Concordance of Interests in Dynamic Models of Social Partnership in the System of Continuing Professional Education

ERIC Educational Resources Information Center

Tarasenko, Larissa V.; Ougolnitsky, Guennady A.; Usov, Anatoly B.; Vaskov, Maksim A.; Kirik, Vladimir A.; Astoyanz, Margarita S.; Angel, Olga Y.

2016-01-01

A dynamic game theoretic model of concordance of interests in the process of social partnership in the system of continuing professional education is proposed. Non-cooperative, cooperative, and hierarchical setups are examined. Analytical solution for a linear state version of the model is provided. Nash equilibrium algorithms (for non-cooperative…

Systems Level Metabolic Phenotype of Methotrexate Administration in the Context of Non-alcoholic Steatohepatitis in the Rat

PubMed Central

Kyriakides, Michael; Hardwick, Rhiannon N.; Jin, Zhaosheng; Goedken, Michael J.; Holmes, Elaine; Cherrington, Nathan J.; Coen, Muireann

2014-01-01

Adverse drug reactions (ADRs) represent a significant clinical challenge with respect to patient morbidity and mortality. We investigated the hepatotoxicity and systems level metabolic phenotype of methotrexate (MTX) in the context of a prevalent liver disease; non-alcoholic steatohepatitis (NASH). A nuclear magnetic resonance spectroscopic-based metabonomic approach was employed to analyze the metabolic consequences of MTX (0, 10, 40, and 100 mg/kg) in the urine and liver of healthy rats (control diet) and in a model of NASH (methionine-choline deficient diet). Histopathological analysis confirmed baseline (0 mg/kg) liver necrosis, liver inflammation, and lipid accumulation in the NASH model. Administration of MTX (40 and 100 mg/kg) led to liver necrosis in the control cohort, whereas the NASH cohort also displayed biliary hyperplasia and liver fibrosis (100 mg/kg), providing evidence of the synergistic effect of MTX and NASH. The complementary hepatic and urinary metabolic phenotypes of the NASH model, at baseline, revealed perturbation of multiple metabolites associated with oxidative and energetic stress, and folate homeostasis. Administration of MTX in both diet cohorts showed dose-dependent metabolic consequences affecting gut microbial, energy, nucleobase, nucleoside, and folate metabolism. Furthermore, a unique panel of metabolic changes reflective of the synergistic effect of MTX and NASH was identified, including the elevation of hepatic phenylalanine, urocanate, acetate, and both urinary and hepatic formiminoglutamic acid. This systems level metabonomic analysis of the hepatotoxicity of MTX in the context of NASH provided novel mechanistic insight of potential wider clinical relevance for further understanding the role of liver pathology as a risk factor for ADRs. PMID:25145655

Studies in the Theory of Quantum Games

NASA Astrophysics Data System (ADS)

Iqbal, Azhar

2005-03-01

Theory of quantum games is a new area of investigation that has gone through rapid development during the last few years. Initial motivation for playing games, in the quantum world, comes from the possibility of re-formulating quantum communication protocols, and algorithms, in terms of games between quantum and classical players. The possibility led to the view that quantum games have a potential to provide helpful insight into working of quantum algorithms, and even in finding new ones. This thesis analyzes and compares some interesting games when played classically and quantum mechanically. A large part of the thesis concerns investigations into a refinement notion of the Nash equilibrium concept. The refinement, called an evolutionarily stable strategy (ESS), was originally introduced in 1970s by mathematical biologists to model an evolving population using techniques borrowed from game theory. Analysis is developed around a situation when quantization changes ESSs without affecting corresponding Nash equilibria. Effects of quantization on solution-concepts other than Nash equilibrium are presented and discussed. For this purpose the notions of value of coalition, backwards-induction outcome, and subgame-perfect outcome are selected. Repeated games are known to have different information structure than one-shot games. Investigation is presented into a possible way where quantization changes the outcome of a repeated game. Lastly, two new suggestions are put forward to play quantum versions of classical matrix games. The first one uses the association of De Broglie's waves, with travelling material objects, as a resource for playing a quantum game. The second suggestion concerns an EPR type setting exploiting directly the correlations in Bell's inequalities to play a bi-matrix game.

Strategic sophistication of individuals and teams. Experimental evidence

PubMed Central

Sutter, Matthias; Czermak, Simon; Feri, Francesco

2013-01-01

Many important decisions require strategic sophistication. We examine experimentally whether teams act more strategically than individuals. We let individuals and teams make choices in simple games, and also elicit first- and second-order beliefs. We find that teams play the Nash equilibrium strategy significantly more often, and their choices are more often a best response to stated first order beliefs. Distributional preferences make equilibrium play less likely. Using a mixture model, the estimated probability to play strategically is 62% for teams, but only 40% for individuals. A model of noisy introspection reveals that teams differ from individuals in higher order beliefs. PMID:24926100

Game among interdependent networks: The impact of rationality on system robustness

NASA Astrophysics Data System (ADS)

Fan, Yuhang; Cao, Gongze; He, Shibo; Chen, Jiming; Sun, Youxian

2016-12-01

Many real-world systems are composed of interdependent networks that rely on one another. Such networks are typically designed and operated by different entities, who aim at maximizing their own payoffs. There exists a game among these entities when designing their own networks. In this paper, we study the game investigating how the rational behaviors of entities impact the system robustness. We first introduce a mathematical model to quantify the interacting payoffs among varying entities. Then we study the Nash equilibrium of the game and compare it with the optimal social welfare. We reveal that the cooperation among different entities can be reached to maximize the social welfare in continuous game only when the average degree of each network is constant. Therefore, the huge gap between Nash equilibrium and optimal social welfare generally exists. The rationality of entities makes the system inherently deficient and even renders it extremely vulnerable in some cases. We analyze our model for two concrete systems with continuous strategy space and discrete strategy space, respectively. Furthermore, we uncover some factors (such as weakening coupled strength of interdependent networks, designing a suitable topology dependence of the system) that help reduce the gap and the system vulnerability.

A Bidding Methodology by Nash Equilibrium for Finite Generators Participating in Imperfect Electricity Markets

NASA Astrophysics Data System (ADS)

Satyaramesh, P. V.

2014-01-01

This paper presents an application of finite n-person non-cooperative game theory for analyzing bidding strategies of generators in a deregulated energy marketplace with Pool Bilateral contracts so as to maximize their net profits. A new methodology to build bidding methodology for generators participating in oligopoly electricity market has been proposed in this paper. It is assumed that each generator bids a supply function. This methodology finds out the coefficients in the supply function of generators in order to maximize benefits in an environment of competing rival bidders. A natural choice for developing strategies is Nash Equilibrium (NE) model incorporating mixed strategies, for solving the bidding problem of electrical market. Associated optimal profits are evaluated for a combination of set of pure strategies of bidding of generators, and payoff matrix has been constructed. The optimal payoff is calculated by using NE. An attempt has also been made to minimize the gap between the optimal payoff and the payoff obtained by a possible mixed strategies combination. The algorithm is coded in MATLAB. A numerical example is used to illustrate the essential features of the approach and the results are proved to be the optimal values.

Answer Sets in a Fuzzy Equilibrium Logic

NASA Astrophysics Data System (ADS)

Schockaert, Steven; Janssen, Jeroen; Vermeir, Dirk; de Cock, Martine

Since its introduction, answer set programming has been generalized in many directions, to cater to the needs of real-world applications. As one of the most general “classical” approaches, answer sets of arbitrary propositional theories can be defined as models in the equilibrium logic of Pearce. Fuzzy answer set programming, on the other hand, extends answer set programming with the capability of modeling continuous systems. In this paper, we combine the expressiveness of both approaches, and define answer sets of arbitrary fuzzy propositional theories as models in a fuzzification of equilibrium logic. We show that the resulting notion of answer set is compatible with existing definitions, when the syntactic restrictions of the corresponding approaches are met. We furthermore locate the complexity of the main reasoning tasks at the second level of the polynomial hierarchy. Finally, as an illustration of its modeling power, we show how fuzzy equilibrium logic can be used to find strong Nash equilibria.

Efficiency and formalism of quantum games

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, C.F.; Johnson, Neil F.

We show that quantum games are more efficient than classical games and provide a saturated upper bound for this efficiency. We also demonstrate that the set of finite classical games is a strict subset of the set of finite quantum games. Our analysis is based on a rigorous formulation of quantum games, from which quantum versions of the minimax theorem and the Nash equilibrium theorem can be deduced.

The ESS and replicator equation in matrix games under time constraints.

PubMed

Garay, József; Cressman, Ross; Móri, Tamás F; Varga, Tamás

2018-06-01

Recently, we introduced the class of matrix games under time constraints and characterized the concept of (monomorphic) evolutionarily stable strategy (ESS) in them. We are now interested in how the ESS is related to the existence and stability of equilibria for polymorphic populations. We point out that, although the ESS may no longer be a polymorphic equilibrium, there is a connection between them. Specifically, the polymorphic state at which the average strategy of the active individuals in the population is equal to the ESS is an equilibrium of the polymorphic model. Moreover, in the case when there are only two pure strategies, a polymorphic equilibrium is locally asymptotically stable under the replicator equation for the pure-strategy polymorphic model if and only if it corresponds to an ESS. Finally, we prove that a strict Nash equilibrium is a pure-strategy ESS that is a locally asymptotically stable equilibrium of the replicator equation in n-strategy time-constrained matrix games.

The rock-paper-scissors game

NASA Astrophysics Data System (ADS)

Zhou, Hai-Jun

2016-04-01

Rock-Paper-Scissors (RPS), a game of cyclic dominance, is not merely a popular children's game but also a basic model system for studying decision-making in non-cooperative strategic interactions. Aimed at students of physics with no background in game theory, this paper introduces the concepts of Nash equilibrium and evolutionarily stable strategy, and reviews some recent theoretical and empirical efforts on the non-equilibrium properties of the iterated RPS, including collective cycling, conditional response patterns and microscopic mechanisms that facilitate cooperation. We also introduce several dynamical processes to illustrate the applications of RPS as a simplified model of species competition in ecological systems and price cycling in economic markets.

Dynamic Power Distribution System Management With a Locally Connected Communication Network

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dall-Anese, Emiliano; Zhang, Kaiqing; Basar, Tamer

Coordinated optimization and control of distribution-level assets can enable a reliable and optimal integration of massive amount of distributed energy resources (DERs) and facilitate distribution system management (DSM). Accordingly, the objective is to coordinate the power injection at the DERs to maintain certain quantities across the network, e.g., voltage magnitude, line flows, or line losses, to be close to a desired profile. By and large, the performance of the DSM algorithms has been challenged by two factors: i) the possibly non-strongly connected communication network over DERs that hinders the coordination; ii) the dynamics of the real system caused by themore » DERs with heterogeneous capabilities, time-varying operating conditions, and real-time measurement mismatches. In this paper, we investigate the modeling and algorithm design and analysis with the consideration of these two factors. In particular, a game theoretic characterization is first proposed to account for a locally connected communication network over DERs, along with the analysis of the existence and uniqueness of the Nash equilibrium (NE) therein. To achieve the equilibrium in a distributed fashion, a projected-gradient-based asynchronous DSM algorithm is then advocated. The algorithm performance, including the convergence speed and the tracking error, is analytically guaranteed under the dynamic setting. Extensive numerical tests on both synthetic and realistic cases corroborate the analytical results derived.« less

Characterizing the Nash equilibria of three-player Bayesian quantum games

NASA Astrophysics Data System (ADS)

Solmeyer, Neal; Balu, Radhakrishnan

2017-05-01

Quantum games with incomplete information can be studied within a Bayesian framework. We analyze games quantized within the EWL framework [Eisert, Wilkens, and Lewenstein, Phys Rev. Lett. 83, 3077 (1999)]. We solve for the Nash equilibria of a variety of two-player quantum games and compare the results to the solutions of the corresponding classical games. We then analyze Bayesian games where there is uncertainty about the player types in two-player conflicting interest games. The solutions to the Bayesian games are found to have a phase diagram-like structure where different equilibria exist in different parameter regions, depending both on the amount of uncertainty and the degree of entanglement. We find that in games where a Pareto-optimal solution is not a Nash equilibrium, it is possible for the quantized game to have an advantage over the classical version. In addition, we analyze the behavior of the solutions as the strategy choices approach an unrestricted operation. We find that some games have a continuum of solutions, bounded by the solutions of a simpler restricted game. A deeper understanding of Bayesian quantum game theory could lead to novel quantum applications in a multi-agent setting.

On 2- and 3-person games on polyhedral sets

DOE Office of Scientific and Technical Information (OSTI.GOV)

Belenky, A.S.

1994-12-31

Special classes of 3 person games are considered where the sets of players` allowable strategies are polyhedral and the payoff functions are defined as maxima, on a polyhedral set, of certain kind of sums of linear and bilinear functions. Necessary and sufficient conditions, which are easy to verify, for a Nash point in these games are established, and a finite method, based on these conditions, for calculating Nash points is proposed. It is shown that the game serves as a generalization of a model for a problem of waste products evacuation from a territory. The method makes it possible tomore » reduce calculation of a Nash point to solving some linear and quadratic programming problems formulated on the basis of the original 3-person game. A class of 2-person games on connected polyhedral sets is considered, with the payoff function being a sum of two linear functions and one bilinear function. Necessary and sufficient conditions are established for the min-max, the max-min, and for a certain equilibrium. It is shown that the corresponding points can be calculated from auxiliary linear programming problems formulated on the basis of the master game.« less

A longitudinal study of whole body, tissue, and cellular physiology in a mouse model of fibrosing NASH with high fidelity to the human condition.

PubMed

Krishnan, Anuradha; Abdullah, Tasduq Sheikh; Mounajjed, Taofic; Hartono, Stella; McConico, Andrea; White, Thomas; LeBrasseur, Nathan; Lanza, Ian; Nair, Sreekumaran; Gores, Gregory; Charlton, Michael

2017-06-01

The sequence of events that lead to inflammation and fibrosing nonalcoholic steatohepatitis (NASH) is incompletely understood. Hence, we investigated the chronology of whole body, tissue, and cellular events that occur during the evolution of diet-induced NASH. Male C57Bl/6 mice were assigned to a fast-food (FF; high calorie, high cholesterol, high fructose) or standard-chow (SC) diet over a period of 36 wk. Liver histology, body composition, mitochondrial respiration, metabolic rate, gene expression, and hepatic lipid content were analyzed. Insulin resistance [homeostasis model assessment-insulin resistance (HOMA-IR)] increased 10-fold after 4 wk. Fibrosing NASH was fully established by 16 wk. Total hepatic lipids increased by 4 wk and remained two- to threefold increased throughout. Hepatic triglycerides declined from sixfold increase at 8 wk to threefold increase by 36 wk. In contrast, hepatic cholesterol levels steadily increased from baseline at 8 wk to twofold by 36 wk. The hepatic immune cell population altered over time with macrophages persisting beyond 16 wk. Mitochondrial oxygen flux rates of FF mice diet were uniformly lower with all the tested substrates (13-276 pmol·s -1 ·ml -1 per unit citrate synthase) than SC mice (17-394 pmol·s -1 ·ml -1 per unit citrate synthase) and was accompanied by decreased mitochondrial:nuclear gene copy number ratios after 4 wk. Metabolic rate was lower in FF mice. Mitochondrial glutathione was significantly decreased at 24 wk in FF mice. Expression of dismutases and catalase was also decreased in FF mice. The evolution of NASH in the FF diet-induced model is multiphasic, particularly in terms of hepatic lipid composition. Insulin resistance precedes hepatic inflammation and fibrosis. Mitochondrial dysfunction and depletion occur after the histological features of NASH are apparent. Collectively, these observations provide a unique overview of the sequence of changes that coevolve with the histological evolution of NASH. NEW & NOTEWORTHY This study demonstrates in a first of kind longitudinal analysis, the evolution of nonalcoholic steatohepatitis (NASH) on a fast-food diet-induced model. Key findings include 1 ) hepatic lipid composition changes in a multiphasic fashion as NASH evolves; 2 ) insulin resistance precedes hepatic inflammation and fibrosis, answering a longstanding chicken-and-egg question regarding the relationship of insulin resistance to liver histology in NASH; and 3 ) mitochondrial dysfunction and depletion occur after the histological features of NASH are apparent. Copyright © 2017 the American Physiological Society.

Accelerating Multiagent Reinforcement Learning by Equilibrium Transfer.

PubMed

Hu, Yujing; Gao, Yang; An, Bo

2015-07-01

An important approach in multiagent reinforcement learning (MARL) is equilibrium-based MARL, which adopts equilibrium solution concepts in game theory and requires agents to play equilibrium strategies at each state. However, most existing equilibrium-based MARL algorithms cannot scale due to a large number of computationally expensive equilibrium computations (e.g., computing Nash equilibria is PPAD-hard) during learning. For the first time, this paper finds that during the learning process of equilibrium-based MARL, the one-shot games corresponding to each state's successive visits often have the same or similar equilibria (for some states more than 90% of games corresponding to successive visits have similar equilibria). Inspired by this observation, this paper proposes to use equilibrium transfer to accelerate equilibrium-based MARL. The key idea of equilibrium transfer is to reuse previously computed equilibria when each agent has a small incentive to deviate. By introducing transfer loss and transfer condition, a novel framework called equilibrium transfer-based MARL is proposed. We prove that although equilibrium transfer brings transfer loss, equilibrium-based MARL algorithms can still converge to an equilibrium policy under certain assumptions. Experimental results in widely used benchmarks (e.g., grid world game, soccer game, and wall game) show that the proposed framework: 1) not only significantly accelerates equilibrium-based MARL (up to 96.7% reduction in learning time), but also achieves higher average rewards than algorithms without equilibrium transfer and 2) scales significantly better than algorithms without equilibrium transfer when the state/action space grows and the number of agents increases.

Algebraic Riccati equations in zero-sum differential games

NASA Technical Reports Server (NTRS)

Johnson, T. L.; Chao, A.

1974-01-01

The procedure for finding the closed-loop Nash equilibrium solution of two-player zero-sum linear time-invariant differential games with quadratic performance criteria and classical information pattern may be reduced in most cases to the solution of an algebraic Riccati equation. Based on the results obtained by Willems, necessary and sufficient conditions for existence of solutions to these equations are derived, and explicit conditions for a scalar example are given.

The Evolution of Generosity in the Ultimatum Game

PubMed Central

Hintze, Arend; Hertwig, Ralph

2016-01-01

When humans fail to make optimal decisions in strategic games and economic gambles, researchers typically try to explain why that behaviour is biased. To this end, they search for mechanisms that cause human behaviour to deviate from what seems to be the rational optimum. But perhaps human behaviour is not biased; perhaps research assumptions about the optimality of strategies are incomplete. In the one-shot anonymous symmetric ultimatum game (UG), humans fail to play optimally as defined by the Nash equilibrium. However, the distinction between kin and non-kin—with kin detection being a key evolutionary adaption—is often neglected when deriving the “optimal” strategy. We computationally evolved strategies in the UG that were equipped with an evolvable probability to discern kin from non-kin. When an opponent was not kin, agents evolved strategies that were similar to those used by humans. We therefore conclude that the strategy humans play is not irrational. The deviation between behaviour and the Nash equilibrium may rather be attributable to key evolutionary adaptations, such as kin detection. Our findings further suggest that social preference models are likely to capture mechanisms that permit people to play optimally in an evolutionary context. Once this context is taken into account, human behaviour no longer appears irrational. PMID:27677330

The Evolution of Generosity in the Ultimatum Game.

PubMed

Hintze, Arend; Hertwig, Ralph

2016-09-28

When humans fail to make optimal decisions in strategic games and economic gambles, researchers typically try to explain why that behaviour is biased. To this end, they search for mechanisms that cause human behaviour to deviate from what seems to be the rational optimum. But perhaps human behaviour is not biased; perhaps research assumptions about the optimality of strategies are incomplete. In the one-shot anonymous symmetric ultimatum game (UG), humans fail to play optimally as defined by the Nash equilibrium. However, the distinction between kin and non-kin-with kin detection being a key evolutionary adaption-is often neglected when deriving the "optimal" strategy. We computationally evolved strategies in the UG that were equipped with an evolvable probability to discern kin from non-kin. When an opponent was not kin, agents evolved strategies that were similar to those used by humans. We therefore conclude that the strategy humans play is not irrational. The deviation between behaviour and the Nash equilibrium may rather be attributable to key evolutionary adaptations, such as kin detection. Our findings further suggest that social preference models are likely to capture mechanisms that permit people to play optimally in an evolutionary context. Once this context is taken into account, human behaviour no longer appears irrational.

Bounded rationality in volunteering public goods games.

PubMed

Xu, Zhaojin; Wang, Zhen; Zhang, Lianzhong

2010-05-07

It is one of the fundamental problems in biology and social sciences how to maintain high levels of cooperation among selfish individuals. Theorists present an effective mechanism promoting cooperation by allowing for voluntary participation in public goods games. But Nash's theory predicts that no one can do better or worse than loners (players unwilling to join the public goods game) in the long run, and that the frequency of participants is independent of loners' payoff. In this paper, we introduce a degree of rationality and investigate the model by means of an approximate best response dynamics. Our research shows that the payoffs of the loners have a significant effect in anonymous voluntary public goods games by this introduction and that the dynamics will drive the system to a fixed point, which is different from the Nash equilibrium. In addition, we also qualitatively explain the existing experimental results. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

Bistability of Evolutionary Stable Vaccination Strategies in the Reinfection SIRI Model.

PubMed

Martins, José; Pinto, Alberto

2017-04-01

We use the reinfection SIRI epidemiological model to analyze the impact of education programs and vaccine scares on individuals decisions to vaccinate or not. The presence of the reinfection provokes the novelty of the existence of three Nash equilibria for the same level of the morbidity relative risk instead of a single Nash equilibrium as occurs in the SIR model studied by Bauch and Earn (PNAS 101:13391-13394, 2004). The existence of three Nash equilibria, with two of them being evolutionary stable, introduces two scenarios with relevant and opposite features for the same level of the morbidity relative risk: the low-vaccination scenario corresponding to the evolutionary stable vaccination strategy, where individuals will vaccinate with a low probability; and the high-vaccination scenario corresponding to the evolutionary stable vaccination strategy, where individuals will vaccinate with a high probability. We introduce the evolutionary vaccination dynamics for the SIRI model and we prove that it is bistable. The bistability of the evolutionary dynamics indicates that the damage provoked by false scares on the vaccination perceived morbidity risks can be much higher and much more persistent than in the SIR model. Furthermore, the vaccination education programs to be efficient they need to implement a mechanism to suddenly increase the vaccination coverage level.

Optimal generator bidding strategies for power and ancillary services

NASA Astrophysics Data System (ADS)

Morinec, Allen G.

As the electric power industry transitions to a deregulated market, power transactions are made upon price rather than cost. Generator companies are interested in maximizing their profits rather than overall system efficiency. A method to equitably compensate generation providers for real power, and ancillary services such as reactive power and spinning reserve, will ensure a competitive market with an adequate number of suppliers. Optimizing the generation product mix during bidding is necessary to maximize a generator company's profits. The objective of this research work is to determine and formulate appropriate optimal bidding strategies for a generation company in both the energy and ancillary services markets. These strategies should incorporate the capability curves of their generators as constraints to define the optimal product mix and price offered in the day-ahead and real time spot markets. In order to achieve such a goal, a two-player model was composed to simulate market auctions for power generation. A dynamic game methodology was developed to identify Nash Equilibria and Mixed-Strategy Nash Equilibria solutions as optimal generation bidding strategies for two-player non-cooperative variable-sum matrix games with incomplete information. These games integrated the generation product mix of real power, reactive power, and spinning reserve with the generators's capability curves as constraints. The research includes simulations of market auctions, where strategies were tested for generators with different unit constraints, costs, types of competitors, strategies, and demand levels. Studies on the capability of large hydrogen cooled synchronous generators were utilized to derive useful equations that define the exact shape of the capability curve from the intersections of the arcs defined by the centers and radial vectors of the rotor, stator, and steady-state stability limits. The available reactive reserve and spinning reserve were calculated given a generator operating point in the P-Q plane. Four computer programs were developed to automatically perform the market auction simulations using the equal incremental cost rule. The software calculates the payoffs for the two competing competitors, dispatches six generators, and allocates ancillary services for 64 combinations of bidding strategies, three levels of system demand, and three different types of competitors. Matrix Game theory was utilized to calculate Nash Equilibrium solutions and mixed-strategy Nash solutions as the optimal generator bidding strategies. A method to incorporate ancillary services into the generation bidding strategy, to assure an adequate supply of ancillary services, and to allocate these necessary resources to the on-line units was devised. The optimal generator bid strategy in a power auction was shown to be the Nash Equilibrium solution found in two-player variable-sum matrix games.

Stability of Mixed-Strategy-Based Iterative Logit Quantal Response Dynamics in Game Theory

PubMed Central

Zhuang, Qian; Di, Zengru; Wu, Jinshan

2014-01-01

Using the Logit quantal response form as the response function in each step, the original definition of static quantal response equilibrium (QRE) is extended into an iterative evolution process. QREs remain as the fixed points of the dynamic process. However, depending on whether such fixed points are the long-term solutions of the dynamic process, they can be classified into stable (SQREs) and unstable (USQREs) equilibriums. This extension resembles the extension from static Nash equilibriums (NEs) to evolutionary stable solutions in the framework of evolutionary game theory. The relation between SQREs and other solution concepts of games, including NEs and QREs, is discussed. Using experimental data from other published papers, we perform a preliminary comparison between SQREs, NEs, QREs and the observed behavioral outcomes of those experiments. For certain games, we determine that SQREs have better predictive power than QREs and NEs. PMID:25157502

Access point selection game with mobile users using correlated equilibrium.

PubMed

Sohn, Insoo

2015-01-01

One of the most important issues in wireless local area network (WLAN) systems with multiple access points (APs) is the AP selection problem. Game theory is a mathematical tool used to analyze the interactions in multiplayer systems and has been applied to various problems in wireless networks. Correlated equilibrium (CE) is one of the powerful game theory solution concepts, which is more general than the Nash equilibrium for analyzing the interactions in multiplayer mixed strategy games. A game-theoretic formulation of the AP selection problem with mobile users is presented using a novel scheme based on a regret-based learning procedure. Through convergence analysis, we show that the joint actions based on the proposed algorithm achieve CE. Simulation results illustrate that the proposed algorithm is effective in a realistic WLAN environment with user mobility and achieves maximum system throughput based on the game-theoretic formulation.

Access Point Selection Game with Mobile Users Using Correlated Equilibrium

PubMed Central

Sohn, Insoo

2015-01-01

One of the most important issues in wireless local area network (WLAN) systems with multiple access points (APs) is the AP selection problem. Game theory is a mathematical tool used to analyze the interactions in multiplayer systems and has been applied to various problems in wireless networks. Correlated equilibrium (CE) is one of the powerful game theory solution concepts, which is more general than the Nash equilibrium for analyzing the interactions in multiplayer mixed strategy games. A game-theoretic formulation of the AP selection problem with mobile users is presented using a novel scheme based on a regret-based learning procedure. Through convergence analysis, we show that the joint actions based on the proposed algorithm achieve CE. Simulation results illustrate that the proposed algorithm is effective in a realistic WLAN environment with user mobility and achieves maximum system throughput based on the game-theoretic formulation. PMID:25785726

Behavioral heterogeneity affects individual performances in experimental and computational lowest unique integer games

NASA Astrophysics Data System (ADS)

Yamada, Takashi

2017-12-01

This study computationally examines (1) how the behaviors of subjects are represented, (2) whether the classification of subjects is related to the scale of the game, and (3) what kind of behavioral models are successful in small-sized lowest unique integer games (LUIGs). In a LUIG, N (>= 3) players submit a positive integer up to M(> 1) and the player choosing the smallest number not chosen by anyone else wins. For this purpose, the author considers four LUIGs with N = {3, 4} and M = {3, 4} and uses the behavioral data obtained in the laboratory experiment by Yamada and Hanaki (Physica A 463, pp. 88–102, 2016). For computational experiments, the author calibrates the parameters of typical learning models for each subject and then pursues round robin competitions. The main findings are in the following: First, the subjects who played not differently from the mixed-strategy Nash equilibrium (MSE) prediction tended to made use of not only their choices but also the game outcomes. Meanwhile those who deviated from the MSE prediction took care of only their choices as the complexity of the game increased. Second, the heterogeneity of player strategies depends on both the number of players (N) and the upper limit (M). Third, when groups consist of different agents like in the earlier laboratory experiment, sticking behavior is quite effective to win.

On a Game of Large-Scale Projects Competition

NASA Astrophysics Data System (ADS)

Nikonov, Oleg I.; Medvedeva, Marina A.

2009-09-01

The paper is devoted to game-theoretical control problems motivated by economic decision making situations arising in realization of large-scale projects, such as designing and putting into operations the new gas or oil pipelines. A non-cooperative two player game is considered with payoff functions of special type for which standard existence theorems and algorithms for searching Nash equilibrium solutions are not applicable. The paper is based on and develops the results obtained in [1]-[5].

Quantum Strategies: Proposal to Experimentally Test a Quantum Economics Protocol

DTIC Science & Technology

2009-04-09

fact that this al- gorithm requires only bipartite entangled states what makes it feasible to implement, and a key focus of a larger program in quantum...passes through what is effectively a huge Mach-Zender fiber-interferometer bounded by the Sagnac loop and PPBS1- is affected by this time-varying...strategy, no matter what the other players do. As we noted above, this means that there is no (classical) correlated equilibrium other than the Nash

Evaluation on Influence of Unstable Primary-Energy Price in a Deregulated Electric Power Market—Analysis based on a simulation model approach—

NASA Astrophysics Data System (ADS)

Maitani, Tatsuyuki; Tezuka, Tetsuo

The electric power market of Japan has been locally monopolized for a long time. But, like many countries, Japan is moving forward with the deregulation of its electric power industry so that any power generation company could sell electric power in the market. The power price, however, will fluctuate inevitably to balance the power supply and demand. A new appropriate market design is indispensable when introducing new market mechanisms in the electric power market to avoid undesirable results of the market. The first stage of deregulation will be the competition between an existing large-scaled power utility and a new power generation company. In this paper we have investigated the wholesale market with competition of these two power companies based on a simulation model approach. Under the competitive situation the effects of exogenous disturbance may bring serious results and we estimated the influence on the market when the price of fossil fuel rises. The conclusion of this study is that several types of Nash equilibriums have been found in the market: the larger the new power generation company becomes, the higher the electricity price under the Nash equilibriums rises. Because of the difference in their structure of generation capacity, the existing large-scaled power utility gets more profit while the new power generation company loses its profit when the price of fossil fuel rises.

Replicator dynamics with turnover of players

NASA Astrophysics Data System (ADS)

Juul, Jeppe; Kianercy, Ardeshir; Bernhardsson, Sebastian; Pigolotti, Simone

2013-08-01

We study adaptive dynamics in games where players abandon the population at a given rate and are replaced by naive players characterized by a prior distribution over the admitted strategies. We demonstrate how such a process leads macroscopically to a variant of the replicator equation, with an additional term accounting for player turnover. We study how Nash equilibria and the dynamics of the system are modified by this additional term for prototypical examples such as the rock-paper-scissors game and different classes of two-action games played between two distinct populations. We conclude by showing how player turnover can account for nontrivial departures from Nash equilibria observed in data from lowest unique bid auctions.

Establishing rational networking using the DL04 quantum secure direct communication protocol

NASA Astrophysics Data System (ADS)

Qin, Huawang; Tang, Wallace K. S.; Tso, Raylin

2018-06-01

The first rational quantum secure direct communication scheme is proposed, in which we use the game theory with incomplete information to model the rational behavior of the participant, and give the strategy space and utility function. The rational participant can get his maximal utility when he performs the protocol faithfully, and then the Nash equilibrium of the protocol can be achieved. Compared to the traditional schemes, our scheme will be more practical in the presence of rational participant.

Green wireless body area nanonetworks: energy management and the game of survival.

PubMed

Misra, Sudip; Islam, Nabiul; Mahapatro, Judhistir; Rodrigues, Joel Jose P C

2014-03-01

In this paper, we envisage the architecture of Green Wireless Body Area Nanonetwork (GBAN) as a collection of nanodevices, in which each device is capable of communicating in both the molecular and wireless electromagnetic communication modes. The term green refers to the fact that the nanodevices in such a network can harvest energy from their surrounding environment, so that no nanodevice gets old solely due to the reasons attributed to energy depletion. However, the residual energy of a nanodevice can deplete substantially with the lapse of time, if the rate of energy consumption is not comparable with the rate of energy harvesting. It is observed that the rate of energy harvesting is nonlinear and sporadic in nature. So, the management of energy of the nanodevices is fundamentally important. We specifically address this problem in a ubiquitous healthcare monitoring scenario and formulate it as a cooperative Nash Bargaining game. The optimal strategy obtained from the Nash equilibrium solution provides improved network performance in terms of throughput and delay.

Imitative and best response behaviors in a nonlinear Cournotian setting

NASA Astrophysics Data System (ADS)

Cerboni Baiardi, Lorenzo; Naimzada, Ahmad K.

2018-05-01

We consider the competition among quantity setting players in a deterministic nonlinear oligopoly framework characterized by an isoelastic demand curve. Players are characterized by having heterogeneous decisional mechanisms to set their outputs: some players are imitators, while the remaining others adopt a rational-like rule according to which their past decisions are adjusted towards their static expectation best response. The Cournot-Nash production level is a stationary state of our model together with a further production level that can be interpreted as the competitive outcome in case only imitators are present. We found that both the number of players and the relative fraction of imitators influence stability of the Cournot-Nash equilibrium with an ambiguous role, and double instability thresholds may be observed. Global analysis shows that a wide variety of complex dynamic scenarios emerge. Chaotic trajectories as well as multi-stabilities, where different attractors coexist, are robust phenomena that can be observed for a wide spectrum of parameter sets.

Social Interactions under Incomplete Information: Games, Equilibria, and Expectations

NASA Astrophysics Data System (ADS)

Yang, Chao

My dissertation research investigates interactions of agents' behaviors through social networks when some information is not shared publicly, focusing on solutions to a series of challenging problems in empirical research, including heterogeneous expectations and multiple equilibria. The first chapter, "Social Interactions under Incomplete Information with Heterogeneous Expectations", extends the current literature in social interactions by devising econometric models and estimation tools with private information in not only the idiosyncratic shocks but also some exogenous covariates. For example, when analyzing peer effects in class performances, it was previously assumed that all control variables, including individual IQ and SAT scores, are known to the whole class, which is unrealistic. This chapter allows such exogenous variables to be private information and models agents' behaviors as outcomes of a Bayesian Nash Equilibrium in an incomplete information game. The distribution of equilibrium outcomes can be described by the equilibrium conditional expectations, which is unique when the parameters are within a reasonable range according to the contraction mapping theorem in function spaces. The equilibrium conditional expectations are heterogeneous in both exogenous characteristics and the private information, which makes estimation in this model more demanding than in previous ones. This problem is solved in a computationally efficient way by combining the quadrature method and the nested fixed point maximum likelihood estimation. In Monte Carlo experiments, if some exogenous characteristics are private information and the model is estimated under the mis-specified hypothesis that they are known to the public, estimates will be biased. Applying this model to municipal public spending in North Carolina, significant negative correlations between contiguous municipalities are found, showing free-riding effects. The Second chapter "A Tobit Model with Social Interactions under Incomplete Information", is an application of the first chapter to censored outcomes, corresponding to the situation when agents" behaviors are subjected to some binding restrictions. In an interesting empirical analysis for property tax rates set by North Carolina municipal governments, it is found that there is a significant positive correlation among near-by municipalities. Additionally, some private information about its own residents is used by a municipal government to predict others' tax rates, which enriches current empirical work about tax competition. The third chapter, "Social Interactions under Incomplete Information with Multiple Equilibria", extends the first chapter by investigating effective estimation methods when the condition for a unique equilibrium may not be satisfied. With multiple equilibria, the previous model is incomplete due to the unobservable equilibrium selection. Neither conventional likelihoods nor moment conditions can be used to estimate parameters without further specifications. Although there are some solutions to this issue in the current literature, they are based on strong assumptions such as agents with the same observable characteristics play the same strategy. This paper relaxes those assumptions and extends the all-solution method used to estimate discrete choice games to a setting with both discrete and continuous choices, bounded and unbounded outcomes, and a general form of incomplete information, where the existence of a pure strategy equilibrium has been an open question for a long time. By the use of differential topology and functional analysis, it is found that when all exogenous characteristics are public information, there are a finite number of equilibria. With privately known exogenous characteristics, the equilbria can be represented by a compact set in a Banach space and be approximated by a finite set. As a result, a finite-state probability mass function can be used to specify a probability measure for equilibrium selection, which completes the model. From Monte Carlo experiments about two types of binary choice models, it is found that assuming equilibrium uniqueness can bring in estimation biases when the true value of interaction intensity is large and there are multiple equilibria in the data generating process.

Towards understanding the guessing game: a dynamical systems’ perspective

NASA Astrophysics Data System (ADS)

Reimann, Stefan

2004-08-01

The so-called “Guessing Game” or α-Beauty Contest serves as a paradigmatic conceptual framework for competitive price formation on financial markets beyond traditional equilibrium finance. It highlights features that are reasonable to consider when dealing with price formation on real markets. Nonetheless this game is still poorly understood. We propose a model which is essentially based on two assumptions: (1) players consider intervals rather than exact numbers to cope with incomplete knowledge and (2) players iteratively update their recent guesses. It provides an explanation for typical patterns observed in real data, such as the strict positivity of outcomes in the 1-shot setting, the skew background distribution of guessed numbers, as well as the polynomial convergence towards the game-theoretic Nash equilibrium in the iterative setting.

Spectrum sharing in cognitive radio networks--an auction-based approach.

PubMed

Wang, Xinbing; Li, Zheng; Xu, Pengchao; Xu, Youyun; Gao, Xinbo; Chen, Hsiao-Hwa

2010-06-01

Cognitive radio is emerging as a promising technique to improve the utilization of the radio frequency spectrum. In this paper, we consider the problem of spectrum sharing among primary (or "licensed") users (PUs) and secondary (or "unlicensed") users (SUs). We formulate the problem based on bandwidth auction, in which each SU makes a bid for the amount of spectrum and each PU may assign the spectrum among the SUs by itself according to the information from the SUs without degrading its own performance. We show that the auction is a noncooperative game and that Nash equilibrium (NE) can be its solution. We first consider a single-PU network to investigate the existence and uniqueness of the NE and further discuss the fairness among the SUs under given conditions. Then, we present a dynamic updating algorithm in which each SU achieves NE in a distributed manner. The stability condition of the dynamic behavior for this spectrum-sharing scheme is studied. The discussion is generalized to the case in which there are multiple PUs in the network, where the properties of the NE are shown under appropriate conditions. Simulations were used to evaluate the system performance and verify the effectiveness of the proposed algorithm.

Game Theory and Social Psychology: Conformity Games

NASA Astrophysics Data System (ADS)

Alessio, Danielle; Kilgour, D. Marc

2011-11-01

Game models can contribute to understanding of how social biases and pressures to conform can lead to puzzling behaviour in social groups. A model of the psychological biases false uniqueness and false consensus is set out. The model predicts the phenomenon of pluralistic ignorance, which is well-studied in social psychology, showing how it arises as a result of the prevalence of false uniqueness and the desire to conform. An efficient method is developed for finding Nash equilibria of the model under certain restrictions.

A stochastic equilibrium model for the North American natural gas market

NASA Astrophysics Data System (ADS)

Zhuang, Jifang

This dissertation is an endeavor in the field of energy modeling for the North American natural gas market using a mixed complementarity formulation combined with the stochastic programming. The genesis of the stochastic equilibrium model presented in this dissertation is the deterministic market equilibrium model developed in [Gabriel, Kiet and Zhuang, 2005]. Based on some improvements that we made to this model, including proving new existence and uniqueness results, we present a multistage stochastic equilibrium model with uncertain demand for the deregulated North American natural gas market using the recourse method of the stochastic programming. The market participants considered by the model are pipeline operators, producers, storage operators, peak gas operators, marketers and consumers. Pipeline operators are described with regulated tariffs but also involve "congestion pricing" as a mechanism to allocate scarce pipeline capacity. Marketers are modeled as Nash-Cournot players in sales to the residential and commercial sectors but price-takers in all other aspects. Consumers are represented by demand functions in the marketers' problem. Producers, storage operators and peak gas operators are price-takers consistent with perfect competition. Also, two types of the natural gas markets are included: the long-term and spot markets. Market participants make both high-level planning decisions (first-stage decisions) in the long-term market and daily operational decisions (recourse decisions) in the spot market subject to their engineering, resource and political constraints, resource constraints as well as market constraints on both the demand and the supply side, so as to simultaneously maximize their expected profits given others' decisions. The model is shown to be an instance of a mixed complementarity problem (MiCP) under minor conditions. The MiCP formulation is derived from applying the Karush-Kuhn-Tucker optimality conditions of the optimization problems faced by the market participants. Some theoretical results regarding the market prices in both markets are shown. We also illustrate the model on a representative, sample network of two production nodes, two consumption nodes with discretely distributed end-user demand and three seasons using four cases.

Stochastic Gain in Population Dynamics

NASA Astrophysics Data System (ADS)

Traulsen, Arne; Röhl, Torsten; Schuster, Heinz Georg

2004-07-01

We introduce an extension of the usual replicator dynamics to adaptive learning rates. We show that a population with a dynamic learning rate can gain an increased average payoff in transient phases and can also exploit external noise, leading the system away from the Nash equilibrium, in a resonancelike fashion. The payoff versus noise curve resembles the signal to noise ratio curve in stochastic resonance. Seen in this broad context, we introduce another mechanism that exploits fluctuations in order to improve properties of the system. Such a mechanism could be of particular interest in economic systems.

Mechanism Design for Multi-slot Ads Auction in Sponsored Search Markets

NASA Astrophysics Data System (ADS)

Deng, Xiaotie; Sun, Yang; Yin, Ming; Zhou, Yunhong

In this paper, we study pricing models for multi-slot advertisements, where advertisers can bid to place links to their sales webpages at one or multiple slots on a webpage, called the multi-slot AD auction problem. We develop and analyze several important mechanisms, including the VCG mechanism for multi-slot ads auction, the optimal social welfare solution, as well as two weighted GSP-like protocols (mixed and hybrid). Furthermore, we consider that forward-looking Nash equilibrium and prove its existence in the weighted GSP-like pricing protocols.

The physician-patient relationship as a game of strategic information transmission.

PubMed

De Jaegher, K; Jegers, M

2001-10-01

We show that the intuition underlying the supplier-induced demand (SID) hypothesis is reflected in the cheap-talk literature from game theory, and in the credence-good literature from the economics of information. Applying these theories, we conclude that a neoclassical version of the SID hypothesis is only relevant for treatment decisions involving an expensive treatment that is equally effective in curing several states, but efficient in curing only some of these states (in that a cheaper treatment is efficient otherwise). For a simple game involving such a treatment decision, we show that a Nash equilibrium exists where the patient is able to constrain the physician in inducing demand, without the market for the potentially induced treatment failing. This equilibrium allows us to derive comparative statistics and welfare results. Copyright 2001 John Wiley & Sons, Ltd.

A new class of problems in the calculus of variations

NASA Astrophysics Data System (ADS)

Ekeland, Ivar; Long, Yiming; Zhou, Qinglong

2013-11-01

This paper investigates an infinite-horizon problem in the one-dimensional calculus of variations, arising from the Ramsey model of endogeneous economic growth. Following Chichilnisky, we introduce an additional term, which models concern for the well-being of future generations. We show that there are no optimal solutions, but that there are equilibrium strateges, i.e. Nash equilibria of the leader-follower game between successive generations. To solve the problem, we approximate the Chichilnisky criterion by a biexponential criterion, we characterize its equilibria by a pair of coupled differential equations of HJB type, and we go to the limit. We find all the equilibrium strategies for the Chichilnisky criterion. The mathematical analysis is difficult because one has to solve an implicit differential equation in the sense of Thom. Our analysis extends earlier work by Ekeland and Lazrak.

Kolkata Paise Restaurant Problem and the Cyclically Fair Norm

NASA Astrophysics Data System (ADS)

Banerjee, Priyodorshi; Mitra, Manipushpak; Mukherjee, Conan

In this paper we revisit the Kolkata Paise Restaurant problem by allowing for a more general (but common) preference of the n customers defined over the set of n restaurants. This generalization allows for the possibility that each pure strategy Nash equilibrium differs from the Pareto efficient allocation. By assuming that n is small and by allowing for mutual interaction across all customers we design strategies to sustain cyclically fair norm as a sub-game perfect equilibrium of the Kolkata Paise Restaurant problem. We have a cyclically fair norm if n strategically different Pareto efficient strategies are sequentially sustained in a way such that each customer gets serviced in all the n restaurants exactly once between periods 1 and n and then again the same process is repeated between periods (n+1) and 2n and so on.

Structure theorems for game trees

PubMed Central

Govindan, Srihari; Wilson, Robert

2002-01-01

Kohlberg and Mertens [Kohlberg, E. & Mertens, J. (1986) Econometrica 54, 1003–1039] proved that the graph of the Nash equilibrium correspondence is homeomorphic to its domain when the domain is the space of payoffs in normal-form games. A counterexample disproves the analog for the equilibrium outcome correspondence over the space of payoffs in extensive-form games, but we prove an analog when the space of behavior strategies is perturbed so that every path in the game tree has nonzero probability. Without such perturbations, the graph is the closure of the union of a finite collection of its subsets, each diffeomorphic to a corresponding path-connected open subset of the space of payoffs. As an application, we construct an algorithm for computing equilibria of an extensive-form game with a perturbed strategy space, and thus approximate equilibria of the unperturbed game. PMID:12060702

Structure theorems for game trees.

PubMed

Govindan, Srihari; Wilson, Robert

2002-06-25

Kohlberg and Mertens [Kohlberg, E. & Mertens, J. (1986) Econometrica 54, 1003-1039] proved that the graph of the Nash equilibrium correspondence is homeomorphic to its domain when the domain is the space of payoffs in normal-form games. A counterexample disproves the analog for the equilibrium outcome correspondence over the space of payoffs in extensive-form games, but we prove an analog when the space of behavior strategies is perturbed so that every path in the game tree has nonzero probability. Without such perturbations, the graph is the closure of the union of a finite collection of its subsets, each diffeomorphic to a corresponding path-connected open subset of the space of payoffs. As an application, we construct an algorithm for computing equilibria of an extensive-form game with a perturbed strategy space, and thus approximate equilibria of the unperturbed game.

Is the Reaction Equilibrium Composition in Non-ideal Mixtures Uniquely Determined by the Initial Composition?

NASA Astrophysics Data System (ADS)

Sefcik, Jan

1998-05-01

Reaction equilibrium can be mathematically described by the equilibrium equation and the reaction equilibrium composition can be calculated by solving this equation. It can be proved by non-elementary thermodynamic arguments that for a generic system with given initial composition, temperature and pressure there is a unique stable equilibrium state corresponding to the global minimum of the Gibbs free energy function. However, when the concept of equilibrium is introduced in undergraduate chemistry and chemical engineering courses, such arguments are generally not accessible. When there is a single reaction equilibrium among mixture components and the components form an ideal mixture, it has been demonstrated by a simple, elegant mathematical argument that there is a unique composition satisfying the equilibrium equation. It has been also suggested that this particular argument extends to non-ideal mixtures by simply incorporating activity coefficients. We show that the argument extension to non-ideal systems is not generally valid. Increasing non-ideality can result in non-monotonicity of the function crucial for the simple uniqueness argument, and only later it leads to non-uniqueness and hence phase separation. The main feature responsible for this is a composition dependence of activity coefficients in non-ideal mixtures.

Galectin-3 and IL-33/ST2 axis roles and interplay in diet-induced steatohepatitis

PubMed Central

Pejnovic, Nada; Jeftic, Ilija; Jovicic, Nemanja; Arsenijevic, Nebojsa; Lukic, Miodrag L

2016-01-01

Immune reactivity and chronic low-grade inflammation (metaflammation) play an important role in the pathogenesis of obesity-associated metabolic disorders, including type 2 diabetes and nonalcoholic fatty liver disease (NAFLD), a spectrum of diseases that include liver steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. Increased adiposity and insulin resistance contribute to the progression from hepatic steatosis to NASH and fibrosis through the development of proinflammatory and profibrotic processes in the liver, including increased hepatic infiltration of innate and adaptive immune cells, altered balance of cytokines and chemokines, increased reactive oxygen species generation and hepatocellular death. Experimental models of dietary-induced NAFLD/NASH in mice on different genetic backgrounds or knockout mice with different immune reactivity are used for elucidating the pathogenesis of NASH and liver fibrosis. Galectin-3 (Gal-3), a unique chimera-type β-galactoside-binding protein of the galectin family has a regulatory role in immunometabolism and fibrogenesis. Mice deficient in Gal-3 develop pronounced adiposity, hyperglycemia and hepatic steatosis, as well as attenuated liver inflammation and fibrosis when fed an obesogenic high-fat diet. Interleukin (IL)-33, a member of the IL-1 cytokine family, mediates its effects through the ST receptor, which is present on immune and nonimmune cells and participates in immunometabolic and fibrotic disorders. Recent evidence, including our own data, suggests a protective role for the IL-33/IL-33R (ST2) signaling pathway in obesity, adipose tissue inflammation and atherosclerosis, but a profibrotic role in NASH development. The link between Gal-3 and soluble ST2 in myocardial fibrosis and heart failure progression has been demonstrated and we have recently shown that Gal-3 and the IL-33/ST2 pathway interact and both have a profibrotic role in diet-induced NASH. This review discusses the current evidence on the roles of Gal-3 and the IL-33/ST2 pathway and their interplay in obesity-associated hepatic inflammation and fibrogenesis that may be of interest in the development of therapeutic interventions to prevent and/or reverse obesity-associated hepatic inflammation and fibrosis. PMID:27956794

Efficient Nash Equilibrium Resource Allocation Based on Game Theory Mechanism in Cloud Computing by Using Auction

PubMed Central

Nezarat, Amin; Dastghaibifard, GH

2015-01-01

One of the most complex issues in the cloud computing environment is the problem of resource allocation so that, on one hand, the cloud provider expects the most profitability and, on the other hand, users also expect to have the best resources at their disposal considering the budget constraints and time. In most previous work conducted, heuristic and evolutionary approaches have been used to solve this problem. Nevertheless, since the nature of this environment is based on economic methods, using such methods can decrease response time and reducing the complexity of the problem. In this paper, an auction-based method is proposed which determines the auction winner by applying game theory mechanism and holding a repetitive game with incomplete information in a non-cooperative environment. In this method, users calculate suitable price bid with their objective function during several round and repetitions and send it to the auctioneer; and the auctioneer chooses the winning player based the suggested utility function. In the proposed method, the end point of the game is the Nash equilibrium point where players are no longer inclined to alter their bid for that resource and the final bid also satisfies the auctioneer’s utility function. To prove the response space convexity, the Lagrange method is used and the proposed model is simulated in the cloudsim and the results are compared with previous work. At the end, it is concluded that this method converges to a response in a shorter time, provides the lowest service level agreement violations and the most utility to the provider. PMID:26431035

Efficient Nash Equilibrium Resource Allocation Based on Game Theory Mechanism in Cloud Computing by Using Auction.

PubMed

Nezarat, Amin; Dastghaibifard, G H

2015-01-01

One of the most complex issues in the cloud computing environment is the problem of resource allocation so that, on one hand, the cloud provider expects the most profitability and, on the other hand, users also expect to have the best resources at their disposal considering the budget constraints and time. In most previous work conducted, heuristic and evolutionary approaches have been used to solve this problem. Nevertheless, since the nature of this environment is based on economic methods, using such methods can decrease response time and reducing the complexity of the problem. In this paper, an auction-based method is proposed which determines the auction winner by applying game theory mechanism and holding a repetitive game with incomplete information in a non-cooperative environment. In this method, users calculate suitable price bid with their objective function during several round and repetitions and send it to the auctioneer; and the auctioneer chooses the winning player based the suggested utility function. In the proposed method, the end point of the game is the Nash equilibrium point where players are no longer inclined to alter their bid for that resource and the final bid also satisfies the auctioneer's utility function. To prove the response space convexity, the Lagrange method is used and the proposed model is simulated in the cloudsim and the results are compared with previous work. At the end, it is concluded that this method converges to a response in a shorter time, provides the lowest service level agreement violations and the most utility to the provider.

A biomarker panel for non-alcoholic steatohepatitis (NASH) and NASH-related fibrosis.

PubMed

Younossi, Zobair M; Page, Sandra; Rafiq, Nila; Birerdinc, Aybike; Stepanova, Maria; Hossain, Noreen; Afendy, Arian; Younoszai, Zahra; Goodman, Zachary; Baranova, Ancha

2011-04-01

Patients with biopsy-proven NASH and especially those with fibrosis are at risk for progressive liver disease, emphasizing the clinical importance of developing non-invasive biomarkers for NASH and NASH-related fibrosis. This study examines the performance of a new biomarker panel for NASH and NASH-related fibrosis with a combination of clinical and laboratory variables. Enrolled patients had biopsy-proven NAFLD. Clinical data, laboratory data, and serum samples were collected at the time of biopsy. Fasting serum was assayed for adiponectin, resistin, glucose, M30, M65, Tissue inhibitor of metalloproteinases-1 (Timp-1), ProCollagen 3 N-terminal peptide (PIIINP), and hyaluronic acid (HA). Regression models predictive of NASH, NASH-related fibrosis, and NASH-related advanced fibrosis were designed and cross-validated. Of the 79 enrolled NAFLD patients, 40 had biopsy-proven NASH and 39 had non-NASH NAFLD. Clinical and laboratory data were from this cohort were used to develop a NAFLD Diagnostic Panel that includes three models (models for NASH, NASH-related fibrosis, and NASH-related advanced fibrosis). The model for predicting NASH includes diabetes, gender, BMI, triglycerides, M30 (apoptosis), and M65-M30 (necrosis) [AUC: 0.81, 95% CI, 0.70-0.89, 300 p value <9E 301 (-06)]. The NASH-related fibrosis prediction model includes the same predictors [AUC: 0.80, 95% CI 0.68-0.88, 307 p value <0.00014]. Finally, the NASH-related advanced fibrosis model includes type 2 diabetes, serum triglycerides, Timp-1, and AST [AUC: 0.81, 95% CI, 0.70-0.89; p value, 0.000062]. This NAFLD Diagnostic Panel based on a clinical and laboratory data has good performance characteristics and is easy to use. This biomarker panel could become useful in the management of patients with NAFLD.

Noisy relativistic quantum games in noninertial frames

NASA Astrophysics Data System (ADS)

Khan, Salman; Khan, M. Khalid

2013-02-01

The influence of noise and of Unruh effect on quantum Prisoners' dilemma is investigated both for entangled and unentangled initial states. The noise is incorporated through amplitude damping channel. For unentangled initial state, the decoherence compensates for the adverse effect of acceleration of the frame and the effect of acceleration becomes irrelevant provided the game is fully decohered. It is shown that the inertial player always out scores the noninertial player by choosing defection. For maximally entangled initially state, we show that for fully decohered case every strategy profile results in either of the two possible equilibrium outcomes. Two of the four possible strategy profiles become Pareto optimal and Nash equilibrium and no dilemma is leftover. It is shown that other equilibrium points emerge for different region of values of decoherence parameter that are either Pareto optimal or Pareto inefficient in the quantum strategic spaces. It is shown that the Eisert et al. (Phys Rev Lett 83:3077, 1999) miracle move is a special move that leads always to distinguishable results compare to other moves. We show that the dilemma like situation is resolved in favor of one player or the other.

A Hierarchy of Heuristic-Based Models of Crowd Dynamics

NASA Astrophysics Data System (ADS)

Degond, P.; Appert-Rolland, C.; Moussaïd, M.; Pettré, J.; Theraulaz, G.

2013-09-01

We derive a hierarchy of kinetic and macroscopic models from a noisy variant of the heuristic behavioral Individual-Based Model of Ngai et al. (Disaster Med. Public Health Prep. 3:191-195, 2009) where pedestrians are supposed to have constant speeds. This IBM supposes that pedestrians seek the best compromise between navigation towards their target and collisions avoidance. We first propose a kinetic model for the probability distribution function of pedestrians. Then, we derive fluid models and propose three different closure relations. The first two closures assume that the velocity distribution function is either a Dirac delta or a von Mises-Fisher distribution respectively. The third closure results from a hydrodynamic limit associated to a Local Thermodynamical Equilibrium. We develop an analogy between this equilibrium and Nash equilibria in a game theoretic framework. In each case, we discuss the features of the models and their suitability for practical use.

Self-organizing intelligent network of smart electrical heating devices as an alternative to traditional ways of heating

NASA Astrophysics Data System (ADS)

Zaslavsky, Aleksander M.; Tkachov, Viktor V.; Protsenko, Stanislav M.; Bublikov, Andrii V.; Suleimenov, Batyrbek; Orshubekov, Nurbek; Gromaszek, Konrad

2017-08-01

The paper considers the problem of automated decentralized distribution of the electric energy among unlimited-power electric heaters providing the given temperature distribution within the zones of monitored object heating in the context of maximum use of electric power which limiting level is time-dependent randomly. Principles of collective selforganization automata for solving the problem are analyzed. It has been shown that after all the automata make decision, equilibrium of Nash type is attained when unused power within the electric network is not more than a power of any non-energized electric heater.

Spatial correlated games

PubMed Central

2017-01-01

This article studies correlated two-person games constructed from games with independent players as proposed in Iqbal et al. (2016 R. Soc. open sci. 3, 150477. (doi:10.1098/rsos.150477)). The games are played in a collective manner, both in a two-dimensional lattice where the players interact with their neighbours, and with players interacting at random. Four game types are scrutinized in iterated games where the players are allowed to change their strategies, adopting that of their best paid mate neighbour. Particular attention is paid in the study to the effect of a variable degree of correlation on Nash equilibrium strategy pairs. PMID:29291120

A Game Theory Algorithm for Intra-Cluster Data Aggregation in a Vehicular Ad Hoc Network

PubMed Central

Chen, Yuzhong; Weng, Shining; Guo, Wenzhong; Xiong, Naixue

2016-01-01

Vehicular ad hoc networks (VANETs) have an important role in urban management and planning. The effective integration of vehicle information in VANETs is critical to traffic analysis, large-scale vehicle route planning and intelligent transportation scheduling. However, given the limitations in the precision of the output information of a single sensor and the difficulty of information sharing among various sensors in a highly dynamic VANET, effectively performing data aggregation in VANETs remains a challenge. Moreover, current studies have mainly focused on data aggregation in large-scale environments but have rarely discussed the issue of intra-cluster data aggregation in VANETs. In this study, we propose a multi-player game theory algorithm for intra-cluster data aggregation in VANETs by analyzing the competitive and cooperative relationships among sensor nodes. Several sensor-centric metrics are proposed to measure the data redundancy and stability of a cluster. We then study the utility function to achieve efficient intra-cluster data aggregation by considering both data redundancy and cluster stability. In particular, we prove the existence of a unique Nash equilibrium in the game model, and conduct extensive experiments to validate the proposed algorithm. Results demonstrate that the proposed algorithm has advantages over typical data aggregation algorithms in both accuracy and efficiency. PMID:26907272

Security Investment in Contagious Networks.

PubMed

Hasheminasab, Seyed Alireza; Tork Ladani, Behrouz

2018-01-16

Security of the systems is normally interdependent in such a way that security risks of one part affect other parts and threats spread through the vulnerable links in the network. So, the risks of the systems can be mitigated through investments in the security of interconnecting links. This article takes an innovative look at the problem of security investment of nodes on their vulnerable links in a given contagious network as a game-theoretic model that can be applied to a variety of applications including information systems. In the proposed game model, each node computes its corresponding risk based on the value of its assets, vulnerabilities, and threats to determine the optimum level of security investments on its external links respecting its limited budget. Furthermore, direct and indirect nonlinear influences of a node's security investment on the risks of other nodes are considered. The existence and uniqueness of the game's Nash equilibrium in the proposed game are also proved. Further analysis of the model in a practical case revealed that taking advantage of the investment effects of other players, perfectly rational players (i.e., those who use the utility function of the proposed game model) make more cost-effective decisions than selfish nonrational or semirational players. © 2018 Society for Risk Analysis.

A Game Theory Algorithm for Intra-Cluster Data Aggregation in a Vehicular Ad Hoc Network.

PubMed

Chen, Yuzhong; Weng, Shining; Guo, Wenzhong; Xiong, Naixue

2016-02-19

Vehicular ad hoc networks (VANETs) have an important role in urban management and planning. The effective integration of vehicle information in VANETs is critical to traffic analysis, large-scale vehicle route planning and intelligent transportation scheduling. However, given the limitations in the precision of the output information of a single sensor and the difficulty of information sharing among various sensors in a highly dynamic VANET, effectively performing data aggregation in VANETs remains a challenge. Moreover, current studies have mainly focused on data aggregation in large-scale environments but have rarely discussed the issue of intra-cluster data aggregation in VANETs. In this study, we propose a multi-player game theory algorithm for intra-cluster data aggregation in VANETs by analyzing the competitive and cooperative relationships among sensor nodes. Several sensor-centric metrics are proposed to measure the data redundancy and stability of a cluster. We then study the utility function to achieve efficient intra-cluster data aggregation by considering both data redundancy and cluster stability. In particular, we prove the existence of a unique Nash equilibrium in the game model, and conduct extensive experiments to validate the proposed algorithm. Results demonstrate that the proposed algorithm has advantages over typical data aggregation algorithms in both accuracy and efficiency.

Learning dynamics in social dilemmas

PubMed Central

Macy, Michael W.; Flache, Andreas

2002-01-01

The Nash equilibrium, the main solution concept in analytical game theory, cannot make precise predictions about the outcome of repeated mixed-motive games. Nor can it tell us much about the dynamics by which a population of players moves from one equilibrium to another. These limitations, along with concerns about the cognitive demands of forward-looking rationality, have motivated efforts to explore backward-looking alternatives to analytical game theory. Most of the effort has been invested in evolutionary models of population dynamics. We shift attention to a learning-theoretic alternative. Computational experiments with adaptive agents identify a fundamental solution concept for social dilemmas–−stochastic collusion–−based on a random walk from a self-limiting noncooperative equilibrium into a self-reinforcing cooperative equilibrium. However, we show that this solution is viable only within a narrow range of aspiration levels. Below the lower threshold, agents are pulled into a deficient equilibrium that is a stronger attractor than mutual cooperation. Above the upper threshold, agents are dissatisfied with mutual cooperation. Aspirations that adapt with experience (producing habituation to stimuli) do not gravitate into the window of viability; rather, they are the worst of both worlds. Habituation destabilizes cooperation and stabilizes defection. Results from the two-person problem suggest that applications to multiplex and embedded relationships will yield unexpected insights into the global dynamics of cooperation in social dilemmas. PMID:12011402

Equivalent survival following liver transplantation in patients with non-alcoholic steatohepatitis compared with patients with other liver diseases.

PubMed

Kennedy, Christopher; Redden, David; Gray, Stephen; Eckhoff, Devin; Massoud, Omar; McGuire, Brendan; Alkurdi, Basem; Bloomer, Joseph; DuBay, Derek A

2012-09-01

Orthotopic liver transplantation (LT) in non-alcoholic steatohepatitis (NASH) is increasing in parallel with the obesity epidemic. This study retrospectively reviewed the clinical outcomes of LTs in NASH (n = 129) and non-NASH (n = 775) aetiologies carried out at a single centre between 1999 and 2009. Rates of 1-, 3- and 5-year overall survival in NASH (90%, 88% and 85%, respectively) were comparable with those in non-NASH (92%, 86% and 80%, respectively) patients. Mortality within 4 months of LT was twice as high in NASH as in non-NASH patients (8.5% vs. 4.2%; P = 0.04). Compared with non-NASH patients, post-LT mortality in NASH patients was more commonly caused by infectious (38% vs. 26%; P < 0.05) or cardiac (19% vs. 7%; P < 0.05) aetiologies. Five-year survival was lower in NASH patients with a high-risk phenotype (age >60 years, body mass index >30 kg/m(2), with hypertension and diabetes) than in NASH patients without these characteristics (72% vs. 87%; P = 0.02). Subgroup analyses revealed that 5-year overall survival in NASH was equivalent to that in Laennec's cirrhosis (85% vs. 80%; P 0.87), but lower than that in cirrhosis of cryptogenic aetiology (85% vs. 96%; P = 0.04). Orthotopic LT in NASH was associated with increased early postoperative mortality, but 1-, 3- and 5-year overall survival rates were equivalent to those in non-NASH patients. © 2012 International Hepato-Pancreato-Biliary Association.

Nash: genius with schizophrenia or vice versa?

PubMed

Funaki, Tevita

2009-11-01

Schizophrenia has many negative impacts on the wellbeing of individuals (sufferers). I will critically analyse Nash's experience with his illness of schizophrenia and his concept of wellness based on themes, his journey with schizophrenia and the support of this wife and friends. Ron Howard directed the movie, A Beautiful Mind based on Nash's biography about his mathematical genius and his struggle with schizophrenia. Nash only had one sister, Martha Nash who was born on November 16th, 1930. In terms of his mental health and wellness, Nash began to show signs of schizophrenia in 1958, on the threshold of his career. After 1970, by his choice, he never took antipsychotic medication again. In 1978, Nash was awarded the John von Neumann Theory Prize for his discovery of non-cooperative equilibria, now called Nash equilibria. As a result of Nash's illness, he adopted unhealthy practices that did not help him cope with schizophrenia. Recovery from mental illness has emphasised the importance of hope for the people experiencing mental illness. Nash's self-determinations enabled him to overcome the stigmatisation suffering due to schizophrenia. Nash experienced the five stages of coping with mental illness. The support of Nash's wife Alicia and the few close friends he had were paramount to his recovery and living with schizophrenia. Alicia had used cognitive coping strategies with her caring for Nash by having positive thinking in attempting to accept Nash's illness rather than denying that it existed and to understand the life experiences of a person with schizophrenia. Howard (2001) stated that it's about a 25% chance, that survivors of schizophrenia can regain clarity as Nash did within a certain time period.

Why Women Are Progressive in Education? Gender Disparities in Human Capital, Labor Markets, and Family Arrangement in the Philippines

ERIC Educational Resources Information Center

Yamauchi, Futoshi; Tiongco, Marites

2013-01-01

This paper shows mutually consistent evidence to support female advantage in education and disadvantage in labor markets observed in the Philippines. We set up a model that shows multiple Nash equilibria to explain schooling and labor market behaviors for females and males. Our evidence from unique sibling data of schooling and work history and…

Unique equilibrium states for Bonatti–Viana diffeomorphisms

NASA Astrophysics Data System (ADS)

Climenhaga, Vaughn; Fisher, Todd; Thompson, Daniel J.

2018-06-01

We show that the robustly transitive diffeomorphisms constructed by Bonatti and Viana have unique equilibrium states for natural classes of potentials. In particular, we characterize the SRB measure as the unique equilibrium state for a suitable geometric potential. The techniques developed are applicable to a wide class of DA diffeomorphisms, and persist under C 1 perturbations of the map. These results are an application of general machinery developed by the first and last named authors.

A short review of game theory for neurosurgeons.

PubMed

Steiger, H-J; Steiger, U R

2011-02-01

Neurosurgery and medicine in general are increasingly dominated by economic factors and considerations. Physicians themselves have partially adopted economic terminology, although they rarely have a profound knowledge of economics. Today game theory is one of the most important factors driving microeconomics, which is the competition for limited resources within a small group of individuals. The purpose of this article is to give a short introduction to game theory and its application to the healthcare system. The Prisoner's Dilemma considers strategies between two persons. In the classic version two burglars are caught. Each could confess and be released from jail if the other does not confess--who will then get a long term in prison. If both confess, both get an intermediate time in jail, and if no one confesses, both get a mild sentence. Wanting to be released from jail, they both confess and get the intermediate term in prison. This remarkable result, initially described by John von Neumann in 1928 and showing that individually rational actions can result in both persons becoming worse off, had a great impact on modern social science. Other scenarios are more complex. The Nash Equilibrium is a wider concept. If there is a set of strategies with the property that no player can benefit by changing his strategy while the other players keep their strategies unchanged, then that set of strategies and the corresponding payoffs constitute the Nash Equilibrium. Another concept particularly important in sociology is the Pareto criterion. If no one can be made better off without making somebody else worse off, then that outcome is Pareto optimal. Respecting these basic principles is a necessary precondition for successful deals and cooperative projects. © Georg Thieme Verlag KG Stuttgart · New York.

Questionnaire survey on lifestyle of patients with nonalcoholic steatohepatitis

PubMed Central

Noto, Haruka; Tokushige, Katsutoshi; Hashimoto, Etsuko; Taniai, Makiko; Shiratori, Keiko

2014-01-01

Lack of exercise and excessive food intake are known to be the important causes of nonalcoholic steatohepatitis (NASH). To elucidate the relationship between lifestyle and NASH, we surveyed exercise and dietary habits, comparing them among 171 biopsy-proven NASH patients, 29 nonalcoholic fatty liver (NAFL) patients and 49 normal subjects. Dietary habits including the duration of dinner time, amount of rice at dinner, and weekly frequencies of meat, fries, Chinese noodles, sweets, and instant food consumption were significantly different in male NASH patients compared to normal male subjects. In women, differences were seen in the amount of rice at dinner, frequency of eating out, and proclivity for sweets. In male NASH patients, the frequency of physical exercise was significantly lower. The lifestyle tendencies of NASH were almost similar to those of NAFL. In the comparison between obese NASH and non-obese NASH, no clear lifestyle differences were found. In conclusion, the most striking result of this survey was that the lifestyle of males contributed significantly to the development of NASH. These results point to treatment of NASH in males. In female NASH patients, lifestyle differences were minimal, and the effects of other factors such as genetic background will need to be investigated. PMID:25411525

Questionnaire survey on lifestyle of patients with nonalcoholic steatohepatitis.

PubMed

Noto, Haruka; Tokushige, Katsutoshi; Hashimoto, Etsuko; Taniai, Makiko; Shiratori, Keiko

2014-11-01

Lack of exercise and excessive food intake are known to be the important causes of nonalcoholic steatohepatitis (NASH). To elucidate the relationship between lifestyle and NASH, we surveyed exercise and dietary habits, comparing them among 171 biopsy-proven NASH patients, 29 nonalcoholic fatty liver (NAFL) patients and 49 normal subjects. Dietary habits including the duration of dinner time, amount of rice at dinner, and weekly frequencies of meat, fries, Chinese noodles, sweets, and instant food consumption were significantly different in male NASH patients compared to normal male subjects. In women, differences were seen in the amount of rice at dinner, frequency of eating out, and proclivity for sweets. In male NASH patients, the frequency of physical exercise was significantly lower. The lifestyle tendencies of NASH were almost similar to those of NAFL. In the comparison between obese NASH and non-obese NASH, no clear lifestyle differences were found. In conclusion, the most striking result of this survey was that the lifestyle of males contributed significantly to the development of NASH. These results point to treatment of NASH in males. In female NASH patients, lifestyle differences were minimal, and the effects of other factors such as genetic background will need to be investigated.

Virtual bargaining: a theory of social decision-making.

PubMed

Misyak, Jennifer B; Chater, Nick

2014-11-05

An essential element of goal-directed decision-making in social contexts is that agents' actions may be mutually interdependent. However, the most well-developed approaches to such strategic interactions, based on the Nash equilibrium concept in game theory, are sometimes too broad and at other times 'overlook' good solutions to fundamental social dilemmas and coordination problems. The authors propose a new theory of social decision-making-virtual bargaining-in which individuals decide among a set of moves on the basis of what they would agree to do if they could openly bargain. The core principles of a formal account are outlined (vis-à-vis the notions of 'feasible agreement' and explicit negotiation) and further illustrated with the introduction of a new game, dubbed the 'Boobytrap game' (a modification on the canonical Prisoner's Dilemma paradigm). In the first empirical data of how individuals play the Boobytrap game, participants' experimental choices accord well with a virtual bargaining perspective, but do not match predictions from a standard Nash account. Alternative frameworks are discussed, with specific empirical tests between these and virtual bargaining identified as future research directions. Lastly, it is proposed that virtual bargaining underpins a vast range of human activities, from social decision-making to joint action and communication.

Pursuit-evasion games with information uncertainties for elusive orbital maneuver and space object tracking

NASA Astrophysics Data System (ADS)

Shen, Dan; Jia, Bin; Chen, Genshe; Blasch, Erik; Pham, Khanh

2015-05-01

This paper develops and evaluates a pursuit-evasion (PE) game approach for elusive orbital maneuver and space object tracking. Unlike the PE games in the literature, where the assumption is that either both players have perfect knowledge of the opponents' positions or use primitive sensing models, the proposed PE approach solves the realistic space situation awareness (SSA) problem with imperfect information, where the evaders will exploit the pursuers' sensing and tracking models to confuse their opponents by maneuvering their orbits to increase the uncertainties, which the pursuers perform orbital maneuvers to minimize. In the game setup, each game player P (pursuer) and E (evader) has its own motion equations with a small continuous low-thrust. The magnitude of the low thrust is fixed and the direction can be controlled by the associated game player. The entropic uncertainty is used to generate the cost functions of game players. The Nash or mixed Nash equilibrium is composed of the directional controls of low-thrusts. Numerical simulations are emulated to demonstrate the performance. Simplified perturbations models (SGP4/SDP4) are exploited to calculate the ground truth of the satellite states (position and speed).

Non-alcoholic fatty liver disease - histological scoring systems: a large cohort single-center, evaluation study.

PubMed

Rastogi, Archana; Shasthry, Saggere Muralikrishna; Agarwal, Ayushi; Bihari, Chhagan; Jain, Priyanka; Jindal, Ankur; Sarin, Shiv

2017-11-01

Non-alcoholic fatty liver disease (NAFLD) is an increasingly common cause of chronic liver disease. Till date, liver biopsy remains the gold standard for identification and quantification of the wide histological spectra of NAFLD. Histological scorings are very useful and widely applied for the diagnosis and management in clinical trials and follow-up studies of non-alcoholic steatohepatitis (NASH). However, in view of scarce published literature, there is a need to evaluate them in large cohort of NAFLD. This study was aimed to evaluate the two histological scoring systems (NAS-CRN, SAF) in the diagnosis of NAFLD and to assess the role of histological characteristics as injury markers in NAFLD. Retrospective histological study of liver biopsies of 1000 patients diagnosed as NAFLD, between 2010 and 2016, was conducted. Histopathologic evaluation and semiquantiative scoring based on NAS-CRN and SAF algorithm and their correlation with serum aminotransferase and fibrosis were performed. Liver biopsies were classified according to the NAS-CRN scoring, as NAS <3 (not NASH) in 72 (7.2%), NAS 3-4 (borderline NASH) in 310 (31%), and NAS ≥5 (definite NASH) in 618 (61.8%), and SAF classified 117 (11.7%) not NASH and 883 (88.3%) definite NASH. There was excellent concordance for definite NASH and not NASH; however, 88.06% of borderline NASH was classified as NASH by SAF. 76.39% by NAS and 78.63% by SAF algorithm who were diagnosed as not NASH showed the presence of fibrosis; however, higher stages of fibrosis were significantly more prevalent in definite NASH, excluding burnt-out cirrhosis. Serum ALT was significantly associated with increasing stages of fibrosis (p < 0.001) and the three categories (not NASH, borderline NASH, and definite NASH) when classified as with/without fibrosis (p < 0.001). Steatosis of higher grades, more ballooned cells, and more foci of Lobular Inflammation were found in significantly higher proportion of patients with NASH (p < 0.001), with higher fibrosis stages (p < 0.001) and higher serum ALT levels (p < 0.001). NAFLD classifications based on histological scoring NAS-CRN and SAF algorithm are concordant for the category of definite NASH and not NASH, while borderline NASH shows discrepant interpretation. There was highly significant correlation between the NAS and SAF categories with high grades of histological characteristics, with serum ALT and with higher stages of fibrosis. Exclusion of fibrosis is a limitation with both scores. © 2017 APMIS. Published by John Wiley & Sons Ltd.

Altered Bile Acid Metabolome in Patients with Nonalcoholic Steatohepatitis.

PubMed

Ferslew, Brian C; Xie, Guoxiang; Johnston, Curtis K; Su, Mingming; Stewart, Paul W; Jia, Wei; Brouwer, Kim L R; Barritt, A Sidney

2015-11-01

The prevalence of nonalcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) is increasing at an alarming rate. The role of bile acids in the development and progression of NAFLD to NASH and cirrhosis is poorly understood. This study aimed to quantify the bile acid metabolome in healthy subjects and patients with non-cirrhotic NASH under fasting conditions and after a standardized meal. Liquid chromatography tandem mass spectroscopy was used to quantify 30 serum and 16 urinary bile acids from 15 healthy volunteers and 7 patients with biopsy-confirmed NASH. Bile acid concentrations were measured at two fasting and four post-prandial time points following a high-fat meal to induce gallbladder contraction and bile acid reabsorption from the intestine. Patients with NASH had significantly higher total serum bile acid concentrations than healthy subjects under fasting conditions (2.2- to 2.4-fold increase in NASH; NASH 2595-3549 µM and healthy 1171-1458 µM) and at all post-prandial time points (1.7- to 2.2-fold increase in NASH; NASH 4444-5898 µM and healthy 2634-2829 µM). These changes were driven by increased taurine- and glycine-conjugated primary and secondary bile acids. Patients with NASH exhibited greater variability in their fasting and post-prandial bile acid profile. Results indicate that patients with NASH have higher fasting and post-prandial exposure to bile acids, including the more hydrophobic and cytotoxic secondary species. Increased bile acid exposure may be involved in liver injury and the pathogenesis of NAFLD and NASH.

Dendritic Cells Limit Fibro-Inflammatory Injury in NASH

PubMed Central

Henning, Justin R.; Graffeo, Christopher S.; Rehman, Adeel; Fallon, Nina C.; Zambirinis, Constantinos P.; Ochi, Atsuo; Barilla, Rocky; Jamal, Mohsin; Deutsch, Michael; Greco, Stephanie; Ego-Osuala, Melvin; Saeed, Usama Bin; Rao, Raghavendra S.; Badar, Sana; Quesada, Juan P.; Acehan, Devrim; Miller, George

2013-01-01

Non-alcoholic steatohepatitis (NASH) is the most common etiology of chronic liver dysfunction in the United States and can progress to cirrhosis and liver failure. Inflammatory insult resulting from fatty infiltration of the liver is central to disease pathogenesis. Dendritic cells (DC) are antigen presenting cells with an emerging role in hepatic inflammation. We postulated that DC are important in the progression of NASH. We found that intrahepatic DC expand and mature in NASH liver and assume an activated immune-phenotype. However, rather than mitigating the severity of NASH, DC depletion markedly exacerbated intrahepatic fibro-inflammation. Our mechanistic studies support a regulatory role for DC in NASH by limiting sterile inflammation via their role in clearance of apoptotic cells and necrotic debris. We found that DC limit CD8+ T cell expansion and restrict Toll-like receptor expression and cytokine production in innate immune effector cells in NASH, including Kupffer cells, neutrophils, and inflammatory monocytes. Consistent with their regulatory role in NASH, during the recovery phase of disease, ablation of DC populations results in delayed resolution of intrahepatic inflammation and fibroplasia. Conclusion Our findings support a role for DC in modulating NASH. Targeting DC functional properties may hold promise for therapeutic intervention in NASH. PMID:23322710

Impact of uncertainty in expected return estimation on stock price volatility

NASA Astrophysics Data System (ADS)

Kostanjcar, Zvonko; Jeren, Branko; Juretic, Zeljan

2012-11-01

We investigate the origin of volatility in financial markets by defining an analytical model for time evolution of stock share prices. The defined model is similar to the GARCH class of models, but can additionally exhibit bimodal behaviour in the supply-demand structure of the market. Moreover, it differs from existing Ising-type models. It turns out that the constructed model is a solution of a thermodynamic limit of a Gibbs probability measure when the number of traders and the number of stock shares approaches infinity. The energy functional of the Gibbs probability measure is derived from the Nash equilibrium of the underlying game.

Two-echelon logistics service supply chain decision game considering quality supervision

NASA Astrophysics Data System (ADS)

Shi, Jiaying

2017-10-01

Due to the increasing importance of supply chain logistics service, we established the Stackelberg game model between single integrator and single subcontractors under decentralized and centralized circumstances, and found that logistics services integrators as a leader prefer centralized decision-making but logistics service subcontractors tend to the decentralized decision-making. Then, we further analyzed why subcontractor chose to deceive and rebuilt a principal-agent game model to monitor the logistics services quality of them. Mixed Strategy Nash equilibrium and related parameters were discussed. The results show that strengthening the supervision and coordination can improve the quality level of logistics service supply chain.

A Study of Normal Shock-Wave Turbulent Boundary-Layer Interactions at Mach Numbers of 1.3, 1.4 and 1.5.

DTIC Science & Technology

1982-10-01

Veigas 13used a third technique which was to hold the normal shock wave steady in a supersonic tube by the adjustment of a conical choke downstream of...the equilibrium functioii E (equation (3) as tie eqoi ihri:’ fl -it I lows of East, Sawyer and Nash 2 8 . Although the maximum values of ti wakce :, i...f.. ..l.. .. .. ..t.. fl iC!alaCC CCCCCCCCt t CCCCCifllt CCCCCCCCit C C--- ---- -- C A CCC5C tCC C NC C - f CC1S $ C C A * E~ - - C 2

Collective states in social systems with interacting learning agents

NASA Astrophysics Data System (ADS)

Semeshenko, Viktoriya; Gordon, Mirta B.; Nadal, Jean-Pierre

2008-08-01

We study the implications of social interactions and individual learning features on consumer demand in a simple market model. We consider a social system of interacting heterogeneous agents with learning abilities. Given a fixed price, agents repeatedly decide whether or not to buy a unit of a good, so as to maximize their expected utilities. This model is close to Random Field Ising Models, where the random field corresponds to the idiosyncratic willingness to pay. We show that the equilibrium reached depends on the nature of the information agents use to estimate their expected utilities. It may be different from the systems’ Nash equilibria.

Association of coffee and caffeine consumption with fatty liver disease, nonalcoholic steatohepatitis, and degree of hepatic fibrosis.

PubMed

Molloy, Jeffrey W; Calcagno, Christopher J; Williams, Christopher D; Jones, Frances J; Torres, Dawn M; Harrison, Stephen A

2012-02-01

Coffee caffeine consumption (CC) is associated with reduced hepatic fibrosis in patients with chronic liver diseases, such as hepatitis C. The association of CC with nonalcoholic fatty liver disease (NAFLD) has not been established. The aim of this study was to correlate CC with the prevalence and severity of NAFLD. Patients involved in a previously published NAFLD prevalence study, as well as additional NASH patients identified in the Brooke Army Medical Center Hepatology clinic, were queried about their caffeine intake. A validated questionnaire for CC was utilized to assess for a relationship between caffeine and four groups: ultrasound negative (controls), bland steatosis/not-NASH, NASH stage 0-1, and NASH stage 2-4. A total of 306 patients responded to the CC questionnaire. Average milligrams of total caffeine/coffee CC per day in controls, bland steatosis/not-NASH, NASH stage 0-1, and NASH stage 2-4 were 307/228, 229/160, 351/255, and 252/152, respectively. When comparing patients with bland steatosis/not-NASH to those with NASH stage 0-1, there was a significant difference in CC between the two groups (P = 0.005). Additionally, when comparing patients with NASH stage 0-1 to those with NASH stage 2-4, there was a significant difference in coffee CC (P = 0.016). Spearman's rank correlation analysis further supported a negative relationship between coffee CC and hepatic fibrosis (r = -0.215; P = 0.035). Coffee CC is associated with a significant reduction in risk of fibrosis among NASH patients. Copyright © 2011 American Association for the Study of Liver Diseases.

Overexpression of the Vitronectin V10 Subunit in Patients with Nonalcoholic Steatohepatitis: Implications for Noninvasive Diagnosis of NASH.

PubMed

Del Ben, Maria; Overi, Diletta; Polimeni, Licia; Carpino, Guido; Labbadia, Giancarlo; Baratta, Francesco; Pastori, Daniele; Noce, Valeria; Gaudio, Eugenio; Angelico, Francesco; Mancone, Carmine

2018-02-18

Nonalcoholic steatohepatitis (NASH) is the critical stage of nonalcoholic fatty liver disease (NAFLD). The persistence of necroinflammatory lesions and fibrogenesis in NASH is the leading cause of liver cirrhosis and, ultimately, hepatocellular carcinoma. To date, the histological examination of liver biopsies, albeit invasive, remains the means to distinguish NASH from simple steatosis (NAFL). Therefore, a noninvasive diagnosis by serum biomarkers is eagerly needed. Here, by a proteomic approach, we analysed the soluble low-molecular-weight protein fragments flushed out from the liver tissue of NAFL and NASH patients. On the basis of the assumption that steatohepatitis leads to the remodelling of the liver extracellular matrix (ECM), NASH-specific fragments were in silico analysed for their involvement in the ECM molecular composition. The 10 kDa C-terminal fragment of the ECM protein vitronectin (VTN) was then selected as a promising circulating biomarker in discriminating NASH. The analysis of sera of patients provided these major findings: the circulating VTN fragment (i) is overexpressed in NASH patients and positively correlates with the NASH activity score (NAS); (ii) originates from the disulfide bond reduction between the V10 and the V65 subunits. In conclusion, V10 determination in the serum could represent a reliable tool for the noninvasive discrimination of NASH from simple steatosis.

Prevalence and predictors of nonalcoholic steatohepatitis in obese patients undergoing bariatric surgery: a Department of Defense experience.

PubMed

Reha, Jeffrey L; Lee, Sukhyung; Hofmann, Luke J

2014-06-01

Nonalcoholic steatohepatitis (NASH) is a silent liver disease that can lead to inflammation and subsequent scaring. If left untreated, cirrhosis may ensue. Morbidly obese patients are at an increased risk of NASH. We report the prevalence and predictors of NASH in patients undergoing morbid obesity surgery. A retrospective review was conducted on morbidly obese patients undergoing weight reduction surgery from September 2005 through December 2008. A liver biopsy was performed at the time of surgery. Patients who had a history of hepatitis infection or previous alcohol dependency were excluded. Prevalence of NASH was studied. Predictors of NASH among clinical and biochemical variables were analyzed using multivariate regression analysis. One hundred thirteen patients were analyzed (84% female; mean age, 42.6 ± 11.4 years; mean body mass index, 45.1 ± 5.7 kg/m(2)). Sixty-one patients had systemic hypertension (54%) and 35 patients had diabetes (31%). The prevalence of NASH in this study population was 35 per cent (40 of 113). An additional 59 patients (52%) had simple steatosis without NASH. Only 14 patients had normal liver histology. On multivariate analysis, only elevated aspartate aminotransferase (AST) (greater than 41 IU/L) was the independent predictor for NASH (odds ratio, 5.85; confidence interval, 1.06 to 32.41). Patient age, body mass index, hypertension, diabetes, hypercholesterolemia, and abnormal alanine aminotransferase did not predict NASH. NASH is a common finding in obese population. Abnormal AST was the only predictive factor for NASH.

Identification of novel noninvasive markers for diagnosing nonalcoholic steatohepatitis and related fibrosis by data mining.

PubMed

Yoshimura, Keito; Okanoue, Takeshi; Ebise, Hayao; Iwasaki, Tsuyoshi; Mizuno, Masayuki; Shima, Toshihide; Ichihara, Junji; Yamazaki, Kazuto

2016-02-01

It is important that patients with nonalcoholic steatohepatitis (NASH) are diagnosed and treated early to prevent serious complications, such as liver cirrhosis or hepatocellular carcinoma. However, current methods for NASH diagnosis are invasive given that they rely on liver biopsy, making early diagnosis difficult. In this study, we developed novel noninvasive markers for the diagnosis of NASH and NASH-related fibrosis. A total of 132 Japanese patients with nonalcoholic fatty liver disease were included in this study. Blood samples were collected, and 261 biomolecules were quantified in serum. Using cluster and pathway analyses, we identified biomolecule modules connected to biological events that occur with disease progression to NASH. The modules were used as variables for diagnosis, leading to a NASH diagnostic marker associated with two biological events, that is, protective response to hepatic steatosis and hepatitis-causing innate immune response. Regarding the NASH-related fibrosis marker, immunological responses to hepatocyte injury were identified as a biological event. To develop diagnostic markers for NASH and NASH-related fibrosis, specific biomolecules were selected from each biomolecule module. The former marker was obtained by averaging the levels of four biomolecules, whereas the latter was obtained by averaging the levels of two biomolecules. Both markers achieved a diagnostic accuracy of almost 0.9 of the area under the receiver operating characteristic curve, and the latter exhibited equivalent performance in an independent group of 62 prospectively recruited patients. We developed highly accurate markers for the diagnosis of both NASH and NASH-related fibrosis (i.e., FM-NASH index and FM-fibro index, respectively). These markers may be used as an alternative diagnostic tool to liver biopsy. © 2015 by the American Association for the Study of Liver Diseases.

Development of a novel diagnostic algorithm to predict NASH in HCV-positive patients.

PubMed

Gallotta, Andrea; Paneghetti, Laura; Mrázová, Viera; Bednárová, Adriana; Kružlicová, Dáša; Frecer, Vladimir; Miertus, Stanislav; Biasiolo, Alessandra; Martini, Andrea; Pontisso, Patrizia; Fassina, Giorgio

2018-05-01

Non-alcoholic steato-hepatitis (NASH) is a severe disease characterised by liver inflammation and progressive hepatic fibrosis, which may progress to cirrhosis and hepatocellular carcinoma. Clinical evidence suggests that in hepatitis C virus patients steatosis and NASH are associated with faster fibrosis progression and hepatocellular carcinoma. A safe and reliable non-invasive diagnostic method to detect NASH at its early stages is still needed to prevent progression of the disease. We prospectively enrolled 91 hepatitis C virus-positive patients with histologically proven chronic liver disease: 77 patients were included in our study; of these, 10 had NASH. For each patient, various clinical and serological variables were collected. Different algorithms combining squamous cell carcinoma antigen-immunoglobulin-M (SCCA-IgM) levels with other common clinical data were created to provide the probability of having NASH. Our analysis revealed a statistically significant correlation between the histological presence of NASH and SCCA-IgM, insulin, homeostasis model assessment, haemoglobin, high-density lipoprotein and ferritin levels, and smoke. Compared to the use of a single marker, algorithms that combined four, six or seven variables identified NASH with higher accuracy. The best diagnostic performance was obtained with the logistic regression combination, which included all seven variables correlated with NASH. The combination of SCCA-IgM with common clinical data shows promising diagnostic performance for the detection of NASH in hepatitis C virus patients.

Groundwater flux estimation in streams: A thermal equilibrium approach

NASA Astrophysics Data System (ADS)

Zhou, Yan; Fox, Garey A.; Miller, Ron B.; Mollenhauer, Robert; Brewer, Shannon

2018-06-01

Stream and groundwater interactions play an essential role in regulating flow, temperature, and water quality for stream ecosystems. Temperature gradients have been used to quantify vertical water movement in the streambed since the 1960s, but advancements in thermal methods are still possible. Seepage runs are a method commonly used to quantify exchange rates through a series of streamflow measurements but can be labor and time intensive. The objective of this study was to develop and evaluate a thermal equilibrium method as a technique for quantifying groundwater flux using monitored stream water temperature at a single point and readily available hydrological and atmospheric data. Our primary assumption was that stream water temperature at the monitored point was at thermal equilibrium with the combination of all heat transfer processes, including mixing with groundwater. By expanding the monitored stream point into a hypothetical, horizontal one-dimensional thermal modeling domain, we were able to simulate the thermal equilibrium achieved with known atmospheric variables at the point and quantify unknown groundwater flux by calibrating the model to the resulting temperature signature. Stream water temperatures were monitored at single points at nine streams in the Ozark Highland ecoregion and five reaches of the Kiamichi River to estimate groundwater fluxes using the thermal equilibrium method. When validated by comparison with seepage runs performed at the same time and reach, estimates from the two methods agreed with each other with an R2 of 0.94, a root mean squared error (RMSE) of 0.08 (m/d) and a Nash-Sutcliffe efficiency (NSE) of 0.93. In conclusion, the thermal equilibrium method was a suitable technique for quantifying groundwater flux with minimal cost and simple field installation given that suitable atmospheric and hydrological data were readily available.

Virtual bargaining: a theory of social decision-making

PubMed Central

Misyak, Jennifer B.; Chater, Nick

2014-01-01

An essential element of goal-directed decision-making in social contexts is that agents' actions may be mutually interdependent. However, the most well-developed approaches to such strategic interactions, based on the Nash equilibrium concept in game theory, are sometimes too broad and at other times ‘overlook’ good solutions to fundamental social dilemmas and coordination problems. The authors propose a new theory of social decision-making—virtual bargaining—in which individuals decide among a set of moves on the basis of what they would agree to do if they could openly bargain. The core principles of a formal account are outlined (vis-à-vis the notions of ‘feasible agreement’ and explicit negotiation) and further illustrated with the introduction of a new game, dubbed the ‘Boobytrap game’ (a modification on the canonical Prisoner's Dilemma paradigm). In the first empirical data of how individuals play the Boobytrap game, participants' experimental choices accord well with a virtual bargaining perspective, but do not match predictions from a standard Nash account. Alternative frameworks are discussed, with specific empirical tests between these and virtual bargaining identified as future research directions. Lastly, it is proposed that virtual bargaining underpins a vast range of human activities, from social decision-making to joint action and communication. PMID:25267828

Algorithms, complexity, and the sciences

PubMed Central

Papadimitriou, Christos

2014-01-01

Algorithms, perhaps together with Moore’s law, compose the engine of the information technology revolution, whereas complexity—the antithesis of algorithms—is one of the deepest realms of mathematical investigation. After introducing the basic concepts of algorithms and complexity, and the fundamental complexity classes P (polynomial time) and NP (nondeterministic polynomial time, or search problems), we discuss briefly the P vs. NP problem. We then focus on certain classes between P and NP which capture important phenomena in the social and life sciences, namely the Nash equlibrium and other equilibria in economics and game theory, and certain processes in population genetics and evolution. Finally, an algorithm known as multiplicative weights update (MWU) provides an algorithmic interpretation of the evolution of allele frequencies in a population under sex and weak selection. All three of these equivalences are rife with domain-specific implications: The concept of Nash equilibrium may be less universal—and therefore less compelling—than has been presumed; selection on gene interactions may entail the maintenance of genetic variation for longer periods than selection on single alleles predicts; whereas MWU can be shown to maximize, for each gene, a convex combination of the gene’s cumulative fitness in the population and the entropy of the allele distribution, an insight that may be pertinent to the maintenance of variation in evolution. PMID:25349382

Dendritic cells limit fibroinflammatory injury in nonalcoholic steatohepatitis in mice.

PubMed

Henning, Justin R; Graffeo, Christopher S; Rehman, Adeel; Fallon, Nina C; Zambirinis, Constantinos P; Ochi, Atsuo; Barilla, Rocky; Jamal, Mohsin; Deutsch, Michael; Greco, Stephanie; Ego-Osuala, Melvin; Bin-Saeed, Usama; Rao, Raghavendra S; Badar, Sana; Quesada, Juan P; Acehan, Devrim; Miller, George

2013-08-01

Nonalcoholic steatohepatitis (NASH) is the most common etiology of chronic liver dysfunction in the United States and can progress to cirrhosis and liver failure. Inflammatory insult resulting from fatty infiltration of the liver is central to disease pathogenesis. Dendritic cells (DCs) are antigen-presenting cells with an emerging role in hepatic inflammation. We postulated that DCs are important in the progression of NASH. We found that intrahepatic DCs expand and mature in NASH liver and assume an activated immune phenotype. However, rather than mitigating the severity of NASH, DC depletion markedly exacerbated intrahepatic fibroinflammation. Our mechanistic studies support a regulatory role for DCs in NASH by limiting sterile inflammation through their role in the clearance of apoptotic cells and necrotic debris. We found that DCs limit CD8(+) T-cell expansion and restrict Toll-like receptor expression and cytokine production in innate immune effector cells in NASH, including Kupffer cells, neutrophils, and inflammatory monocytes. Consistent with their regulatory role in NASH, during the recovery phase of disease, ablation of DC populations results in delayed resolution of intrahepatic inflammation and fibroplasia. Our findings support a role for DCs in modulating NASH. Targeting DC functional properties may hold promise for therapeutic intervention in NASH. Copyright © 2013 American Association for the Study of Liver Diseases.

Mechanism of the development of nonalcoholic steatohepatitis after pancreaticoduodenectomy.

PubMed

Nagaya, Tadanobu; Tanaka, Naoki; Kimura, Takefumi; Kitabatake, Hiroyuki; Fujimori, Naoyuki; Komatsu, Michiharu; Horiuchi, Akira; Yamaura, Takahiro; Umemura, Takeji; Sano, Kenji; Gonzalez, Frank J; Aoyama, Toshifumi; Tanaka, Eiji

2015-06-01

It is recognized that nonalcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis (NASH), may develop after pancreaticoduodenectomy (PD). However, the mechanism of NASH development remains unclear. This study aimed to examine the changes in gene expression associated with NASH occurrence following PD. The expression of genes related to fatty acid/triglyceride (FA/TG) metabolism and inflammatory signaling was examined using liver samples obtained from 7 post-PD NASH patients and compared with 6 healthy individuals and 32 conventional NASH patients. The livers of post-PD NASH patients demonstrated significant up-regulation of the genes encoding CD36, FA-binding proteins 1 and 4, acetyl-coenzyme A carboxylase α, diacylglycerol acyltransferase 2, and peroxisome proliferator-activated receptor (PPAR) γ compared with normal and conventional NASH livers. Although serum apolipoprotein B (ApoB) and TG were decreased in post-PD NASH patients, the mRNAs of ApoB and microsomal TG transfer protein were robustly increased, indicating impaired TG export from the liver as very-low-density lipoprotein (VLDL). Additionally, elevated mRNA levels of myeloid differentiation primary response 88 and superoxide dismutases in post-PD NASH livers suggested significant activation of innate immune response and augmentation of oxidative stress generation. Enhanced FA uptake into hepatocytes and lipogenesis, up-regulation of PPARγ, and disruption of VLDL excretion into the circulation are possible mechanisms of steatogenesis after PD. These results provide a basis for understanding the pathogenesis of NAFLD/NASH following PD.

Expression of cytokine signaling genes in morbidly obese patients with non-alcoholic steatohepatitis and hepatic fibrosis.

PubMed

Estep, J Michael; Baranova, Ancha; Hossain, Noreen; Elariny, Hazem; Ankrah, Kathy; Afendy, Arian; Chandhoke, Vikas; Younossi, Zobair M

2009-05-01

White adipose tissue (WAT) from visceral adiposity plays an important role in the pathogenesis of non-alcoholic steatohepatitis (NASH). Development of NASH and its progression to fibrosis is partially due to cytokines and adipokines produced by WAT. The aim of this study was to assess the association of hepatic fibrosis and NASH by evaluating the intrinsic differences in the inflammatory cytokine signaling in the visceral adipose tissue obtained from morbidly obese patients. We used targeted microarrays representing human genes involved in the inflammatory and fibrogenic reactions to profile visceral adipose samples of 15 well-matched NASH patients with and without fibrosis. Additionally, visceral adipose samples were subjected to real-time polymerase chain reaction profiling of 84 inflammations related genes. Eight genes (CCL2, CCL4, CCL18, CCR1, IL10RB, IL15RA, and LTB) were differentially expressed in NASH with fibrosis. Additionally, an overlapping but distinct list of the differentially expressed genes were found in NASH with type II diabetes (DM; IL8, BLR1, IL2RA, CD40LG, IL1RN, IL15RA, and CCL4) as compared to NASH without DM. Inflammatory cytokines are differentially expressed in the adipose tissue of NASH with fibrosis, as well in NASH with DM. These findings point at the interaction of adipose inflammatory cytokines, DM, hepatic fibrosis in NASH, and its progression to cirrhosis and end-stage liver disease.

Paraoxonase 1 and oxidative stress in paediatric non-alcoholic steatohepatitis.

PubMed

Desai, Sonal; Baker, Susan S; Liu, Wensheng; Moya, Diana A; Browne, Richard W; Mastrandrea, Lucy; Baker, Robert D; Zhu, Lixin

2014-01-01

Non-alcoholic steatohepatitis (NASH) in children is a significant public health concern. Oxidative stress is an important component in the pathophysiology of NASH. Several enzymatic antioxidant mechanisms protect the liver from oxidative injury. Examination of the expression of these enzymes in NASH livers may provide insight on the roles for these antioxidant mechanisms in the pathophysiology of NASH. The mRNA expression of catalase, glutathione peroxidase 1 (GPX1), glutathione reductase (GSR), paraoxonase 1 (PON1) and other reactive oxygen species-related genes was evaluated by microarray and quantitative real-time PCR analyses. The PON1 protein levels were evaluated in liver and serum by Western blot analyses. Serum enzymatic activities of GPX, GSR and PON1 (paraoxonase and arylesterase activities) were examined. NASH livers exhibited elevated mRNA expression of catalase and PON1, but not GPX1 or GSR. No difference in serum GPX or GSR activity was detected between NASH patients and controls. Elevated expression of PON1 mRNA and protein was detected in NASH livers, but serum PON1 protein and activities were not elevated. Elevated expression of catalase and PON1 suggests protective roles for these antioxidants in NASH livers. Given the importance of oxidative stress in the pathophysiology of NASH, future studies focusing on these enzymes could identify important targets for therapeutic or preventive interventions for NASH patients. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

[Prevalence of non-alcoholic fatty liver disease in a population with elevated transaminases and level of accuracy of the diagnosis in Primary Care].

PubMed

Samperio-González, María Amelia; Selvi-Blasco, Marta; Manzano-Montero, Mónica; Méndez-Gómez, Judit; Gil-Prades, Montserrat; Azagra, Rafael

2016-05-01

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of elevated transaminases in adults. Determine the prevalence of NASH in patients with sustained hypertransaminasemia, and Know the adequacy of the registered in Primary Care (AP) diagnosis. 1) Cross-sectional study with a random sample of patients with elevated alanine aminotransferase (ALT) held (ALT> 32 for ≥6 months), ruling out other causes of liver disease, according to clinical, laboratory and ultrasound scan criteria in AP and 2) cross-sectional description of all cases diagnosed with NASH recorded (K76 - ICD10) with diagnostic adequacy analysis according to standard criteria. 290 patients were analyzed: 76 were diagnosed as NASH (26.1%), 44 women (57.9%). Multivariate analysis adjusted for age and sex showed no association between NASH and male gender (OR: 0.5; CI95%: 0.3-0.9), diabetes mellitus (DM) (OR: 2.42; CI95%: 1.2-4.9) and hypertension blood pressure (HBP) (OR: 3.07; CI 95% 1.6-5.6). Of the 209 diagnosed with NASH record: 51 (24.4%) met the criteria for NASH. The rest had insufficient records. 53.1% lacked sustained hypertransaminasemia; 48% of viral serology; 11% supported and 53.1% abdominal ultrasound registration of alcohol. Severe NASH is frequent among patients with sustained hypertransaminasemia. The DM and hypertension significantly increase the risk of NASH. The diagnosis of NASH is recorded without considering all criteria and mainly NASH made by ultrasonography. They should unify diagnostic criteria in the register of NASH. Copyright © 2015 Elsevier España, S.L.U. All rights reserved.

Game-theoretic perspective of Ping-Pong protocol

NASA Astrophysics Data System (ADS)

Kaur, Hargeet; Kumar, Atul

2018-01-01

We analyse Ping-Pong protocol from the point of view of a game. The analysis helps us in understanding the different strategies of a sender and an eavesdropper to gain the maximum payoff in the game. The study presented here characterizes strategies that lead to different Nash equilibriums. We further demonstrate the condition for Pareto optimality depending on the parameters used in the game. Moreover, we also analysed LM05 protocol and compared it with PP protocol from the point of view of a generic two-way QKD game with or without entanglement. Our results provide a deeper understanding of general two-way QKD protocols in terms of the security and payoffs of different stakeholders in the protocol.

Quality effort decision in service supply chain with quality preference based on quantum game

NASA Astrophysics Data System (ADS)

Zhang, Cuihua; Xing, Peng; Wang, Jianwei

2015-04-01

Service quality preference behaviors of both members are considered in service supply chain (SSC) including a service integrator and a service provider with stochastic demand. Through analysis of service quality cost and revenue, the utility functions are established on service quality effort degree and service quality preference level in integrated and decentralized SSC. Nash equilibrium and quantum game are used to optimize the models. By comparing the different solutions, the optimal strategies are obtained in SSC with quality preference. Then some numerical examples are studied and the changing trend of service quality effort is further analyzed by the influence of the entanglement operator and quality preferences.

Game theory-based visual tracking approach focusing on color and texture features.

PubMed

Jin, Zefenfen; Hou, Zhiqiang; Yu, Wangsheng; Chen, Chuanhua; Wang, Xin

2017-07-20

It is difficult for a single-feature tracking algorithm to achieve strong robustness under a complex environment. To solve this problem, we proposed a multifeature fusion tracking algorithm that is based on game theory. By focusing on color and texture features as two gamers, this algorithm accomplishes tracking by using a mean shift iterative formula to search for the Nash equilibrium of the game. The contribution of different features is always keeping the state of optical balance, so that the algorithm can fully take advantage of feature fusion. According to the experiment results, this algorithm proves to possess good performance, especially under the condition of scene variation, target occlusion, and similar interference.

Pricing, manufacturing and inventory policies for raw material in a three-level supply chain

NASA Astrophysics Data System (ADS)

Allah Taleizadeh, Ata; Noori-daryan, Mahsa

2016-03-01

We studied a decentralised three-layer supply chain including a supplier, a producer and some retailers. All the retailers order their demands to the producer and the producer order his demands to the supplier. We assumed that the demand is price sensitive and shortage is not permitted. The goal of the paper is to optimise the total cost of the supply chain network by coordinating decision-making policy using Stackelberg-Nash equilibrium. The decision variables of our model are the supplier's price, the producer's price and the number of shipments received by the supplier and producer, respectively. To illustrate the applicability of the proposed model numerical examples are presented.

Decoupling Coupled Constraints Through Utility Design

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, N; Marden, JR

2014-08-01

Several multiagent systems exemplify the need for establishing distributed control laws that ensure the resulting agents' collective behavior satisfies a given coupled constraint. This technical note focuses on the design of such control laws through a game-theoretic framework. In particular, this technical note provides two systematic methodologies for the design of local agent objective functions that guarantee all resulting Nash equilibria optimize the system level objective while also satisfying a given coupled constraint. Furthermore, the designed local agent objective functions fit into the framework of state based potential games. Consequently, one can appeal to existing results in game-theoretic learning tomore » derive a distributed process that guarantees the agents will reach such an equilibrium.« less

Serum uric acid concentrations and fructose consumption are independently associated with NASH in children and adolescents.

PubMed

Mosca, Antonella; Nobili, Valerio; De Vito, Rita; Crudele, Annalisa; Scorletti, Eleonora; Villani, Alberto; Alisi, Anna; Byrne, Christopher D

2017-05-01

Recent research has suggested that dietary fructose intake may increase serum uric acid (UA) concentrations. Both UA concentration and fructose consumption maybe also increase in NAFLD. It is not known whether dietary fructose consumption and UA concentration are independently associated with non-alcoholic steatohepatitis (NASH). Our aim was to investigate the factors associated with NASH in children and adolescents with proven NAFLD, and to test whether UA concentrations and fructose consumption are independently associated with NASH. Obese children with NAFLD were studied (n=271). NASH was diagnosed by a NAFLD activity score ⩾5 and the fatty liver inhibition of progression (FLIP) algorithm. Fructose consumption (g/day) was assessed by food frequency questionnaire, and UA (mg/dl) was measured in serum. Binary logistic regression with adjustment for covariates and potential confounders was undertaken to test factors independently associated with NASH. NASH occurred in 37.6% of patients. Hyperuricaemia (UA ⩾5.9mg/dl) was present in 47% of patients with NASH compared with 29.7% of non-NASH patients (p=0.003). Both UA concentration (OR=2.488, 95% CI: 1.87-2.83, p=0.004) and fructose consumption (OR=1.612, 95% CI 1.25-1.86, p=0.001) were independently associated with NASH, after adjustment for multiple (and all) measured confounders. Fructose consumption was independently associated with hyperuricaemia (OR=2.021, 95% CI: 1.66-2.78, p=0.01). These data were confirmed using the FLIP algorithm. Both dietary fructose consumption and serum UA concentrations are independently associated with NASH. Fructose consumption was the only factor independently associated with serum UA concentration. Currently, it is not known whether dietary fructose consumption and uric acid (UA) concentration are linked with non-alcoholic steatohepatitis (NASH) in children and adolescents. Our aim was to test whether UA concentrations and fructose consumption are independently associated with NASH in children and adolescents with proven non-alcoholic fatty liver disease (NAFLD). We show that both dietary fructose consumption and serum UA concentrations are independently associated with NASH and fructose consumption was independently linked with high serum UA concentrations. Copyright © 2017 European Association for the Study of the Liver. All rights reserved.

Prevalence and Outcome of Nonalcoholic Fatty Liver Disease in Adolescents and Young Adults Undergoing Weight Loss Surgery

PubMed Central

Corey, Kathleen E.; Stanley, Takara L.; Misdraji, Joseph; Scirica, Christina; Pratt, Janey; Hoppin, Alison; Misra, Madhusmita

2014-01-01

We evaluated the prevalence of NAFLD (nonalcoholic fatty liver disease) and NASH (nonalcoholic steatohepatitis) in 27 adolescents referred for weight loss surgery (WLS). On biopsy 18 patients (66.7%) had NAFLD, and of those, 10 patients (37.0%) had NASH and 11 (40.7%) had fibrosis. Insulin, HbA1C and homeostatic model assessment of insulin resistance (HOMA-IR) were significantly higher in patients with NASH than those without NASH. Following WLS, 40% of NASH patients had persistently elevated aminotransferase levels despite weight loss. We found that NASH is underdiagnosed in adolescents referred for WLS and hyperinsulinemia, HOMA-IR and HbA1c can aid in identifying high-risk patients. PMID:24677740

Potential for Dietary ω-3 Fatty Acids to Prevent Nonalcoholic Fatty Liver Disease and Reduce the Risk of Primary Liver Cancer123

PubMed Central

Jump, Donald B; Depner, Christopher M; Tripathy, Sasmita; Lytle, Kelli A

2015-01-01

Nonalcoholic fatty liver disease (NAFLD) has increased in parallel with central obesity, and its prevalence is anticipated to increase as the obesity epidemic remains unabated. NAFLD is now the most common cause of chronic liver disease in developed countries and is defined as excessive lipid accumulation in the liver, that is, hepatosteatosis. NAFLD ranges in severity from benign fatty liver to nonalcoholic steatohepatitis (NASH), and NASH is characterized by hepatic injury, inflammation, oxidative stress, and fibrosis. NASH can progress to cirrhosis, and cirrhosis is a risk factor for primary hepatocellular carcinoma (HCC). The prevention of NASH will lower the risk of cirrhosis and NASH-associated HCC. Our studies have focused on NASH prevention. We developed a model of NASH by using mice with the LDL cholesterol receptor gene ablated fed the Western diet (WD). The WD induces a NASH phenotype in these mice that is similar to that seen in humans and includes robust induction of hepatic steatosis, inflammation, oxidative stress, and fibrosis. With the use of transcriptomic, lipidomic, and metabolomic approaches, we examined the capacity of 2 dietary ω-3 (n–3) polyunsaturated fatty acids, eicosapentaenoic acid (20:5ω-3; EPA) and docosahexaenoic acid (22:6ω-3; DHA), to prevent WD-induced NASH. Dietary DHA was superior to EPA at attenuating WD-induced changes in plasma lipids and hepatic injury and at reversing WD effects on hepatic metabolism, oxidative stress, and fibrosis. The outcome of these studies suggests that DHA may be useful in preventing NASH and reducing the risk of HCC. PMID:26567194

Acidophil Bodiesin Nonalcoholic Steatohepatitis

PubMed Central

Yeh, Matthew M.; Belt, Patricia; Brunt, Elizabeth M.; Kowdley, Kris V.; Wilson, Laura A.; Ferrell, Linda

2016-01-01

The significance of the quantity of acidophil bodies (AB)in nonalcoholic steatohepatitis (NASH) is not certain. We quantified AB in liver biopsies and examined the association with the diagnosis of NASH and other histologic features. We reviewed 157 liver biopsies from the NASH CRN Database collected in 2006. 127 biopsies were from adult patients. Diagnoses were 94 definite NASH, 40 borderline NASH, and 23 definitely not NASH. The total length and average width of the core biopsies were measured and the biopsy areas were calculated (mm2). Total AB were counted and mean AB count per mm2 was calculated (AB/mm2) to deriveacidophil body index (ABI). ABI was 0.04 (±0.08) in definite NASH and 0.02 (±0.05) in borderline/definitely not NASH groups combined (p=0.02) in all 157 biopsies; similar findings were present in the 127 adult only biopsies (0.04±0.05 and 0.02±0.05, respectively, p=0.05). In all 157 biopsies, increased ABI was associated with greater lobular inflammation (p=0.01) and many ballooned hepatocytes (p=0.048). There was a positive relationship between ABI and high nonalcoholic fatty liver disease (NAFLD) activity scores (NAS), but this association was not statistically significant. There was no association between ABI and steatosis or fibrosis stage in either the entire cohorts or in the subset of adult patients. In conclusion, the density of AB is associated with lobular inflammation, ballooned hepatocytes, and the diagnosis of NASH in adult and pediatric liver biopsies, suggesting the implication of the apoptotic pathway in NASH-associated liver cell injury. PMID:26980020

Combined Adiponectin Deficiency and Resistance in Obese Patients: Can It Solve Part of the Puzzle in Nonalcoholic Steatohepatitis.

PubMed

Salman, Ahmed; Hegazy, Mona; AbdElfadl, Soheir

2015-06-15

Nonalcoholic fatty liver disease (NAFLD) has become the most prevalent cause of liver disease, nonalcoholic steatohepatitis (NASH) and fibrosis in obese patients identifies the risk group with increased incidence of liver-related deaths. To clarify the role of serum adiponectin and its receptor liver gene expression in the progression of liver damage in NAFLD. Fifty four (54) obese patients with NAFLD preliminary diagnosed by liver ultra-sound were recruited. Full medical history, anthropometric measurement, biochemical studies, serum adiponectin level, liver biopsy for histological examination and NAS score to identify NASH patients, and assessment of adiponectin receptor gene expression by RT-PCR, were conducted for each patients. Fifteen ages matched average weight healthy adult had been chosen as a control for serum adiponectin level. According to NAS score, patients were divided into non- NASH (8 patients), and NASH (46 patients). Serum adiponectin level was significantly lower in NAFLD patients compared to normal participants (p < 0.004). Serum adiponectin level was lower in NASH patients (4.437 ± 2.569 ng/dl in NASH vs. 5.138 ± 2.841 ng/dl in non-NASH). Adiponectin receptor liver gene expression was lower in NASH patients (0.8459 ± 0.4671 vs. 1.0688 ± 0.3965 in non-NASH). Both adiponectin deficiency and resistance had a role in progression of simple liver steatosis to severe injury in obese patients.

Promising therapies for treatment of nonalcoholic steatohepatitis

PubMed Central

Noureddin, Mazen; Zhang, Alice; Loomba, Rohit

2018-01-01

Introduction Non-alcoholic fatty liver disease (NAFLD) has become the most common etiology for abnormal aminotransferase levels and chronic liver disease. Its growing prevalence is largely linked to the presence of metabolic syndrome, particularly diabetes and insulin resistance. It is estimated that 60–80% of the type 2 diabetic population has NAFLD. NAFLD encompasses a range of conditions ranging from simple steatosis to nonalcoholic steatohepatitis (NASH). A subset of patients with hepatic steatosis progress to NASH, while 15–20% of patients with NASH develop cirrhosis. This progression is thought to be multifactorial, and there are currently no FDA-approved medications for the treatment of NASH. Areas covered We review drugs currently in Phase II and III clinical trials for treatment of NAFLD and NASH, including their mechanisms of action, relationship to the pathophysiology of NASH, and rationale for their development. Expert opinion The treatment of NASH is complex and necessitates targeting a number of different pathways. Combination therapy, preferably tailored toward the disease stage and severity, will be needed to achieve maximum therapeutic effect. With multiple agents currently being developed, there may soon be an ability to effectively slow or even reverse the disease process in many NAFLD/NASH patients. PMID:27501374

Metabolism dysregulation induces a specific lipid signature of nonalcoholic steatohepatitis in patients

PubMed Central

Chiappini, Franck; Coilly, Audrey; Kadar, Hanane; Gual, Philippe; Tran, Albert; Desterke, Christophe; Samuel, Didier; Duclos-Vallée, Jean-Charles; Touboul, David; Bertrand-Michel, Justine; Brunelle, Alain; Guettier, Catherine; Le Naour, François

2017-01-01

Nonalcoholic steatohepatitis (NASH) is a condition which can progress to cirrhosis and hepatocellular carcinoma. Markers for NASH diagnosis are still lacking. We performed a comprehensive lipidomic analysis on human liver biopsies including normal liver, nonalcoholic fatty liver and NASH. Random forests-based machine learning approach allowed characterizing a signature of 32 lipids discriminating NASH with 100% sensitivity and specificity. Furthermore, we validated this signature in an independent group of NASH patients. Then, metabolism dysregulations were investigated in both patients and murine models. Alterations of elongase and desaturase activities were observed along the fatty acid synthesis pathway. The decreased activity of the desaturase FADS1 appeared as a bottleneck, leading upstream to an accumulation of fatty acids and downstream to a deficiency of long-chain fatty acids resulting to impaired phospholipid synthesis. In NASH, mass spectrometry imaging on tissue section revealed the spreading into the hepatic parenchyma of selectively accumulated fatty acids. Such lipids constituted a highly toxic mixture to human hepatocytes. In conclusion, this study characterized a specific and sensitive lipid signature of NASH and positioned FADS1 as a significant player in accumulating toxic lipids during NASH progression. PMID:28436449

Molecular Pathogenesis of NASH

PubMed Central

Caligiuri, Alessandra; Gentilini, Alessandra; Marra, Fabio

2016-01-01

Nonalcoholic steatohepatitis (NASH) is the main cause of chronic liver disease in the Western world and a major health problem, owing to its close association with obesity, diabetes, and the metabolic syndrome. NASH progression results from numerous events originating within the liver, as well as from signals derived from the adipose tissue and the gastrointestinal tract. In a fraction of NASH patients, disease may progress, eventually leading to advanced fibrosis, cirrhosis and hepatocellular carcinoma. Understanding the mechanisms leading to NASH and its evolution to cirrhosis is critical to identifying effective approaches for the treatment of this condition. In this review, we focus on some of the most recent data reported on the pathogenesis of NASH and its fibrogenic progression, highlighting potential targets for treatment or identification of biomarkers of disease progression. PMID:27657051

De Novo and Recurrence of Nonalcoholic Steatohepatitis After Liver Transplantation.

PubMed

Kappus, Matthew; Abdelmalek, Manal

2017-05-01

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in developing countries. Approximately 25% of patients with NAFLD develop nonalcoholic steatohepatitis (NASH). NASH-related cirrhosis is now a leading listing indication for liver transplantation in the United States. Although posttransplant survival for NASH-related cirrhosis is comparable with that of other liver diseases, many patients have features of metabolic syndrome, which can contribute to a recurrence of NAFLD or NASH. This article reviews the epidemiology, pathophysiology, and treatment of de novo and recurrence of NASH after liver transplantation. Copyright © 2017 Elsevier Inc. All rights reserved.

Is cryptogenic cirrhosis different from NASH cirrhosis?

PubMed

Thuluvath, Paul J; Kantsevoy, Sergey; Thuluvath, Avesh J; Savva, Yulia

2018-03-01

We hypothesized that patients currently diagnosed with cryptogenic cirrhosis (CC) have truly 'cryptogenic' liver disease, which is unlikely to have evolved from NASH. The aim of this study is to characterize patients with CC, and compare their characteristics to patients with cirrhosis of other etiologies. To investigate this, we compared the clinical characteristics of adults with CC (n = 7,999) to those with cirrhosis caused by non-alcoholic steatohepatitis (NASH) (n = 11,302), alcohol (n = 21,714) and autoimmune hepatitis (n = 3,447), using the UNOS database from 2002-16. We performed an age, gender and year of listing matched comparison of CC and NASH (n = 7,201 in each group), and also stratified patients by the presence of obesity or diabetes mellitus (DM). From 2002 to 2016, patients listed with a diagnosis of NASH increased from about 1% to 16% while CC decreased from 8% to 4%. A logistic regression model using the entire United Network for Organ Sharing data (n = 138,021) suggested that the strongest predictors of NASH were type 2 DM, obesity, age ≥60 years, female gender and white race. Type 2 DM was more common in patients with NASH (53%) than those with CC (29%), alcoholic cirrhosis (16%) and autoimmune hepatitis (16%), and obesity was more common in NASH (65.3%) compared to the other three groups (33-42%). There were more white individuals (82.3%) in the NASH group and a lower prevalence of black, Hispanic and Asian individuals, compared to the other three groups. Hepatocellular carcinoma was more commonly seen in NASH (19% vs. 9-13% in the other groups) and this is not influenced by obesity and type 2 DM. The differences between CC and NASH remained unchanged even when two groups were matched for age, gender and year of listing, or when stratified by the presence or absence of obesity or type 2DM. Based on risk perspectives, CC should not be equated with the term 'NASH cirrhosis'. We hypothesized that cryptogenic cirrhosis is a distinct condition from cirrhosis caused by non-alcoholic steatohepatitis (NASH). By comparing cryptogenic cirrhosis with cirrhosis of other causes, we found clear clinical differences. Therefore, cryptogenic cirrhosis should not be considered the same as NASH cirrhosis. Further investigations are required to identify unknown causes of cirrhosis. Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Progression and Regression of Hepatic Lesions in a Mouse Model of NASH Induced by Dietary Intervention and Its Implications in Pharmacotherapy.

PubMed

Ding, Zhi-Ming; Xiao, Yue; Wu, Xikun; Zou, Haixia; Yang, Shurong; Shen, Yiyun; Xu, Juehua; Workman, Heather C; Usborne, Amy L; Hua, Haiqing

2018-01-01

Understanding of the temporal changes of hepatic lesions in the progression and regression of non-alcoholic steatohepatitis (NASH) is vital to elucidation of the pathogenesis of NASH, and critical to the development of a strategy for NASH pharmacotherapy. There are challenges in studying hepatic lesion progression and regression in NASH patients due to the slow development of NASH in humans, one being the requirement for multiple biopsies during the longitudinal follow-up. Here we studied lesion progression and regression in the diet-induced animal model of NASH by application or removal of the pathogenic diet for multiple time periods. Male C57BL/6 mice fed Western diet developed progressive hepatic steatosis/macrovesicular vacuolation, inflammation, and hepatocyte degeneration, as well as perisinusoidal fibrosis and occasionally portal fibrosis as early as 2 months after initiation of the Western diet. In the same period, the mice exhibited elevated ALT (alanine aminotransferase) and AST (aspartate aminotransferase) enzyme activities, CK18 (cytokeratin-18), PIIINP (N-terminal propeptide of type III collagen), and TIMP-1 (tissue inhibitor of metalloproteinase-1). Hepatic steatosis diminished rapidly when the Western diet was replaced by normal rodent chow diet and hepatic inflammation and hepatocyte degeneration were also reduced. Interestingly, perisinusoidal fibrosis and portal fibrosis regressed 8 months after chow diet replacement. To understand pharmacotherapy for NASH, mice with established NASH hepatic lesions were treated with either FXR agonist obeticholic acid (Ocaliva), or CCR2/5 antagonist Cenicriviroc. Similar to the diet replacement, metabolic modulator Ocaliva markedly reduced steatosis/macrovesicular vacuolation, hepatic inflammation, and hepatocyte degeneration effectively, but exhibited no significant effect on liver fibrosis. Anti-inflammation drug Cenicriviroc, on the other hand, markedly decreased inflammation and hepatocyte degeneration, and mildly decreased liver fibrosis, but exhibited no effect on hepatic steatosis/macrovesicular vacuolation. In conclusion, we found the progression of NASH hepatic steatosis/macrovesicular vacuolation, and inflammation eventually lead to hepatocyte death and fibrosis. Life style change and current pharmacotherapies in development may be effective in treating NASH, but their effects on NASH-induced fibrosis may be mild. Since fibrosis is known to be an independent risk for decompensated cirrhosis, cardiovascular events, and mortality, our study suggests that effective anti-fibrosis therapy should be an essential component of the combined pharmacotherapy for advanced NASH.

Children's strategic theory of mind.

PubMed

Sher, Itai; Koenig, Melissa; Rustichini, Aldo

2014-09-16

Human strategic interaction requires reasoning about other people's behavior and mental states, combined with an understanding of their incentives. However, the ontogenic development of strategic reasoning is not well understood: At what age do we show a capacity for sophisticated play in social interactions? Several lines of inquiry suggest an important role for recursive thinking (RT) and theory of mind (ToM), but these capacities leave out the strategic element. We posit a strategic theory of mind (SToM) integrating ToM and RT with reasoning about incentives of all players. We investigated SToM in 3- to 9-y-old children and adults in two games that represent prevalent aspects of social interaction. Children anticipate deceptive and competitive moves from the other player and play both games in a strategically sophisticated manner by 7 y of age. One game has a pure strategy Nash equilibrium: In this game, children achieve equilibrium play by the age of 7 y on the first move. In the other game, with a single mixed-strategy equilibrium, children's behavior moved toward the equilibrium with experience. These two results also correspond to two ways in which children's behavior resembles adult behavior in the same games. In both games, children's behavior becomes more strategically sophisticated with age on the first move. Beyond the age of 7 y, children begin to think about strategic interaction not myopically, but in a farsighted way, possibly with a view to cooperating and capitalizing on mutual gains in long-run relationships.

Children’s strategic theory of mind

PubMed Central

Sher, Itai; Koenig, Melissa; Rustichini, Aldo

2014-01-01

Human strategic interaction requires reasoning about other people’s behavior and mental states, combined with an understanding of their incentives. However, the ontogenic development of strategic reasoning is not well understood: At what age do we show a capacity for sophisticated play in social interactions? Several lines of inquiry suggest an important role for recursive thinking (RT) and theory of mind (ToM), but these capacities leave out the strategic element. We posit a strategic theory of mind (SToM) integrating ToM and RT with reasoning about incentives of all players. We investigated SToM in 3- to 9-y-old children and adults in two games that represent prevalent aspects of social interaction. Children anticipate deceptive and competitive moves from the other player and play both games in a strategically sophisticated manner by 7 y of age. One game has a pure strategy Nash equilibrium: In this game, children achieve equilibrium play by the age of 7 y on the first move. In the other game, with a single mixed-strategy equilibrium, children’s behavior moved toward the equilibrium with experience. These two results also correspond to two ways in which children’s behavior resembles adult behavior in the same games. In both games, children’s behavior becomes more strategically sophisticated with age on the first move. Beyond the age of 7 y, children begin to think about strategic interaction not myopically, but in a farsighted way, possibly with a view to cooperating and capitalizing on mutual gains in long-run relationships. PMID:25197065

Gut microbiome composition in lean patients with NASH is associated with liver damage independent of caloric intake: A prospective pilot study.

PubMed

Duarte, S M B; Stefano, J T; Miele, L; Ponziani, F R; Souza-Basqueira, M; Okada, L S R R; de Barros Costa, F G; Toda, K; Mazo, D F C; Sabino, E C; Carrilho, F J; Gasbarrini, A; Oliveira, C P

2018-04-01

The aim of the study was to compare the gut microbiomes from obese and lean patients with or without NASH to outline phenotypic differences. We performed a cross-sectional pilot study comprising biopsy-proven NASH patients grouped according to BMI. Microbiome DNA was extracted from stool samples, and PCR amplification was performed using primers for the V4 region of the 16S rRNA gene. The amplicons were sequenced using the Ion PGM Torrent platform, and data were analyzed using QIIME software. Macronutrient consumption was analyzed by a 7-day food record. Liver fibrosis ≥ F2 was associated with increased abundance of Lactobacilli (p = 0.0007). NASH patients showed differences in Faecalibacterium, Ruminococcus, Lactobacillus and Bifidobacterium abundance compared with the control group. Lean NASH patients had a 3-fold lower abundance of Faecalibacterium and Ruminococcus (p = 0.004), obese NASH patients were enriched in Lactobacilli (p = 0.002), and overweight NASH patients had reduced Bifidobacterium (p = 0.018). Moreover, lean NASH patients showed a deficiency in Lactobacillus compared with overweight and obese NASH patients. This group also appeared similar to the control group with regard to gut microbiome alpha diversity. Although there were qualitative differences between lean NASH and overweight/obese NASH, they were not statistically significant (p = 0.618). The study limitations included a small sample size, a food questionnaire that collected only qualitative and semi-quantitative data, and variations in group gender composition that may influence differences in FXR signaling, bile acids metabolism and the composition of gut microbiota. Our preliminary finding of a different pathogenetic process in lean NASH patients needs to be confirmed by larger studies, including those with patient populations stratified by sex and dietary habits. Copyright © 2017 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.

Decreased hepatotoxic bile acid composition and altered synthesis in progressive human nonalcoholic fatty liver disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lake, April D.; Novak, Petr; Shipkova, Petia

2013-04-15

Bile acids (BAs) have many physiological roles and exhibit both toxic and protective influences within the liver. Alterations in the BA profile may be the result of disease induced liver injury. Nonalcoholic fatty liver disease (NAFLD) is a prevalent form of chronic liver disease characterized by the pathophysiological progression from simple steatosis to nonalcoholic steatohepatitis (NASH). The hypothesis of this study is that the ‘classical’ (neutral) and ‘alternative’ (acidic) BA synthesis pathways are altered together with hepatic BA composition during progression of human NAFLD. This study employed the use of transcriptomic and metabolomic assays to study the hepatic toxicologic BAmore » profile in progressive human NAFLD. Individual human liver samples diagnosed as normal, steatosis, and NASH were utilized in the assays. The transcriptomic analysis of 70 BA genes revealed an enrichment of downregulated BA metabolism and transcription factor/receptor genes in livers diagnosed as NASH. Increased mRNA expression of BAAT and CYP7B1 was observed in contrast to decreased CYP8B1 expression in NASH samples. The BA metabolomic profile of NASH livers exhibited an increase in taurine together with elevated levels of conjugated BA species, taurocholic acid (TCA) and taurodeoxycholic acid (TDCA). Conversely, cholic acid (CA) and glycodeoxycholic acid (GDCA) were decreased in NASH liver. These findings reveal a potential shift toward the alternative pathway of BA synthesis during NASH, mediated by increased mRNA and protein expression of CYP7B1. Overall, the transcriptomic changes of BA synthesis pathway enzymes together with altered hepatic BA composition signify an attempt by the liver to reduce hepatotoxicity during disease progression to NASH. - Highlights: ► Altered hepatic bile acid composition is observed in progressive NAFLD. ► Bile acid synthesis enzymes are transcriptionally altered in NASH livers. ► Increased levels of taurine and conjugated bile acids are observed in NASH. ► Hepatic bile acid synthesis shifts toward the alternative pathway in NASH.« less

Noninvasive Differentiation between Hepatic Steatosis and Steatohepatitis with MR Imaging Enhanced with USPIOs in Patients with Nonalcoholic Fatty Liver Disease: A Proof-of-Concept Study.

PubMed

Smits, Loek P; Coolen, Bram F; Panno, Maria D; Runge, Jurgen H; Nijhof, Wouter H; Verheij, Joanne; Nieuwdorp, Max; Stoker, Jaap; Beuers, Ulrich H; Nederveen, Aart J; Stroes, Erik S

2016-03-01

To (a) study the optimal timing and dosing for ultrasmall superparamagnetic iron oxide particle (USPIO)-enhanced magnetic resonance (MR) imaging of the liver in nonalcoholic fatty liver disease, (b) evaluate whether hepatic USPIO uptake is decreased in nonalcoholic steatohepatitis (NASH), and (c) study the diagnostic accuracy of USPIO-enhanced MR imaging to distinguish between NASH and simple steatosis. This prospective study was approved by the local institutional review board, and informed consent was obtained from all patients. Quantitative R2* MR imaging of the liver was performed at baseline and 72 hours after USPIO administration in patients with biopsy-proven NASH (n = 13), hepatic steatosis without NASH (n = 11), and healthy control subjects (n = 9). The hepatic USPIO uptake in the liver was quantified by the difference in R2* (ΔR2*) between the contrast material-enhanced images and baseline images. Between-group differences in mean ΔR2* were tested with the Student t test, and diagnostic accuracy was tested by calculating the area under the receiver operating characteristic curve. Patients with NASH had a significantly lower ΔR2* 72 hours after USPIO administration when compared with patients who had simple steatosis and healthy control subjects (mean ± standard deviation for patients with NASH, 37.0 sec(-1) ± 16.1; patients with simple steatosis, 61.0 sec(-1) ± 17.3; and healthy control subjects, 72.2 sec(-1) ± 22.0; P = .006 for NASH vs simple steatosis; P < .001 for NASH vs healthy control subjects). The area under the receiver operating characteristic curve to distinguish NASH from simple steatosis was 0.87 (95% confidence interval: 0.72, 1.00). This proof-of-concept study provides clues that hepatic USPIO uptake in patients with NASH is decreased and that USPIO MR imaging can be used to differentiate NASH from simple steatosis.

Ability of Cytokeratin-18 Fragments and FIB-4 Index to Diagnose Overall and Mild Fibrosis Nonalcoholic Steatohepatitis in Japanese Nonalcoholic Fatty Liver Disease Patients.

PubMed

Kobayashi, Natsuko; Kumada, Takashi; Toyoda, Hidenori; Tada, Toshifumi; Ito, Takanori; Kage, Masayoshi; Okanoue, Takeshi; Kudo, Masatoshi

2017-01-01

Several laboratory markers used in lieu of liver biopsy are reportedly useful in the diagnosis of nonalcoholic steatohepatitis (NASH). In the present study, we investigated the diagnostic impact of various non-invasive markers for predicting NASH. A total of 229 nonalcoholic fatty liver disease (NAFLD) patients who underwent liver biopsy were enrolled for the study. The diagnostic ability of various markers to diagnose NASH from NAFLD was investigated. A total of 140 patients were histologically diagnosed with NASH. Of these, 104 had degree 0-2 fibrosis (F0-2), and 36 had degree 3-4 fibrosis (F3-4). Multiple logistic regression analysis identified hyaluronic acid (HA) (OR 1.014; 95% CI 1.002-1.026; p = 0.024), FIB-4 index (OR 2.097; 95% CI 1.177-3.735; p = 0.012), and cytokeratin-18 fragments (CK-18F) (OR 1.002; 95% CI 1.001-1.002; p < 0.001) as factors independently associated with the diagnosis of NASH. The areas under the receiver operating characteristic curves (AUROCs) of HA, FIB-4 index, and CK-18F for the diagnosis of NASH were 0.77, 0.76, and 0.72, respectively. In addition, FIB-4 index (OR 1.907; 95% CI 1.063-3.419; p = 0.03) and CK-18F (OR 1.002; 95% CI 1.001-1.002; p < 0.001) could differentiate between NASH and NAFL, even when NASH patients with advanced fibrosis (F3-4) were excluded. AUROCs of FIB-4 index and CK-18F for the diagnosis of NASH with mild fibrosis (F0-2) from NAFLD were 0.70 and 0.70, respectively. FIB-4 index and CK-18F have good diagnostic abilities not only for NASH overall, but also for NASH with mild fibrosis. © 2017 S. Karger AG, Basel.

A clinical scoring system for predicting nonalcoholic steatohepatitis in morbidly obese patients.

PubMed

Campos, Guilherme M; Bambha, Kiran; Vittinghoff, Eric; Rabl, Charlotte; Posselt, Andrew M; Ciovica, Ruxandra; Tiwari, Umesh; Ferrel, Linda; Pabst, Mark; Bass, Nathan M; Merriman, Raphael B

2008-06-01

Nonalcoholic steatohepatitis (NASH) is common in morbidly obese persons. Liver biopsy is diagnostic but technically challenging in such individuals. This study was undertaken to develop a clinically useful scoring system to predict the probability of NASH in morbidly obese persons, thus assisting in the decision to perform liver biopsy. Consecutive subjects undergoing bariatric surgery without evidence of other liver disease underwent intraoperative liver biopsy. The outcome was pathologic diagnosis of NASH. Predictors evaluated were demographic, clinical, and laboratory variables. A clinical scoring system was constructed by rounding the estimated regression coefficients for the independent predictors in a multivariate logistic model for the diagnosis of NASH. Of 200 subjects studied, 64 (32%) had NASH. Median body mass index was 48 kg/m(2) (interquartile range, 43-55). Multivariate analysis identified six predictive factors for NASH: the diagnosis of hypertension (odds ratio [OR], 2.4; 95% confidence interval [CI], 1-5.6), type 2 diabetes (OR, 2.6; 95% CI, 1.1-6.3), sleep apnea (OR, 4.0; 95% CI, 1.3-12.2), AST > 27 IU/L (OR, 2.9; 95% CI, 1.2-7.0), alanine aminotransferase (ALT) > 27 IU/L (OR, 3.3; 95% CI, 1.4-8.0), and non-Black race (OR, 8.4; 95% CI, 1.9-37.1). A NASH Clinical Scoring System for Morbid Obesity was derived to predict the probability of NASH in four categories (low, intermediate, high, and very high). The proposed clinical scoring can predict NASH in morbidly obese persons with sufficient accuracy to be considered for clinical use, identifying a very high-risk group in whom liver biopsy would be very likely to detect NASH, as well as a low-risk group in whom biopsy can be safely delayed or avoided.

Water extract of Vitis coignetiae Pulliat leaves attenuates oxidative stress and inflammation in progressive NASH rats.

PubMed

Pak, Wing; Takayama, Fusako; Hasegawa, Azusa; Mankura, Mitsumasa; Egashira, Toru; Ueki, Keiji; Nakamoto, Kazuo; Kawasaki, Hiromu; Mori, Akitane

2012-01-01

This study aimed to investigate the therapeutic effects of the water extract of leaves of Vitis coignetiae Pulliat (VCPL) on nonalcoholic steatohepatitis (NASH) with advanced fibrosis, as our previous study exhibited its preventive effect on NASH. The NASH animal model [PCT/JP2007/52477] was prepared by loading recurrent and intermittent hypoxemia stress to a rat with fatty liver, which resembled the condition occurring in patients with obstructive sleep apnea (OSA) and fatty liver, who have a high incidence of NASH. Intermittent hypoxemia stress is regarded as a condition similar to warm ischemia followed by re-oxygenation, which induces oxidative stress (OS). The daily 100 or 300 mg/kg VCPL administrations were performed for 3 weeks perorally beginning at the time of detection of advanced liver fibrosis. The therapeutic efficacy of VCPL on NASH was demonstrated by the reduction of the leakage of hepato-biliary enzymes and the amelioration of liver fibrosis. The OS elevation in NASH rats was measured based on the derivation of reactive oxygen species from liver mitochondrial energy metabolism and on the decrease in plasma SOD-like activity. The aggravation of inflammatory responses was demonstrated by the neutrophil infiltration (elevated myeloperoxidase activity) and the progression of fibrosis in the livers of NASH rats. In addition, the NASH rats without VCPL treatment also exhibited activation of nuclear factor-κB, a key factor in the link between oxidative stress and inflammation. All of these changes were reduced dose-dependently by the VCPL administration. These findings indicate that VCPL may improve hepatic fibrosis or at least suppress the progression of NASH, by breaking the crosstalk between OS and inflammation.

Dynamical and thermodynamical coupling between the North Atlantic subtropical high and the marine boundary layer clouds in boreal summer

NASA Astrophysics Data System (ADS)

Wei, Wei; Li, Wenhong; Deng, Yi; Yang, Song; Jiang, Jonathan H.; Huang, Lei; Liu, W. Timothy

2018-04-01

This study investigates dynamical and thermodynamical coupling between the North Atlantic subtropical high (NASH), marine boundary layer (MBL) clouds, and the local sea surface temperatures (SSTs) over the North Atlantic in boreal summer for 1984-2009 using NCEP/DOE Reanalysis 2 dataset, various cloud data, and the Hadley Centre sea surface temperature. On interannual timescales, the summer mean subtropical MBL clouds to the southeast of the NASH is actively coupled with the NASH and local SSTs: a stronger (weaker) NASH is often accompanied with an increase (a decrease) of MBL clouds and abnormally cooler (warmer) SSTs along the southeast flank of the NASH. To understand the physical processes between the NASH and the MBL clouds, the authors conduct a data diagnostic analysis and implement a numerical modeling investigation using an idealized anomalous atmospheric general circulation model (AGCM). Results suggest that significant northeasterly anomalies in the southeast flank of the NASH associated with an intensified NASH tend to induce stronger cold advection and coastal upwelling in the MBL cloud region, reducing the boundary surface temperature. Meanwhile, warm advection associated with the easterly anomalies from the African continent leads to warming over the MBL cloud region at 700 hPa. Such warming and the surface cooling increase the atmospheric static stability, favoring growth of the MBL clouds. The anomalous diabatic cooling associated with the growth of the MBL clouds dynamically excites an anomalous anticyclone to its north and contributes to strengthening of the NASH circulation in its southeast flank. The dynamical and thermodynamical couplings and their associated variations in the NASH, MBL clouds, and SSTs constitute an important aspect of the summer climate variability over the North Atlantic.

Plasma phospholipids and fatty acid composition differ between liver biopsy-proven nonalcoholic fatty liver disease and healthy subjects

PubMed Central

Ma, D W L; Arendt, B M; Hillyer, L M; Fung, S K; McGilvray, I; Guindi, M; Allard, J P

2016-01-01

Background: There is growing evidence that nonalcoholic fatty liver disease (NAFLD) is associated with perturbations in liver lipid metabolism. Liver phospholipid and fatty acid composition have been shown to be altered in NAFLD. However, detailed profiles of circulating lipids in the pathogenesis of NAFLD are lacking. Objective: Therefore, the objective of the present study was to examine circulating lipids and potential mechanisms related to hepatic gene expression between liver biopsy-proven simple steatosis (SS), nonalcoholic steatohepatitis (NASH) and healthy subjects. Subjects: Plasma phospholipid and fatty acid composition were determined in 31 healthy living liver donors as healthy controls (HC), 26 patients with simple hepatic steatosis (SS) and 20 with progressive NASH. Hepatic gene expression was analyzed by Illumina microarray in a subset of 22 HC, 16 SS and 14 NASH. Results: Concentrations of phosphatidylethanolamine (PE) increased relative to disease progression, HC

Noninvasive clinical model for the diagnosis of nonalcoholic steatohepatitis in overweight and morbidly obese patients undergoing bariatric surgery.

PubMed

Pirvulescu, I; Gheorghe, L; Csiki, I; Becheanu, G; Dumbravă, M; Fica, S; Martin, S; Sarbu, A; Gheorghe, C; Diculescu, M; Copăescu, C

2012-01-01

Liver biopsy, an invasive method, is the gold standard for differentiate nonalcoholic steatohepatitis (NASH) from other stages of fatty liver disease. A noninvasive test to diagnose NASH and disease severity before surgery and also for monitoring disease status after bariatric surgery (BS) will be an important medical challenge. To create a noninvasive biomarkers model for the diagnosis of NASH in overweight, obese and morbidly obese patients (MOP). Sixty patients (mean BMI= 47.81kg/m2) were admitted after exclusion of other causes of liver disease. Liver biopsies were obtained at the time of the bariatric surgery or by percutaneous liver biopsy and graded using Kleiner score. Continuous variables were compared using Wilcoxon rank sum test and for prediction of NASH we used logistic regression. Logistic regression analysis showed that BMI, ALT, AST, alkaline phosphatase (ALP), HOMA-R, hs-CRP, M30, M65, leptine and adiponectine levels remained independent predictors for NASH (p less than 0.02). Using AUC analysis, we established the following cutoff levels being indicative of NASH: BMI ė 47 kg/m2, ALT ė 32 IU/mL, AST ė 25 IU/mL, ALP ė 85 IU/mL, HOMA-IR ė 4, M65 ė 389 U/L. Adiponectine less than 13.5 mg/L. A NASH-score, calculated as the sum of these 7 parameters, at a cutoff level of 4 points, can accurately predict NASH (sensitivity of 90%, specificity of 93.94% and AUC of 0.9576). We propose a noninvasive model for NASH diagnosis in MOP that should be validated prospectively. Using this noninvasive score, NASH would be predicted without the risks of liver biopsy. Celsius.

Uncovering a Predictive Molecular Signature for the Onset of NASH-Related Fibrosis in a Translational NASH Mouse Model.

PubMed

van Koppen, Arianne; Verschuren, Lars; van den Hoek, Anita M; Verheij, Joanne; Morrison, Martine C; Li, Kelvin; Nagabukuro, Hiroshi; Costessi, Adalberto; Caspers, Martien P M; van den Broek, Tim J; Sagartz, John; Kluft, Cornelis; Beysen, Carine; Emson, Claire; van Gool, Alain J; Goldschmeding, Roel; Stoop, Reinout; Bobeldijk-Pastorova, Ivana; Turner, Scott M; Hanauer, Guido; Hanemaaijer, Roeland

2018-01-01

The incidence of nonalcoholic steatohepatitis (NASH) is increasing. The pathophysiological mechanisms of NASH and the sequence of events leading to hepatic fibrosis are incompletely understood. The aim of this study was to gain insight into the dynamics of key molecular processes involved in NASH and to rank early markers for hepatic fibrosis. A time-course study in low-density lipoprotein-receptor knockout. Leiden mice on a high-fat diet was performed to identify the temporal dynamics of key processes contributing to NASH and fibrosis. An integrative systems biology approach was used to elucidate candidate markers linked to the active fibrosis process by combining transcriptomics, dynamic proteomics, and histopathology. The translational value of these findings were confirmed using human NASH data sets. High-fat-diet feeding resulted in obesity, hyperlipidemia, insulin resistance, and NASH with fibrosis in a time-dependent manner. Temporal dynamics of key molecular processes involved in the development of NASH were identified, including lipid metabolism, inflammation, oxidative stress, and fibrosis. A data-integrative approach enabled identification of the active fibrotic process preceding histopathologic detection using a novel molecular fibrosis signature. Human studies were used to identify overlap of genes and processes and to perform a network biology-based prioritization to rank top candidate markers representing the early manifestation of fibrosis. An early predictive molecular signature was identified that marked the active profibrotic process before histopathologic fibrosis becomes manifest. Early detection of the onset of NASH and fibrosis enables identification of novel blood-based biomarkers to stratify patients at risk, development of new therapeutics, and help shorten (pre)clinical experimental time frames.

Prevalence and outcome of non-alcoholic fatty liver disease in adolescents and young adults undergoing weight loss surgery.

PubMed

Corey, K E; Stanley, T L; Misdraji, J; Scirica, C; Pratt, J; Hoppin, A; Misra, M

2014-10-01

We evaluated the prevalence of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) in 27 adolescents referred for weight loss surgery (WLS). On biopsy, 18 patients (66.7%) had NAFLD, and of those, 10 (37.0%) had NASH and 11 (40.7%) had fibrosis. Insulin, HbA1C and homeostatic model assessment of insulin resistance (HOMA-IR) were significantly higher in patients with NASH than those without NASH. Following WLS, 40% of patients with NASH had persistently elevated aminotransferase levels despite weight loss. We found that NASH is underdiagnosed in adolescents referred for WLS, and that hyperinsulinaemia, HOMA-IR and HbA1c can aid in identifying high-risk patients. © 2014 The Authors. Pediatric Obesity © 2014 International Association for the Study of Obesity.

Liver injury and fibrosis induced by dietary challenge in the Ossabaw miniature Swine.

PubMed

Liang, Tiebing; Alloosh, Mouhamad; Bell, Lauren N; Fullenkamp, Allison; Saxena, Romil; Van Alstine, William; Bybee, Phelan; Werling, Klára; Sturek, Michael; Chalasani, Naga; Masuoka, Howard C

2015-01-01

Ossabaw miniature swine when fed a diet high in fructose, saturated fat and cholesterol (NASH diet) develop metabolic syndrome and nonalcoholic steatohepatitis (NASH) characterized by liver injury and fibrosis. This study was conducted to further characterize the development of NASH in this large animal model. Ossabaw swine were fed standard chow (control group; n = 6) or NASH diet (n = 6) for 24 weeks. Blood and liver tissue were collected and liver histology were characterized at 0, 8, 16 and 24 weeks of dietary intervention. Hepatic apoptosis and lipid levels were assessed at week 24. The NASH diet group developed metabolic syndrome and progressive histologic features of NASH including: (a) hepatocyte ballooning at 8 weeks which progressed to extensive ballooning (>90% hepatocytes), (b) hepatic fibrosis at week 16, which progressed to moderate fibrosis, and (c) Kupffer cell accumulation with vacuolization at 8 weeks which progressed through week 24. The NASH diet group showed increased hepatocyte apoptosis that correlated with hepatic total and free cholesterol and free fatty acids, but not esterified cholesterol or triglycerides. This report further characterizes the progression of diet-induced NASH in the Ossabaw swine model. In Ossabaw swine fed the NASH diet: (a) hepatocyte injury and fibrosis can occur without macrovesicular steatosis or excess triglyceride accumulation; (b) hepatocyte ballooning generally precedes the development of fibrosis; (c) there is increased hepatocyte apoptosis, and it is correlated more significantly with hepatic free cholesterol than hepatic free fatty acids and had no correlation with hepatic triglycerides.

Hyperthyroidism Improves the Pathological Condition of Nonalcoholic Steatohepatitis: A Case of Nonalcoholic Steatohepatitis with Graves' Disease.

PubMed

Miyake, Teruki; Matsuura, Bunzo; Furukawa, Shinya; Todo, Yasuhiko; Yamamoto, Shin; Yoshida, Osamu; Imai, Yusuke; Watanabe, Takao; Yamamoto, Yasunori; Hirooka, Masashi; Tokumoto, Yoshio; Kumagi, Teru; Abe, Masanori; Seike, Hirotaka; Miyauchi, Shozo; Hiasa, Yoichi

2016-01-01

3,5,3'-triiodo-L-thyronine regulates the glucose metabolism, lipid metabolism, and hepatic steatosis. Several groups have shown the relationships between hypothyroidism and nonalcoholic fatty liver and hypothyroidism and nonalcoholic steatohepatitis (NASH). However, the effect of hyperthyroidism on NASH has not yet been investigated. We herein report effects of thyroid hormone on the pathological condition of NASH in a patient with NASH complicated by Graves' disease. In our case, the liver enzyme level improved with the increasing thyroid hormone level; however, the liver enzyme level was aggravated with the improving thyroid hormone level. Therefore, hyperthyroidism may improve the pathological condition of NASH.

How Do Doctors Diagnose NAFLD and NASH?

MedlinePlus

... NAFLD and NASH, such as overweight or obesity insulin resistance high levels of triglycerides or abnormal levels of ... NASH, such as an enlarged liver signs of insulin resistance such as darkened skin patches over your knuckles, ...

Stochastic differential game formulation on the reinsurance and investment problem

NASA Astrophysics Data System (ADS)

Li, Danping; Rong, Ximin; Zhao, Hui

2015-09-01

This paper focuses on a stochastic differential game between two insurance companies, a big one and a small one. The big company has sufficient asset to invest in a risk-free asset and a risky asset and is allowed to purchase proportional reinsurance or acquire new business, and the small company can transfer part of the risk to a reinsurer via proportional reinsurance. The game studied here is zero-sum, where the big company is trying to maximise the expected exponential utility of the difference between two insurance companies' surpluses at the terminal time to keep its advantage on surplus, while simultaneously the small company is trying to minimise the same quantity to reduce its disadvantage. Particularly, the relationships between the surplus processes and the price process of the risky asset are considered. By applying stochastic control theory, we provide and prove the verification theorem and obtain the Nash equilibrium strategy of the game, explicitly. Furthermore, numerical simulations are presented to illustrate the effects of parameters on the equilibrium strategy as well as the economic meanings behind.

Group size effect on cooperation in one-shot social dilemmas

PubMed Central

Barcelo, Hélène; Capraro, Valerio

2015-01-01

Social dilemmas are central to human society. Depletion of natural resources, climate protection, security of energy supply, and workplace collaborations are all examples of social dilemmas. Since cooperative behaviour in a social dilemma is individually costly, Nash equilibrium predicts that humans should not cooperate. Yet experimental studies show that people do cooperate even in anonymous one-shot interactions. In spite of the large number of participants in many modern social dilemmas, little is known about the effect of group size on cooperation. Does larger group size favour or prevent cooperation? We address this problem both experimentally and theoretically. Experimentally, we find that there is no general answer: it depends on the strategic situation. Specifically, we find that larger groups are more cooperative in the Public Goods game, but less cooperative in the N-person Prisoner's dilemma. Theoretically, we show that this behaviour is not consistent with either the Fehr & Schmidt model or (a one-parameter version of) the Charness & Rabin model, but it is consistent with the cooperative equilibrium model introduced by the second author. PMID:25605124

Social cycling and conditional responses in the Rock-Paper-Scissors game

PubMed Central

Wang, Zhijian; Xu, Bin; Zhou, Hai-Jun

2014-01-01

How humans make decisions in non-cooperative strategic interactions is a big question. For the fundamental Rock-Paper-Scissors (RPS) model game system, classic Nash equilibrium (NE) theory predicts that players randomize completely their action choices to avoid being exploited, while evolutionary game theory of bounded rationality in general predicts persistent cyclic motions, especially in finite populations. However as empirical studies have been relatively sparse, it is still a controversial issue as to which theoretical framework is more appropriate to describe decision-making of human subjects. Here we observe population-level persistent cyclic motions in a laboratory experiment of the discrete-time iterated RPS game under the traditional random pairwise-matching protocol. This collective behavior contradicts with the NE theory but is quantitatively explained, without any adjustable parameter, by a microscopic model of win-lose-tie conditional response. Theoretical calculations suggest that if all players adopt the same optimized conditional response strategy, their accumulated payoff will be much higher than the reference value of the NE mixed strategy. Our work demonstrates the feasibility of understanding human competition behaviors from the angle of non-equilibrium statistical physics. PMID:25060115

Integral Equation for the Equilibrium State of Colliding Electron Beams

DOE Office of Scientific and Technical Information (OSTI.GOV)

Warnock, Robert L.

2002-11-11

We study a nonlinear integral equation for the equilibrium phase distribution of stored colliding electron beams. It is analogous to the Haissinski equation, being derived from Vlasov-Fokker-Planck theory, but is quite different in form. We prove existence of a unique solution, thus the existence of a unique equilibrium state, for sufficiently small current. This is done for the Chao-Ruth model of the beam-beam interaction in one degree of freedom. We expect no difficulty in generalizing the argument to more realistic models.

Hepatic FTO expression is increased in NASH and its silencing attenuates palmitic acid-induced lipotoxicity.

PubMed

Lim, Andrea; Zhou, Jin; Sinha, Rohit A; Singh, Brijesh K; Ghosh, Sujoy; Lim, Kiat-Hon; Chow, Pierce Kah-Hoe; Woon, Esther C Y; Yen, Paul M

2016-10-21

Non-alcoholic steatohepatitis (NASH) is one of the most common causes of liver failure worldwide. It is characterized by excess fat accumulation, inflammation, and increased lipotoxicity in hepatocytes. Currently, there are limited treatment options for NASH due to lack of understanding of its molecular etiology. In the present study, we demonstrate that the expression of fat mass and obesity associated gene (FTO) is significantly increased in the livers of NASH patients and in a rodent model of NASH. Furthermore, using human hepatic cells, we show that genetic silencing of FTO protects against palmitate-induced oxidative stress, mitochondrial dysfunction, ER stress, and apoptosis in vitro. Taken together, our results show that FTO may have a deleterious role in hepatic cells during lipotoxic conditions, and strongly suggest that up-regulation of FTO may contribute to the increased liver damage in NASH. Copyright © 2016 Elsevier Inc. All rights reserved.

Quantum Games under Decoherence

NASA Astrophysics Data System (ADS)

Huang, Zhiming; Qiu, Daowen

2016-02-01

Quantum systems are easily influenced by ambient environments. Decoherence is generated by system interaction with external environment. In this paper, we analyse the effects of decoherence on quantum games with Eisert-Wilkens-Lewenstein (EWL) (Eisert et al., Phys. Rev. Lett. 83(15), 3077 1999) and Marinatto-Weber (MW) (Marinatto and Weber, Phys. Lett. A 272, 291 2000) schemes. Firstly, referring to the analytical approach that was introduced by Eisert et al. (Phys. Rev. Lett. 83(15), 3077 1999), we analyse the effects of decoherence on quantum Chicken game by considering different traditional noisy channels. We investigate the Nash equilibria and changes of payoff in specific two-parameter strategy set for maximally entangled initial states. We find that the Nash equilibria are different in different noisy channels. Since Unruh effect produces a decoherence-like effect and can be perceived as a quantum noise channel (Omkar et al., arXiv: 1408.1477v1), with the same two parameter strategy set, we investigate the influences of decoherence generated by the Unruh effect on three-player quantum Prisoners' Dilemma, the non-zero sum symmetric multiplayer quantum game both for unentangled and entangled initial states. We discuss the effect of the acceleration of noninertial frames on the the game's properties such as payoffs, symmetry, Nash equilibrium, Pareto optimal, dominant strategy, etc. Finally, we study the decoherent influences of correlated noise and Unruh effect on quantum Stackelberg duopoly for entangled and unentangled initial states with the depolarizing channel. Our investigations show that under the influence of correlated depolarizing channel and acceleration in noninertial frame, some critical points exist for an unentangled initial state at which firms get equal payoffs and the game becomes a follower advantage game. It is shown that the game is always a leader advantage game for a maximally entangled initial state and there appear some points at which the payoffs become zero.

Domino effects within a chemical cluster: a game-theoretical modeling approach by using Nash-equilibrium.

PubMed

Reniers, Genserik; Dullaert, Wout; Karel, Soudan

2009-08-15

Every company situated within a chemical cluster faces domino effect risks, whose magnitude depends on every company's own risk management strategies and on those of all others. Preventing domino effects is therefore very important to avoid catastrophes in the chemical process industry. Given that chemical companies are interlinked by domino effect accident links, there is some likelihood that even if certain companies fully invest in domino effects prevention measures, they can nonetheless experience an external domino effect caused by an accident which occurred in another chemical enterprise of the cluster. In this article a game-theoretic approach to interpret and model behaviour of chemical plants within chemical clusters while negotiating and deciding on domino effects prevention investments is employed.

Modeling of geographical pricing: A game analysis of siberian fuel costs

NASA Astrophysics Data System (ADS)

Sivushina, Anastasiya; Kombu, Anchy; Ryumkin, Valeriy

2017-11-01

In the present study, we propose a novel game-theoretic pricing model describing the interaction between producers and retailers of goods in conditions of poor transport infrastructure and sparse geographical distribution of the points of sale. The proposed model generalizes the Stackelberg leadership model for an arbitrary number of leaders and followers. We show that the model always has a Nash and Stackelberg equilibria. We also provide formulas for the equilibrium prices and volume of sales. As an example we model diesel pricing in south Siberia. Our model found no signs of a cartel. The results of this paper can be used by policymakers to inform market regulations aimed at promoting free competition and avoiding monopolies in production and retail of goods.

Rational Density Functional Selection Using Game Theory.

PubMed

McAnanama-Brereton, Suzanne; Waller, Mark P

2018-01-22

Theoretical chemistry has a paradox of choice due to the availability of a myriad of density functionals and basis sets. Traditionally, a particular density functional is chosen on the basis of the level of user expertise (i.e., subjective experiences). Herein we circumvent the user-centric selection procedure by describing a novel approach for objectively selecting a particular functional for a given application. We achieve this by employing game theory to identify optimal functional/basis set combinations. A three-player (accuracy, complexity, and similarity) game is devised, through which Nash equilibrium solutions can be obtained. This approach has the advantage that results can be systematically improved by enlarging the underlying knowledge base, and the deterministic selection procedure mathematically justifies the density functional and basis set selections.

The Ecology of Defensive Medicine and Malpractice Litigation

PubMed Central

2016-01-01

Using an evolutionary game, we show that patients and physicians can interact with predator-prey relationships. Litigious patients who seek compensation are the ‘predators’ and physicians are their ‘prey’. Physicians can adapt to the risk of being sued by performing defensive medicine. We find that improvements in clinical safety can increase the share of litigious patients and leave unchanged the share of physicians who perform defensive medicine. This paradoxical result is consistent with increasing trends in malpractice claims in spite of safety improvements, observed for example in empirical studies on anesthesiologists. Perfect cooperation with neither defensive nor litigious behaviors can be the Pareto-optimal solution when it is not a Nash equilibrium, so maximizing social welfare may require government intervention. PMID:26982056

Liver Injury and Fibrosis Induced by Dietary Challenge in the Ossabaw Miniature Swine

PubMed Central

Liang, Tiebing; Alloosh, Mouhamad; Bell, Lauren N.; Fullenkamp, Allison; Saxena, Romil; Van Alstine, William; Bybee, Phelan; Werling, Klára; Sturek, Michael; Chalasani, Naga; Masuoka, Howard C.

2015-01-01

Background Ossabaw miniature swine when fed a diet high in fructose, saturated fat and cholesterol (NASH diet) develop metabolic syndrome and nonalcoholic steatohepatitis (NASH) characterized by liver injury and fibrosis. This study was conducted to further characterize the development of NASH in this large animal model. Methods Ossabaw swine were fed standard chow (control group; n = 6) or NASH diet (n = 6) for 24 weeks. Blood and liver tissue were collected and liver histology were characterized at 0, 8, 16 and 24 weeks of dietary intervention. Hepatic apoptosis and lipid levels were assessed at week 24. Results The NASH diet group developed metabolic syndrome and progressive histologic features of NASH including: (a) hepatocyte ballooning at 8 weeks which progressed to extensive ballooning (>90% hepatocytes), (b) hepatic fibrosis at week 16, which progressed to moderate fibrosis, and (c) Kupffer cell accumulation with vacuolization at 8 weeks which progressed through week 24. The NASH diet group showed increased hepatocyte apoptosis that correlated with hepatic total and free cholesterol and free fatty acids, but not esterified cholesterol or triglycerides. Conclusions This report further characterizes the progression of diet-induced NASH in the Ossabaw swine model. In Ossabaw swine fed the NASH diet: (a) hepatocyte injury and fibrosis can occur without macrovesicular steatosis or excess triglyceride accumulation; (b) hepatocyte ballooning generally precedes the development of fibrosis; (c) there is increased hepatocyte apoptosis, and it is correlated more significantly with hepatic free cholesterol than hepatic free fatty acids and had no correlation with hepatic triglycerides. PMID:25978364

Gender difference in NASH susceptibility: Roles of hepatocyte Ikkβ and Sult1e1

PubMed Central

Matsushita, Noriko; Hassanein, Mohamed T.; Martinez-Clemente, Marcos; Lazaro, Raul; French, Samuel W.; Xie, Wen; Lai, Keane; Karin, Michael; Tsukamoto, Hidekazu

2017-01-01

Myeloid cell and hepatocyte IKKβ may mediate the genesis of obesity and insulin resistance in mice fed high fat diet. However, their gender-specific roles in the pathogenesis of non-alcoholic steatohepatitis (NASH) are not known. Here we demonstrate myeloid IKKβ deficiency prevents Western diet-induced obesity and visceral adiposity in females but not in males, and attenuates hyperglycemia, global IR, and NASH in both genders. In contrast, all metabolic sequela including NASH are aggravated by hepatocyte IKKβ deficiency (IkbkbΔhep) in male but not female mice. Gene profiling identifies sulfotransferase family 1E (Sult1e1), which encodes a sulfotransferase E1 responsible for inactivation of estrogen, as a gene upregulated in NASH in both genders and most conspicuously in male IkbkbΔhep mice having worst NASH and lowest plasma estradiol levels. LXRα is enriched to LXRE on Sult1e1 promoter in male WT and IkbkbΔhep mice with NASH, and a Sult1e1 promoter activity is increased by LXRα and its ligand and augmented by expression of a S32A mutant of IκBα. These results demonstrate striking gender differences in regulation by IKKβ of high cholesterol saturated fat diet-induced metabolic changes including NASH and suggest hepatocyte IKKβ is protective in male due at least in part to its ability to repress LXR-induced Sult1e1. Our findings also raise a caution for systemic IKK inhibition for the treatment of NASH as it may exacerbate the disease in male patients. PMID:28797077

NARSTO SOS99NASH WIND PROFILER DATA

Atmospheric Science Data Center

2018-04-16

NARSTO SOS99NASH WIND PROFILER DATA Project Title:  NARSTO ... Platform:  Ground Station Instrument:  Wind Profiler Location:  Nashville, Tennessee Spatial ... Data Guide Documents:  SOS99Nash Wind Profiler Guide Related Data:  Southern Oxidants ...

Non-alcoholic steatohepatitis (NASH) in patients with polycystic ovarian syndrome (PCOS).

PubMed

Hossain, Noreen; Stepanova, Maria; Afendy, Arian; Nader, Fatema; Younossi, Youssef; Rafiq, Nila; Goodman, Zachary; Younossi, Zobair M

2011-04-01

Both non-alcoholic steatohepatitis (NASH) and polycystic ovary syndrome (PCOS) are associated with metabolic syndrome (MS) and insulin resistance (IR). Except for a few case reports, there are no systematic assessments of NASH in PCOS patients. To determine the prevalence of NASH and independent factors associated with NASH in a cohort of patients with documented PCOS. Patients with established diagnosis of PCOS and matched controls (matched for gender, age, and body mass index (BMI)) were included in the study. Causes of other liver diseases were systematically excluded by clinical and laboratory tests. Excessive alcohol use was defined as alcohol consumption of greater than 10 g/day. All liver biopsies were read by a single pathologist blinded to the clinical data. Histologic NASH was defined as steatosis with lobular inflammation and ballooning degeneration of hepatocytes with or without Mallory-Denk bodies or pericellular fibrosis. Univariate and multivariate analyses with logistic regression were performed to compare PCOS to matched controls. Sixty-six patients were included in the study (34 PCOS and 32 matched controls). Of PCOS patients, 73% had a liver biopsy while 78% of the matched controls had a liver biopsy. In comparing PCOS patients to the matched controls, clinical (BMI, waist circumference, type 2 diabetes, MS, or its components, any alcohol consumption in the prior year, ethnic background, age, gender, etc.) and laboratory data (aminotransferases, ferritin, glucose, etc.) were not significantly different (p > 0.05). However, PCOS patients tended to have more histologic NASH on their liver biopsies (44.0% vs. 20.8%, p = 0.08). Independent predictors of histologic NASH in PCOS patients were elevated aspartate aminotransferase (AST), high triglycerides and small amounts of alcohol consumption (p = 0.019, 10-fold cross-validated AUC = 0.80, 95% CI = 0.56-0.94). Although about half of PCOS patients did not report any alcohol consumption, 50% did report rare alcohol use. In fact, PCOS patients with histologic NASH tended to report higher alcohol consumption per week than PCOS without NASH (3.80 ± 6.16 vs. 1.11 ± 1.87 g/week, p = 0.1). Nevertheless, these amounts of alcohol consumption were quite minimal. Despite similar clinical and laboratory profiles to the matched controls, PCOS patients seem to have more histologic NASH. Although alcohol consumption was rare for both PCOS and controls, even rare alcohol consumption in PCOS patients was independently associated with histologic NASH.

Docosahexaenoic acid blocks progression of western diet-induced nonalcoholic steatohepatitis in obese Ldlr-/- mice

PubMed Central

Lytle, Kelli A.; Wong, Carmen P.

2017-01-01

Background Nonalcoholic fatty liver disease (NAFLD) is a major public health concern in western societies. Nonalcoholic steatohepatitis (NASH), the progressive form of NAFLD, is characterized by hepatic steatosis, inflammation, oxidative stress and fibrosis. NASH is a risk factor for cirrhosis and hepatocellular carcinoma. NASH is predicted to be the leading cause of liver transplants by 2020. Despite this growing public health concern, there remain no Food and Drug Administration (FDA) approved NASH treatments. Using Ldlr -/- mice as a preclinical model of western diet (WD)-induced NASH, we previously established that dietary supplementation with docosahexaenoic acid (DHA, 22:6,ω3) attenuated WD-induced NASH in a prevention study. Herein, we evaluated the capacity of DHA supplementation of the WD and a low fat diet to fully reverse NASH in mice with pre-existing disease. Methods Ldlr -/- mice fed the WD for 22 wks developed metabolic syndrome (MetS) and a severe NASH phenotype, including obesity, dyslipidemia, hyperglycemia, hepatic steatosis, inflammation, fibrosis and low hepatic polyunsaturated fatty acid (PUFA) content. These mice were randomized to 5 groups: a baseline group (WDB, sacrificed at 22 wks) and 4 treatments: 1) WD + olive oil (WDO); 2) WD + DHA (WDD); 3) returned to chow + olive oil (WDChO); or 4) returned to chow + DHA (WDChD). The four treatment groups were maintained on their respective diets for 8 wks. An additional group was maintained on standard laboratory chow (Reference Diet, RD) for the 30-wk duration of the study. Results When compared to the WDB group, the WDO group displayed increased hepatic expression of genes linked to inflammation (Opn, Il1rn, Gdf15), hepatic fibrosis (collagen staining, Col1A1, Thbs2, Lox) reflecting disease progression. Mice in the WDD group, in contrast, had increased hepatic C20-22 ω3 PUFA and no evidence of NASH progression. MetS and NASH markers in the WDChO or WDChD groups were significantly attenuated and marginally different from the RD group, reflecting disease remission. Conclusion While these studies establish that DHA supplementation of the WD blocks WD-induced NASH progression, DHA alone does not promote full remission of diet-induced MetS or NASH. PMID:28422962

Astaxanthin prevents and reverses diet-induced insulin resistance and steatohepatitis in mice: A comparison with vitamin E.

PubMed

Ni, Yinhua; Nagashimada, Mayumi; Zhuge, Fen; Zhan, Lili; Nagata, Naoto; Tsutsui, Akemi; Nakanuma, Yasuni; Kaneko, Shuichi; Ota, Tsuguhito

2015-11-25

Hepatic insulin resistance and nonalcoholic steatohepatitis (NASH) could be caused by excessive hepatic lipid accumulation and peroxidation. Vitamin E has become a standard treatment for NASH. However, astaxanthin, an antioxidant carotenoid, inhibits lipid peroxidation more potently than vitamin E. Here, we compared the effects of astaxanthin and vitamin E in NASH. We first demonstrated that astaxanthin ameliorated hepatic steatosis in both genetically (ob/ob) and high-fat-diet-induced obese mice. In a lipotoxic model of NASH: mice fed a high-cholesterol and high-fat diet, astaxanthin alleviated excessive hepatic lipid accumulation and peroxidation, increased the proportion of M1-type macrophages/Kupffer cells, and activated stellate cells to improve hepatic inflammation and fibrosis. Moreover, astaxanthin caused an M2-dominant shift in macrophages/Kupffer cells and a subsequent reduction in CD4(+) and CD8(+) T cell recruitment in the liver, which contributed to improved insulin resistance and hepatic inflammation. Importantly, astaxanthin reversed insulin resistance, as well as hepatic inflammation and fibrosis, in pre-existing NASH. Overall, astaxanthin was more effective at both preventing and treating NASH compared with vitamin E in mice. Furthermore, astaxanthin improved hepatic steatosis and tended to ameliorate the progression of NASH in biopsy-proven human subjects. These results suggest that astaxanthin might be a novel and promising treatment for NASH.

Astaxanthin prevents and reverses diet-induced insulin resistance and steatohepatitis in mice: A comparison with vitamin E

PubMed Central

Ni, Yinhua; Nagashimada, Mayumi; Zhuge, Fen; Zhan, Lili; Nagata, Naoto; Tsutsui, Akemi; Nakanuma, Yasuni; Kaneko, Shuichi; Ota, Tsuguhito

2015-01-01

Hepatic insulin resistance and nonalcoholic steatohepatitis (NASH) could be caused by excessive hepatic lipid accumulation and peroxidation. Vitamin E has become a standard treatment for NASH. However, astaxanthin, an antioxidant carotenoid, inhibits lipid peroxidation more potently than vitamin E. Here, we compared the effects of astaxanthin and vitamin E in NASH. We first demonstrated that astaxanthin ameliorated hepatic steatosis in both genetically (ob/ob) and high-fat-diet-induced obese mice. In a lipotoxic model of NASH: mice fed a high-cholesterol and high-fat diet, astaxanthin alleviated excessive hepatic lipid accumulation and peroxidation, increased the proportion of M1-type macrophages/Kupffer cells, and activated stellate cells to improve hepatic inflammation and fibrosis. Moreover, astaxanthin caused an M2-dominant shift in macrophages/Kupffer cells and a subsequent reduction in CD4+ and CD8+ T cell recruitment in the liver, which contributed to improved insulin resistance and hepatic inflammation. Importantly, astaxanthin reversed insulin resistance, as well as hepatic inflammation and fibrosis, in pre-existing NASH. Overall, astaxanthin was more effective at both preventing and treating NASH compared with vitamin E in mice. Furthermore, astaxanthin improved hepatic steatosis and tended to ameliorate the progression of NASH in biopsy-proven human subjects. These results suggest that astaxanthin might be a novel and promising treatment for NASH. PMID:26603489

Phosphoproteomic biomarkers predicting histologic nonalcoholic steatohepatitis and fibrosis.

PubMed

Younossi, Zobair M; Baranova, Ancha; Stepanova, Maria; Page, Sandra; Calvert, Valerie S; Afendy, Arian; Goodman, Zachary; Chandhoke, Vikas; Liotta, Lance; Petricoin, Emanuel

2010-06-04

The progression of nonalcoholic fatty liver disease (NAFLD) has been linked to deregulated exchange of the endocrine signaling between adipose and liver tissue. Proteomic assays for the phosphorylation events that characterize the activated or deactivated state of the kinase-driven signaling cascades in visceral adipose tissue (VAT) could shed light on the pathogenesis of nonalcoholic steatohepatitis (NASH) and related fibrosis. Reverse-phase protein microarrays (RPMA) were used to develop biomarkers for NASH and fibrosis using VAT collected from 167 NAFLD patients (training cohort, N = 117; testing cohort, N = 50). Three types of models were developed for NASH and advanced fibrosis: clinical models, proteomics models, and combination models. NASH was predicted by a model that included measurements of two components of the insulin signaling pathway: AKT kinase and insulin receptor substrate 1 (IRS1). The models for fibrosis were less reliable when predictions were based on phosphoproteomic, clinical, or the combination data. The best performing model relied on levels of the phosphorylation of GSK3 as well as on two subunits of cyclic AMP regulated protein kinase A (PKA). Phosphoproteomics technology could potentially be used to provide pathogenic information about NASH and NASH-related fibrosis. This information can lead to a clinically relevant diagnostic/prognostic biomarker for NASH.

Prevention of nonalcoholic steatohepatitis in rats by two manganese-salen complexes.

PubMed

Rezazadeh, Alireza; Yazdanparast, Razieh

2014-01-01

Nonalcoholic steatohepatitis (NASH), a progressive stage of nonalcoholic fatty liver disease (NAFLD), is characterized by steatosis with inflammation. Investigations have suggested that oxidative stress may play an important role in the progress of NAFLD to NASH. To provide further insights into beneficial effects of antioxidants in NASH prevention, we employed two manganese-superoxide dismutase/catalase mimetics, manganese N,N`-bis(salicyldene) ethylene diamine chloride (EUK-8) and manganese-3-methoxy N,N`-bis(salicyldene)ethylenediamine chloride (EUK-134), as two salen representatives and vitamin C as the standard antioxidant. Experimental NASH was induced in Male N-Mary rats by feeding a methionine/choline-deficient (MCD) diet to rats for 10 weeks. The rats (n = 5, 30 mg/kg/day) were randomly assigned to receive vitamin C, EUK-8, EUK-134 or vehicle orally. Administration of salens together with the MCD diet reduced the serum aminotransferases, glutathione transferase and alkaline phosphatase, cholesterol, and LDL contents. In addition, the EUK-8 and EUK-134 improved NASH pathological features in liver of MCD-fed rats. EUK-8 and EUK-134 supplementation reduces NASH-induced abnormalities, pointing out that antioxidant strategy could be beneficial for prevention of NASH.

Prevention of Nonalcoholic Steatohepatitis in Rats by Two Manganese-Salen Complexes

PubMed Central

Rezazadeh, Alireza; Yazdanparast, Razieh

2014-01-01

Background: Nonalcoholic steatohepatitis (NASH), a progressive stage of nonalcoholic fatty liver disease (NAFLD), is characterized by steatosis with inflammation. Investigations have suggested that oxidative stress may play an important role in the progress of NAFLD to NASH. To provide further insights into beneficial effects of antioxidants in NASH prevention, we employed two manganese-superoxide dismutase/catalase mimetics, manganese N,N`-bis(salicyldene) ethylene diamine chloride (EUK-8) and manganese-3-methoxy N,N`-bis(salicyldene)ethylenediamine chloride (EUK-134), as two salen representatives and vitamin C as the standard antioxidant. Methods: Experimental NASH was induced in Male N-Mary rats by feeding a methionine/choline-deficient (MCD) diet to rats for 10 weeks. The rats (n = 5, 30 mg/kg/day) were randomly assigned to receive vitamin C, EUK-8, EUK-134 or vehicle orally. Results: Administration of salens together with the MCD diet reduced the serum aminotransferases, glutathione transferase and alkaline phosphatase, cholesterol, and LDL contents. In addition, the EUK-8 and EUK-134 improved NASH pathological features in liver of MCD-fed rats. Conclusion: EUK-8 and EUK-134 supplementation reduces NASH-induced abnormalities, pointing out that antioxidant strategy could be beneficial for prevention of NASH. PMID:24375162

Single non-invasive model to diagnose non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

PubMed

Otgonsuren, Munkhzul; Estep, Michael J; Hossain, Nayeem; Younossi, Elena; Frost, Spencer; Henry, Linda; Hunt, Sharon; Fang, Yun; Goodman, Zachary; Younossi, Zobair M

2014-12-01

Non-alcoholic steatohepatitis (NASH) is the progressive form of non-alcoholic fatty liver disease (NAFLD). A liver biopsy is considered the "gold standard" for diagnosing/staging NASH. Identification of NAFLD/NASH using non-invasive tools is important for intervention. The study aims were to: develop/validate the predictive performance of a non-invasive model (index of NASH [ION]); assess the performance of a recognized non-invasive model (fatty liver index [FLI]) compared with ION for NAFLD diagnosis; determine which non-invasive model (FLI, ION, or NAFLD fibrosis score [NFS]) performed best in predicting age-adjusted mortality. From the National Health and Nutrition Examination Survey III database, anthropometric, clinical, ultrasound, laboratory, and mortality data were obtained (n = 4458; n = 861 [19.3%] NAFLD by ultrasound) and used to develop the ION model, and then to compare the ION and FLI models for NAFLD diagnosis. For validation and diagnosis of NASH, liver biopsy data were used (n = 152). Age-adjusted Cox proportional hazard modeling estimated the association among the three non-invasive tests (FLI, ION, and NFS) and mortality. FLI's threshold score > 60 and ION's threshold score > 22 had similar specificity (FLI = 80% vs ION = 82%) for NAFLD diagnosis; FLI < 30 (80% sensitivity) and ION < 11 (81% sensitivity) excluded NAFLD. An ION score > 50 predicted histological NASH (92% specificity); the FLI model did not predict NASH or mortality. The ION model was best in predicting cardiovascular/diabetes-related mortality; NFS predicted overall or diabetes-related mortality. The ION model was superior in predicting NASH and mortality compared with the FLI model. Studies are needed to validate ION. © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

Vitamin B5 and N-acetylcysteine in nonalcoholic steatohepatitis: a pre-clinical study in a dietary mouse model

PubMed Central

Machado, Mariana Verdelho; Kruger, Leandi; Jewell, Mark L.; Michelotti, Gregory Alexander; de Almeida Pereira, Thiago; Xie, Guanhua; Moylan, Cynthia A.; Diehl, Anna Mae

2015-01-01

Background Nonalcoholic fatty liver disease (NAFLD) is the number one cause of chronic liver disease and second indication for liver transplantation in the Western world. Effective therapy is still not available. Previously we showed a critical role for caspase-2 in the pathogenesis of nonalcoholic steatohepatitis (NASH), the potentially progressive form of NAFLD. An imbalance between free Coenzyme A (CoA) and acyl-CoA ratio is known to induce caspase-2 activation. Objectives We aimed to evaluate CoA metabolism and the effects of supplementation with CoA precursors, pantothenate and cysteine, in mouse models of NASH. Methods CoA metabolism was evaluated in methionine-choline deficient (MCD) and Western diet mouse models of NASH. MCD-diet fed mice were treated with pantothenate and N-acetylcysteine or placebo to determine effects on NASH. Results Liver free CoA content was reduced, pantothenate kinase (PANK), the rate-limiting enzyme in the CoA biosynthesis pathway, was down-regulated, and CoA degrading enzymes were increased in mice with NASH. Decreased hepatic free CoA content was associated with increased caspase-2 activity, and correlated with worse liver cell apoptosis, inflammation and fibrosis. Treatment with pantothenate and N-acetylcysteine did not inhibit caspase-2 activation, improve NASH, normalize PANK expression, or restore free CoA levels in MCD diet-fed mice. Conclusion In mice with NASH, hepatic CoA metabolism is impaired, leading to decreased free CoA content, activation of caspase-2, and increased liver cell apoptosis. Dietary supplementation with CoA precursors did not restore CoA levels or improve NASH, suggesting that alternative approaches are necessary to normalize free CoA during NASH. PMID:26403427

Neonatal monosodium glutamate treatment causes obesity, diabetes, and macrovesicular steatohepatitis with liver nodules in DIAR mice.

PubMed

Tsuneyama, Koichi; Nishida, Takeshi; Baba, Hayato; Taira, Shu; Fujimoto, Makoto; Nomoto, Kazuhiro; Hayashi, Shinichi; Miwa, Shigeharu; Nakajima, Takahiko; Sutoh, Mitsuko; Oda, Emu; Hokao, Ryoji; Imura, Johji

2014-09-01

Non-alcoholic steatohepatitis (NASH) is the hepatic manifestation of metabolic syndrome (MS). Monosodium glutamate (MSG)-treated ICR mice is a useful model of MS and NASH, but it shows the different patterns of steatosis from human NASH. Because inbred aged DIAR (ddY, Institute for Animal Reproduction) mice spontaneously show the similar pattern of steatosis as NASH, we analyzed their liver pathology after administering MSG. MSG-treated DIAR mice (DIAR-MSG) and untreated DIAR mice (DIAR-controls) were sacrificed and assessed histopathologically at 29, 32, 40, 48, and 54 weeks of age. The NASH activity score, body mass index, blood glucose level, and oral glucose tolerance test were also assessed. The body mass index and blood glucose levels of DIAR-MSG were significantly higher than controls. The oral glucose tolerance test revealed a type 2 diabetes pattern in DIAR-MSG. The livers of DIAR-MSG mice showed macrovesicular steatosis, lobular inflammation with neutrophils, and ballooning degeneration after 29 weeks. At 54 weeks, mild fibrosis was observed in 5/6 DIAR-MSG and 2/5 DIAR-control mice. In imaging mass spectrometry analysis, cholesterol as well as triglyceride accumulated in the liver of DIAR-MSG mice. Atypical liver nodules were also observed after 32 weeks in DIAR-MSG, some with cellular and structural atypia mimicking human hepatocellular carcinoma. The NASH activity score of DIAR-MSG after 29 weeks was higher than that of control mice, suggesting the development of NASH. DIAR-MSG had NASH-like liver pathology and liver nodules typically associated with MS symptoms. DIAR-MSG provides a valuable animal model to analyze NASH pathogenesis and carcinogenesis. © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

Impact of Renal Impairment on Cardiovascular Disease Mortality After Liver Transplantation for Nonalcoholic Steatohepatitis Cirrhosis

PubMed Central

VanWagner, Lisa B.; Lapin, Brittany; Skaro, Anton I.; Lloyd-Jones, Donald M.; Rinella, Mary E.

2016-01-01

BACKGROUND & AIMS Non-alcoholic steatohepatitis (NASH) is an independent risk factor for cardiovascular disease (CVD) morbidity after liver transplantation, but its impact on CVD mortality is unknown. We sought to assess the impact of NASH on CVD mortality after liver transplantation and to predict which NASH recipients are at highest risk of a CVD-related death following a liver transplant. METHODS Using the Organ Procurement and Transplantation Network database we examined associations between NASH and post liver transplant CVD mortality, defined as primary cause of death from thromboembolism, arrhythmia, heart failure, myocardial infarction, or stroke. A physician panel reviewed cause of death. RESULTS Of 48,360 liver transplants (2/2002–12/2011), 5,057 (10.5%) were performed for NASH cirrhosis. NASH recipients were more likely to be older, female, obese, diabetic, and have history of renal failure or prior CVD versus non-NASH (p<0.001 for all). Although there was no difference in overall all-cause mortality (log-rank p=0.96), both early (30-day) and long-term CVD-specific mortality was increased among NASH recipients (Odds ratio=1.30, 95% Confidence interval (CI): 1.02–1.66; Hazard ratio=1.42, 95% CI: 1.07–1.41, respectively). These associations were no longer significant after adjustment for pre-transplant diabetes, renal impairment or CVD. A risk score comprising age ≥ 55, male sex, diabetes and renal impairment was developed for prediction of post liver transplant CVD mortality (c-statistic 0.60). CONCLUSION NASH recipients have an increased risk of CVD mortality after liver transplantation explained by a high prevalence of co-morbid cardiometabolic risk factors that in aggregate identify those at highest risk of post-transplant CVD mortality. PMID:25977117

A Game Theoretic Approach for Balancing Energy Consumption in Clustered Wireless Sensor Networks.

PubMed

Yang, Liu; Lu, Yinzhi; Xiong, Lian; Tao, Yang; Zhong, Yuanchang

2017-11-17

Clustering is an effective topology control method in wireless sensor networks (WSNs), since it can enhance the network lifetime and scalability. To prolong the network lifetime in clustered WSNs, an efficient cluster head (CH) optimization policy is essential to distribute the energy among sensor nodes. Recently, game theory has been introduced to model clustering. Each sensor node is considered as a rational and selfish player which will play a clustering game with an equilibrium strategy. Then it decides whether to act as the CH according to this strategy for a tradeoff between providing required services and energy conservation. However, how to get the equilibrium strategy while maximizing the payoff of sensor nodes has rarely been addressed to date. In this paper, we present a game theoretic approach for balancing energy consumption in clustered WSNs. With our novel payoff function, realistic sensor behaviors can be captured well. The energy heterogeneity of nodes is considered by incorporating a penalty mechanism in the payoff function, so the nodes with more energy will compete for CHs more actively. We have obtained the Nash equilibrium (NE) strategy of the clustering game through convex optimization. Specifically, each sensor node can achieve its own maximal payoff when it makes the decision according to this strategy. Through plenty of simulations, our proposed game theoretic clustering is proved to have a good energy balancing performance and consequently the network lifetime is greatly enhanced.

Advanced non-alcoholic steatohepatitis cirrhosis: A high-risk population for pre-liver transplant portal vein thrombosis.

PubMed

Stine, Jonathan G; Argo, Curtis K; Pelletier, Shawn J; Maluf, Daniel G; Caldwell, Stephen H; Northup, Patrick G

2017-01-28

To examine if liver transplant recipients with high-risk non-alcoholic steatohepatitis (NASH) are at increased risk for pre-transplant portal venous thrombosis. Data on all liver transplants in the United States from February 2002 through September 2014 were analyzed. Recipients were sorted into three distinct groups: High-risk (age > 60, body mass index > 30 kg/m 2 , hypertension and diabetes), low-risk and non-NASH cirrhosis. Multivariable logistic regression models were constructed. Thirty-five thousand and seventy-two candidates underwent liver transplantation and of those organ recipients, 465 were transplanted for high-risk and 2775 for low-risk NASH. Two thousand six hundred and twenty-six (7.5%) recipients had pre-transplant portal vein thrombosis; 66 (14.2%) of the high-risk NASH group had portal vein thrombosis vs 328 (11.8%) of the low-risk NASH group. In general, all NASH recipients were less likely to be male or African American and more likely to be obese. In adjusted multivariable regression analyses, high-risk recipients had the greatest risk of pre-transplant portal vein thrombosis with OR = 2.11 (95%CI: 1.60-2.76, P < 0.001) when referenced to the non-NASH group. Liver transplant candidates with high-risk NASH are at the greatest risk for portal vein thrombosis development prior to transplantation. These candidates may benefit from interventions to decrease their likelihood of clot formation and resultant downstream hepatic decompensating events. Prospective study is needed.

Mouse Models of Diet-Induced Nonalcoholic Steatohepatitis Reproduce the Heterogeneity of the Human Disease

PubMed Central

Machado, Mariana Verdelho; Michelotti, Gregory Alexander; Xie, Guanhua; de Almeida, Thiago Pereira; Boursier, Jerome; Bohnic, Brittany; Guy, Cynthia D.; Diehl, Anna Mae

2015-01-01

Background and aims Non-alcoholic steatohepatitis (NASH), the potentially progressive form of nonalcoholic fatty liver disease (NAFLD), is the pandemic liver disease of our time. Although there are several animal models of NASH, consensus regarding the optimal model is lacking. We aimed to compare features of NASH in the two most widely-used mouse models: methionine-choline deficient (MCD) diet and Western diet. Methods Mice were fed standard chow, MCD diet for 8 weeks, or Western diet (45% energy from fat, predominantly saturated fat, with 0.2% cholesterol, plus drinking water supplemented with fructose and glucose) for 16 weeks. Liver pathology and metabolic profile were compared. Results The metabolic profile associated with human NASH was better mimicked by Western diet. Although hepatic steatosis (i.e., triglyceride accumulation) was also more severe, liver non-esterified fatty acid content was lower than in the MCD diet group. NASH was also less severe and less reproducible in the Western diet model, as evidenced by less liver cell death/apoptosis, inflammation, ductular reaction, and fibrosis. Various mechanisms implicated in human NASH pathogenesis/progression were also less robust in the Western diet model, including oxidative stress, ER stress, autophagy deregulation, and hedgehog pathway activation. Conclusion Feeding mice a Western diet models metabolic perturbations that are common in humans with mild NASH, whereas administration of a MCD diet better models the pathobiological mechanisms that cause human NAFLD to progress to advanced NASH. PMID:26017539

Taking Student Success to Scale

ERIC Educational Resources Information Center

Martin, Rebecca R.

2017-01-01

In 2014 the National Association of System Heads (NASH) launched the landmark initiative "NASH TS[superscript 3]: Taking Student Success to Scale." Collectively, TS[superscript 3] is made up of 23 systems and over 300 institutions that span 18 states. (NASH: Taking Student Success to Scale 2016) These systems have a combined…

Nash Receives 2004 David Perlman Award for Excellence in Science Writing

NASA Astrophysics Data System (ADS)

Elmer-DeWitt, Philip; Nash, J. Madeleine

2004-07-01

J. Madeleine Nash received the David Perlman Award for Excellence in Science Writing at the AGU Joint Assembly Honors Ceremony, which was held on 19 May 2004, in Montreal, Canada. Nash was honored for ``Fireproofing the Forests,'' an article that appeared in the 18 August 2003 edition of Time Magazine. ``It is an honor to present AGU's 2004 David Perlman Award to Madeleine Nash, a senior contributor to Time Magazine and, if I may say so, one of the great science writers of her generation.''

TNF-α messenger ribonucleic acid (mRNA) in patients with nonalcoholic steatohepatitis.

PubMed

Alaaeddine, Nada; Sidaoui, Joseph; Hilal, George; Serhal, Reem; Abedelrahman, Abir; Khoury, Salem

2012-01-01

tumor necrosis factor (TNF)-α plays a significant role in the pathogenesis of nonalcoholic steatohepatitis (NASH). A few studies have confirmed high TNF-α plasma protein levels in patients with NASH compared to healthy volunteers. We herein aimed to revisit these findings using other molecular techniques. a cross-sectional evaluation of patients newly diagnosed with NASH. A quantitative assay for the measurement of TNF-α messenger ribonucleic acid (mRNA) was performed for NASH patients and controls using real-time reverse transcription polymerase chain reaction (RT-PCR). in 39 patients with NASH (mean age 38.6 ± 9.4 years, range 28-60 years; 79% males), the mean TNF-α mRNA level was significantly higher than that found for controls (137.6 ± 102.3 ng/mL versus 83.5 ± 43.8 ng/mL, respectively; P = 0.012). A TNF-α mRNA cut-off of 100 ng/mL predicted NASH most optimally (AUC 0.685 ± 0.066, P = 0.01; with 66.7% sensitivity and 74.1% specificity). Serum TNF-α and soluble TNF-α receptor II (sTNFRII) levels were significantly higher in patients compared to controls using ELISA. high TNF-α mRNA levels, determined by RT-PCR, characterize patients with NASH.

Anti-oxidative and anti-inflammatory effects of spirulina on rat model of non-alcoholic steatohepatitis

PubMed Central

Pak, Wing; Takayama, Fusako; Mine, Manaka; Nakamoto, Kazuo; Kodo, Yasumasa; Mankura, Mitsumasa; Egashira, Toru; Kawasaki, Hiromu; Mori, Akitane

2012-01-01

The pathogenesis of nonalcoholic steatohepatitis (NASH) remains unclear, but accumulating data suggest oxidative stress and the relationship between inflammation and immunity plays a crucial role. The aim of this study is to investigate the spirulina, which is a blue-green algae rich in proteins and other nutritional elements, and its component-phycocyanin effect on a rat model of NASH. NASH model rats were established by feeding male Wistar rats with choline-deficient high-fat diet (CDHF) and intermittent hypoxemia by sodium nitrite challenge after 5 weeks of CDHF. After experimental period of 10 weeks, blood and liver were collected to determine oxidative stress injuries and efficacies of spirulina or phycocyanin on NASH model rats. In the NASH model rats, increase in plasma liver enzymes and liver fibrosis, increases in productions of reactive oxygen species from liver mitochondria and from leukocytes, the activation of nuclear factor-kappa B, and the change in the lymphocyte surface antigen ratio (CD4+/CD8+) were observed. The spirulina and phycocyanin administration significantly abated these changes. The spirulina or phycocyanin administration to model rats of NASH might lessen the inflammatory response through anti-oxidative and anti-inflammatory mechanisms, breaking the crosstalk between oxidative stress and inflammation, and effectively inhibit NASH progression. PMID:23170052

M1 polarization bias and subsequent nonalcoholic steatohepatitis progression is attenuated by nitric oxide donor DETA NONOate via inhibition of CYP2E1-induced oxidative stress in obese mice.

PubMed

Seth, Ratanesh Kumar; Das, Suvarthi; Pourhoseini, Sahar; Dattaroy, Diptadip; Igwe, Stephen; Ray, Julie Basu; Fan, Daping; Michelotti, Gregory A; Diehl, Anna Mae; Chatterjee, Saurabh

2015-01-01

Activation of M1 macrophages in nonalcoholic steatohepatitis (NASH) is produced by several external or endogenous factors: inflammatory stimuli, oxidative stress, and cytokines are known. However, any direct role of oxidative stress in causing M1 polarization in NASH has been unclear. We hypothesized that CYP2E1-mediated oxidative stress causes M1 polarization in experimental NASH, and that nitric oxide (NO) donor administration inhibits CYP2E1-mediated inflammation with concomitant attenuation of M1 polarization. Because CYP2E1 takes center stage in these studies, we used a toxin model of NASH that uses a ligand and a substrate of CYP2E1 for inducing NASH. Subsequently, we used a methionine and choline-deficient diet-induced rodent NASH model where the role of CYP2E1 in disease progression has been shown. Our results show that CYP2E1 causes M1 polarization bias, which includes a significant increase in interleukin-1β (IL-1β) and IL-12 in both models of NASH, whereas CYP2E1-null mice or diallyl sulfide administration prevented it. Administration of gadolinium chloride (GdCl3), a macrophage toxin, attenuated both the initial M1 response and the subsequent M2 response, showing that the observed increase in cytokine levels is primarily from macrophages. Based on the evidence of an adaptive NO increase, the NO donor administration in vivo that mechanistically inhibited CYP2E1 catalyzed the oxidative stress during the entire study in NASH-abrogated M1 polarization and NASH progression. The results obtained show the association of CYP2E1 in M1 polarization, and that inhibition of CYP2E1 catalyzed oxidative stress by an NO donor (DETA NONOate [(Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate]) can be a promising therapeutic strategy in NASH. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.

M1 Polarization Bias and Subsequent Nonalcoholic Steatohepatitis Progression Is Attenuated by Nitric Oxide Donor DETA NONOate via Inhibition of CYP2E1-Induced Oxidative Stress in Obese Mice

PubMed Central

Seth, Ratanesh Kumar; Das, Suvarthi; Pourhoseini, Sahar; Dattaroy, Diptadip; Igwe, Stephen; Ray, Julie Basu; Fan, Daping; Michelotti, Gregory A.; Diehl, Anna Mae

2015-01-01

Activation of M1 macrophages in nonalcoholic steatohepatitis (NASH) is produced by several external or endogenous factors: inflammatory stimuli, oxidative stress, and cytokines are known. However, any direct role of oxidative stress in causing M1 polarization in NASH has been unclear. We hypothesized that CYP2E1-mediated oxidative stress causes M1 polarization in experimental NASH, and that nitric oxide (NO) donor administration inhibits CYP2E1-mediated inflammation with concomitant attenuation of M1 polarization. Because CYP2E1 takes center stage in these studies, we used a toxin model of NASH that uses a ligand and a substrate of CYP2E1 for inducing NASH. Subsequently, we used a methionine and choline–deficient diet-induced rodent NASH model where the role of CYP2E1 in disease progression has been shown. Our results show that CYP2E1 causes M1 polarization bias, which includes a significant increase in interleukin-1β (IL-1β) and IL-12 in both models of NASH, whereas CYP2E1-null mice or diallyl sulfide administration prevented it. Administration of gadolinium chloride (GdCl3), a macrophage toxin, attenuated both the initial M1 response and the subsequent M2 response, showing that the observed increase in cytokine levels is primarily from macrophages. Based on the evidence of an adaptive NO increase, the NO donor administration in vivo that mechanistically inhibited CYP2E1 catalyzed the oxidative stress during the entire study in NASH-abrogated M1 polarization and NASH progression. The results obtained show the association of CYP2E1 in M1 polarization, and that inhibition of CYP2E1 catalyzed oxidative stress by an NO donor (DETA NONOate [(Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate]) can be a promising therapeutic strategy in NASH. PMID:25347994

Obstructive Sleep Apnea Is Associated with Nonalcoholic Steatohepatitis and Advanced Liver Histology.

PubMed

Corey, Kathleen E; Misdraji, Joseph; Gelrud, Lou; King, Lindsay Y; Zheng, Hui; Malhotra, Atul; Chung, Raymond T

2015-08-01

Nonalcoholic fatty liver disease (NAFLD) and obstructive sleep apnea (OSA) are growing in prevalence in the USA. Existing data on the relationship between OSA and NAFLD are conflicting and limited by the use of various histologic definitions of nonalcoholic steatohepatitis (NASH). Using a robust definition of NASH in a large, well-characterized cohort, we sought to evaluate whether OSA was associated with NASH and advanced fibrosis. Two hundred and thirteen subjects undergoing weight loss surgery were queried for OSA and then underwent liver biopsy. NASH was defined, as recommended by the American Association for the Study of Liver Disease, by the presence of all of the following: >5 % macrovesicular steatosis, lobular inflammation, and hepatocyte ballooning. NAFLD activity score (NAS) was also determined for each subject. Subjects with OSA had significantly higher alanine and aspartate aminotransferase levels than subjects without OSA (ALT 54.1 vs. 37.7 U/L, P = 0.0007; AST 31.7 vs. 20.5 U/L, P = 0.0007). OSA was associated with the presence of NASH, and this remained significant after adjusting for age, gender, race, and diabetes mellitus (P = 0.03 OR 2.01; 95 %, 1.05-3.87). Steatosis grade, lobular inflammation grade, NAS score, and fibrosis stage were all significantly associated with the presence of OSA and remained so after adjustment. OSA is associated with elevated aminotransferase levels, the presence of NASH, and advanced NASH histology. Further studies are needed to evaluate the impact of OSA treatment on NASH.

Obstructive Sleep Apnea is associated with Nonalcoholic Steatohepatitis and Advanced Liver Histology

PubMed Central

Corey, Kathleen E; Misdraji, Joseph; Gelrud, Lou; King, Lindsay Y.; Zheng, Hui; Malhotra, Atul; Chung, Raymond T

2015-01-01

Background and Aims Nonalcoholic fatty liver disease (NAFLD) and obstructive sleep apnea (OSA) are growing in prevalence in the United States. Existing data on the relationship between OSA and NAFLD is conflicting and limited by the use of various histologic definitions of nonalcoholic steatohepatitis (NASH). Using a robust definition of NASH in a large, well-characterized cohort we sought to evaluate whether OSA was associated with NASH and advanced fibrosis. Methods Two hundred thirteen subjects undergoing weight loss surgery were queried for OSA and then underwent liver biopsy. NASH was defined, as recommended by the American Association for the Study of Liver Disease, by the presence of all of the following: >5% macrovesicular steatosis, lobular inflammation and hepatocyte ballooning. NAFLD activity score (NAS) was also determined for each subject. Results Subjects with OSA had significantly higher alanine and aspartate aminotransferase levels than subjects without OSA (ALT 54.1 U/L vs. 37.7 U/L, P=0.0007; AST 31.7 U/L vs. 20.5 U/L, P=0.0007). OSA was associated with the presence of NASH and this remained significant after adjusting for age, gender, race, and diabetes mellitus (P =0.03 OR, 2.01; 95%, 1.05-3.87). Steatosis grade, lobular inflammation grade, NAS score and fibrosis stage were all significantly associated with the presence of OSA and remained so after adjustment. Conclusions OSA is associated with elevated aminotransferase levels, the presence of NASH and advanced NASH histology. Further studies are needed to evaluate the impact of OSA treatment on NASH. PMID:25840922

Influence of gut microbiota on the development and progression of nonalcoholic steatohepatitis.

PubMed

de Faria Ghetti, Fabiana; Oliveira, Daiane Gonçalves; de Oliveira, Juliano Machado; de Castro Ferreira, Lincoln Eduardo Villela Vieira; Cesar, Dionéia Evangelista; Moreira, Ana Paula Boroni

2018-04-01

Nonalcoholic steatohepatitis (NASH) is characterized by the presence of steatosis, inflammation, and ballooning degeneration of hepatocytes, with or without fibrosis. The prevalence of NASH has increased with the obesity epidemic, but its etiology is multifactorial. The current studies suggest the role of gut microbiota in the development and progression of NASH. The aim is to review the studies that investigate the relationship between gut microbiota and NASH. These review also discusses the pathophysiological mechanisms and the influence of diet on the gut-liver axis. The available literature has proposed mechanisms for an association between gut microbiota and NASH, such as: modification energy homeostasis, lipopolysaccharides (LPS)-endotoxemia, increased endogenous production of ethanol, and alteration in the metabolism of bile acid and choline. There is evidence to suggest that NASH patients have a higher prevalence of bacterial overgrowth in the small intestine and changes in the composition of the gut microbiota. However, there is still a controversy regarding the microbiome profile in this population. The abundance of Bacteroidetes phylum may be increased, decreased, or unaltered in NASH patients. There is an increase in the Escherichia and Bacteroides genus. There is depletion of certain taxa, such as Prevotella and Faecalibacterium. Although few studies have evaluated the composition of the gut microbiota in patients with NASH, it is observed that these individuals have a distinct gut microbiota, compared to the control groups, which explains, at least in part, the genesis and progression of the disease through multiple mechanisms. Modulation of the gut microbiota through diet control offers new challenges for future studies.

Rising Rate of Liver Transplantation in the Baby Boomer Generation with Non-alcoholic Steatohepatitis in the United States.

PubMed

Siddique, Osama; Joseph-Talreja, Mairin; Yoo, Eric R; Perumpail, Ryan B; Cholankeril, George; Harrison, Stephen A; Younossi, Zobair M; Wong, Robert J; Ahmed, Aijaz

2017-09-28

Background and Aims: Nonalcoholic steatohepatitis (NASH) is the most rapidly growing indication for liver transplantation (LT) in the United States and is on a trajectory to become the leading indication for LT in the next decade. We aimed to study the trends in NASH-related LT among persons born between 1945 and 1965, the baby boomer (BB) generation. Methods: We performed a retrospective cohort analysis using population-based data from the United Network for Organ Sharing/Organ Procurement and Transplantation Network registry from 2004-2015 to evaluate the birth cohort-specific trends in liver transplant waitlist registrations and liver transplant surgeries in patients with NASH. We stratified our study population into three birth cohorts: 1) birth before 1945, 2) birth between 1945 and 1965, and 3) birth after 1965. Results: The overall rates of NASH-related waitlist registrations and liver transplant surgeries steadily increased from 2004 to 2015 and were reflective of a sharp rise noted in the NASH BB sub-group. From 2004 to 2015, the proportion of BB patients with NASH added to LT waitlist demonstrated an incremental growth, 60.6% in 2004 versus 83.2% in 2015 ( p < 0.01). Among the liver transplant recipients with NASH, the proportion represented by the BB cohort increased from 56.3% in 2004 to 80.0% in 2015 ( p < 0.01). Conclusions: We report rising rates of waitlist registration and LT for the indication of NASH. More importantly, the BB sub-cohort was mainly responsible for these alarming trends.

Rising Rate of Liver Transplantation in the Baby Boomer Generation with Non-alcoholic Steatohepatitis in the United States

PubMed Central

Siddique, Osama; Joseph-Talreja, Mairin; Yoo, Eric R.; Perumpail, Ryan B.; Cholankeril, George; Harrison, Stephen A.; Younossi, Zobair M.; Wong, Robert J.; Ahmed, Aijaz

2017-01-01

Abstract Background and Aims: Nonalcoholic steatohepatitis (NASH) is the most rapidly growing indication for liver transplantation (LT) in the United States and is on a trajectory to become the leading indication for LT in the next decade. We aimed to study the trends in NASH-related LT among persons born between 1945 and 1965, the baby boomer (BB) generation. Methods: We performed a retrospective cohort analysis using population-based data from the United Network for Organ Sharing/Organ Procurement and Transplantation Network registry from 2004–2015 to evaluate the birth cohort-specific trends in liver transplant waitlist registrations and liver transplant surgeries in patients with NASH. We stratified our study population into three birth cohorts: 1) birth before 1945, 2) birth between 1945 and 1965, and 3) birth after 1965. Results: The overall rates of NASH-related waitlist registrations and liver transplant surgeries steadily increased from 2004 to 2015 and were reflective of a sharp rise noted in the NASH BB sub-group. From 2004 to 2015, the proportion of BB patients with NASH added to LT waitlist demonstrated an incremental growth, 60.6% in 2004 versus 83.2% in 2015 (p < 0.01). Among the liver transplant recipients with NASH, the proportion represented by the BB cohort increased from 56.3% in 2004 to 80.0% in 2015 (p < 0.01). Conclusions: We report rising rates of waitlist registration and LT for the indication of NASH. More importantly, the BB sub-cohort was mainly responsible for these alarming trends. PMID:28936399

Understanding Price Formation in Electricity Markets

NASA Astrophysics Data System (ADS)

Kadoya, Toshihisa; Sasaki, Tetsuo; Yokoyama, Akihiko; Ihara, Satoru

The electricity price will influence the future growth and mix of generation capacity that will in turn influence the future electricity price, and therefore, it is important to understand how electricity price is formed as well as its short-term and long-term impacts on the economy. This paper describes evaluation of PJM day-ahead market bidding data and comparison of various electricity markets in terms of the market clearing price and volatility. The objective is to find critical factors and mechanisms determining the movements of electricity price. It was found that speculation by a small number of bidders can cause price spikes, that a Nash equilibrium may exist during a delayed response of the electricity price to a decline of the fuel price, and that the hydro generation with storage capability effectively stabilizes the electricity price.

Adaptive critic designs for discrete-time zero-sum games with application to H(infinity) control.

PubMed

Al-Tamimi, Asma; Abu-Khalaf, Murad; Lewis, Frank L

2007-02-01

In this correspondence, adaptive critic approximate dynamic programming designs are derived to solve the discrete-time zero-sum game in which the state and action spaces are continuous. This results in a forward-in-time reinforcement learning algorithm that converges to the Nash equilibrium of the corresponding zero-sum game. The results in this correspondence can be thought of as a way to solve the Riccati equation of the well-known discrete-time H(infinity) optimal control problem forward in time. Two schemes are presented, namely: 1) a heuristic dynamic programming and 2) a dual-heuristic dynamic programming, to solve for the value function and the costate of the game, respectively. An H(infinity) autopilot design for an F-16 aircraft is presented to illustrate the results.

Wrestling J. B. Nash.

ERIC Educational Resources Information Center

Ellis, Gary D.

This paper focuses on how between 1965 and the present, the field of recreation has and has not accomplished the goals of author and educator J. B. Nash's in regard to recreation, physical education, and health, focusing on public recreation sponsored by city governments, county governments, and special tax districts. The paper looks at Nash's…

Liver fibrosis markers of nonalcoholic steatohepatitis

PubMed Central

Enomoto, Hirayuki; Bando, Yukihiro; Nakamura, Hideji; Nishiguchi, Shuhei; Koga, Masafumi

2015-01-01

Nonalcoholic fatty liver disease (NAFLD) is one of the major causes of chronic liver injury. NAFLD includes a wide range of clinical conditions from simple steatosis to nonalcoholic steatohepatitis (NASH), advanced fibrosis, and liver cirrhosis. The histological findings of NASH indicate hepatic steatosis and inflammation with characteristic hepatocyte injury (e.g., ballooning degeneration), as is observed in the patients with alcoholic liver disease. NASH is considered to be a potentially health-threatening disease that can progress to cirrhosis. A liver biopsy remains the most reliable diagnostic method to appropriately diagnose NASH, evaluate the severity of liver fibrosis, and determine the prognosis and optimal treatment. However, this invasive technique is associated with several limitations in routine use, and a number of biomarkers have been developed in order to predict the degree of liver fibrosis. In the present article, we review the current status of noninvasive biomarkers available to estimate liver fibrosis in the patients with NASH. We also discuss our recent findings on the use of the glycated albumin-to-glycated hemoglobin ratio, which is a new index that correlates to various chronic liver diseases, including NASH. PMID:26139988

Liver fibrosis markers of nonalcoholic steatohepatitis.

PubMed

Enomoto, Hirayuki; Bando, Yukihiro; Nakamura, Hideji; Nishiguchi, Shuhei; Koga, Masafumi

2015-06-28

Nonalcoholic fatty liver disease (NAFLD) is one of the major causes of chronic liver injury. NAFLD includes a wide range of clinical conditions from simple steatosis to nonalcoholic steatohepatitis (NASH), advanced fibrosis, and liver cirrhosis. The histological findings of NASH indicate hepatic steatosis and inflammation with characteristic hepatocyte injury (e.g., ballooning degeneration), as is observed in the patients with alcoholic liver disease. NASH is considered to be a potentially health-threatening disease that can progress to cirrhosis. A liver biopsy remains the most reliable diagnostic method to appropriately diagnose NASH, evaluate the severity of liver fibrosis, and determine the prognosis and optimal treatment. However, this invasive technique is associated with several limitations in routine use, and a number of biomarkers have been developed in order to predict the degree of liver fibrosis. In the present article, we review the current status of noninvasive biomarkers available to estimate liver fibrosis in the patients with NASH. We also discuss our recent findings on the use of the glycated albumin-to-glycated hemoglobin ratio, which is a new index that correlates to various chronic liver diseases, including NASH.

Kupffer Cells Undergo Fundamental Changes during the Development of Experimental NASH and Are Critical in Initiating Liver Damage and Inflammation

PubMed Central

Reid, D. T.; Reyes, J. L.; McDonald, B. A.; Vo, T.; Reimer, R. A.; Eksteen, B.

2016-01-01

Non-alcoholic fatty liver disease has become the leading liver disease in North America and is associated with the progressive inflammatory liver disease non-alcoholic steatohepatitis (NASH). Considerable effort has been made to understand the role of resident and recruited macrophage populations in NASH however numerous questions remain. Our goal was to characterize the dynamic changes in liver macrophages during the initiation of NASH in a murine model. Using the methionine-choline deficient diet we found that liver-resident macrophages, Kupffer cells were lost early in disease onset followed by a robust infiltration of Ly-6C+ monocyte-derived macrophages that retained a dynamic phenotype. Genetic profiling revealed distinct patterns of inflammatory gene expression between macrophage subsets. Only early depletion of liver macrophages using liposomal clodronate prevented the development of NASH in mice suggesting that Kupffer cells are critical for the orchestration of inflammation during experimental NASH. Increased understanding of these dynamics may allow us to target potentially harmful populations whilst promoting anti-inflammatory or restorative populations to ultimately guide the development of effective treatment strategies. PMID:27454866

The Combination of Blueberry Juice and Probiotics Ameliorate Non-Alcoholic Steatohepatitis (NASH) by Affecting SREBP-1c/PNPLA-3 Pathway via PPAR-α

PubMed Central

Ren, Tingting; Zhu, Juanjuan; Zhu, Lili; Cheng, Mingliang

2017-01-01

Nonalcoholic steatohepatitis (NASH) is liver inflammation and a major threat to public health. Several pharmaceutical agents have been used for NASH therapy but their high-rate side effects limit the use. Blueberry juice and probiotics (BP) have anti-inflammation and antibacterial properties, and may be potential candidates for NASH therapy. To understand the molecular mechanism, Sprague Dawley rats were used to create NASH models and received different treatments. Liver tissues were examined using HE (hematoxylin and eosin) and ORO (Oil Red O) stain, and serum biochemical indices were measured. The levels of peroxisome proliferators-activated receptor (PPAR)-α, sterol regulatory element binding protein-1c (SREBP-1c), Patatin-like phospholipase domain-containing protein 3 (PNPLA-3), inflammatory cytokines and apoptosis biomarkers in liver tissues were measured by qRT-PCR and Western blot. HE and ORO analysis indicated that the hepatocytes were seriously damaged with more and larger lipid droplets in NASH models while BP reduced the number and size of lipid droplets (p < 0.05). Meanwhile, BP increased the levels of SOD (superoxide dismutase), GSH (reduced glutathione) and HDL-C (high-density lipoprotein cholesterol), and reduced the levels of AST (aspartate aminotransferase), ALT (alanine aminotransferase), TG (triglycerides), LDL-C (low-density lipoprotein cholesterol) and MDA (malondialdehyde) in NASH models (p < 0.05). BP increased the level of PPAR-α (Peroxisome proliferator-activated receptor α), and reduced the levels of SREBP-1c (sterol regulatory element binding protein-1c) and PNPLA-3 (Patatin-like phospholipase domain-containing protein 3) (p < 0.05). BP reduced hepatic inflammation and apoptosis by affecting IL-6 (interleukin 6), TNF-α (Tumor necrosis factor α), caspase-3 and Bcl-2 in NASH models. Furthermore, PPAR-α inhibitor increased the level of SREBP-1c and PNPLA-3. Therefore, BP prevents NASH progression by affecting SREBP-1c/PNPLA-3 pathway via PPAR-α. PMID:28264426

Clinical and histological determinants of nonalcoholic steatohepatitis and advanced fibrosis in elderly patients.

PubMed

Noureddin, Mazen; Yates, Katherine P; Vaughn, Ivana A; Neuschwander-Tetri, Brent A; Sanyal, Arun J; McCullough, Arthur; Merriman, Raphael; Hameed, Bilal; Doo, Edward; Kleiner, David E; Behling, Cynthia; Loomba, Rohit

2013-11-01

The characteristics of nonalcoholic fatty liver disease (NAFLD) in elderly patients are unknown. Therefore, we aimed to examine the differences between elderly and nonelderly patients with NAFLD and to identify determinants of nonalcoholic steatohepatitis (NASH) and advanced fibrosis (bridging fibrosis or cirrhosis) in elderly patients. This is a cross-sectional analysis of adult participants who were prospectively enrolled in the NASH Clinical Research Network studies. Participants were included based on availability of the centrally reviewed liver histology data within 1 year of enrollment, resulting in 61 elderly (age ≥65 years) and 735 nonelderly (18-64 years) participants. The main outcomes were the presence of NASH and advanced fibrosis. Compared to nonelderly patients with NAFLD, elderly patients had a higher prevalence of NASH (56% versus 72%, P = 0.02), and advanced fibrosis (25% versus 44%, P = 0.002). Compared to nonelderly patients with NASH, elderly patients with NASH had higher rates of advanced fibrosis (35% versus 52%, P = 0.03), as well as other features of severe liver disease including the presence of ballooning degeneration, acidophil bodies, megamitochondria, and Mallory-Denk bodies (P ≤ 0.05 for each). In multiple logistic regression analyses, independent determinants of NASH in elderly patients included higher aspartate aminotransferase (AST) (odds ratio [OR] = 1.12, P = 0.007) and lower platelets (OR = 0.98, P = 0.02); and independent determinants of advanced fibrosis included higher AST (OR = 1.08, P = 0.007), lower alanine aminotransferase value (OR = 0.91, P = 0.002), and an increased odds of having low high-density lipoprotein (OR = 8.35, P = 0.02). Elderly patients are more likely to have NASH and advanced fibrosis than nonelderly patients with NAFLD. Liver biopsy may be considered in elderly patients and treatment should be initiated in those with NASH and advanced fibrosis. © 2013 by the American Association for the Study of Liver Diseases.

Interactions of a PPARGC1A Variant and a PNPLA3 Variant Affect Nonalcoholic Steatohepatitis in Severely Obese Taiwanese Patients.

PubMed

Tai, Chi-Ming; Huang, Chih-Kun; Tu, Hung-Pin; Hwang, Jau-Chung; Yeh, Ming-Lun; Huang, Chung-Feng; Huang, Jee-Fu; Dai, Chia-Yen; Chuang, Wan-Long; Yu, Ming-Lung

2016-03-01

The patatin-like phospholipase domain-containing protein 3 (PNPLA3) variant is associated with nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). However, the role of genetic variations of the peroxisome proliferator-activated receptor gamma coactivator-1-alpha gene (PPARGC1A) and glucokinase regulatory (GCKR) gene on NASH in obese patients remains unclear. We studied the effects and interaction of these genetic polymorphisms on NASH in severely obese Taiwanese patients.The genotypes of PPARGC1A rs8192678, PNPLA3 rs738409, and GCKR rs780094 were determined in 177 severely obese patients who underwent bariatric surgery. NASH was evaluated by liver histopathology.Of 177 patients, 29 (16.4%), 57 (33.2%), and 91 (51.4%) were in the non-NAFLD, steatosis, and NASH groups, respectively. We found that the PPARGC1A and PNPLA3 variants, but not the GCKR variant, were associated with NASH. The PPARGC1A rs8192678 GA/AA genotype was associated with higher steatosis grade and presence of ballooning degeneration. The PNPLA3 rs738409 GG genotype was associated with higher severity in all histologic features except for fibrosis. In multivariate analysis, both the PPARGC1A rs8192678 GA/AA genotype (odds ratio [OR] 2.32; 95% confidence interval [CI] 1.08-4.98; P = 0.031) and the PNPLA3 rs738409 GG genotype (OR 4.05; 95% CI 1.24-13.23; P = 0.021), and also body mass index were independent risk factors for NASH. Further, there was an additive effect of the PPARGC1A rs8192678 GA/AA genotype and the PNPLA3 rs738409 GG genotype on the presence of NASH (OR 6.83; 95% CI 1.61-29.01; P = 0.009).The PPARGC1A rs8192678 GA/AA genotype and the PNPLA3 rs738409 GG genotype had an additive effect on NASH in severely obese Taiwanese patients.

The Combination of Blueberry Juice and Probiotics Ameliorate Non-Alcoholic Steatohepatitis (NASH) by Affecting SREBP-1c/PNPLA-3 Pathway via PPAR-α.

PubMed

Ren, Tingting; Zhu, Juanjuan; Zhu, Lili; Cheng, Mingliang

2017-02-27

Nonalcoholic steatohepatitis (NASH) is liver inflammation and a major threat to public health. Several pharmaceutical agents have been used for NASH therapy but their high-rate side effects limit the use. Blueberry juice and probiotics (BP) have anti-inflammation and antibacterial properties, and may be potential candidates for NASH therapy. To understand the molecular mechanism, Sprague Dawley rats were used to create NASH models and received different treatments. Liver tissues were examined using HE (hematoxylin and eosin) and ORO (Oil Red O) stain, and serum biochemical indices were measured. The levels of peroxisome proliferators-activated receptor (PPAR)-α, sterol regulatory element binding protein-1c (SREBP-1c), Patatin-like phospholipase domain-containing protein 3 (PNPLA-3), inflammatory cytokines and apoptosis biomarkers in liver tissues were measured by qRT-PCR and Western blot. HE and ORO analysis indicated that the hepatocytes were seriously damaged with more and larger lipid droplets in NASH models while BP reduced the number and size of lipid droplets ( p < 0.05). Meanwhile, BP increased the levels of SOD (superoxide dismutase), GSH (reduced glutathione) and HDL-C (high-density lipoprotein cholesterol), and reduced the levels of AST (aspartate aminotransferase), ALT (alanine aminotransferase), TG (triglycerides), LDL-C (low-density lipoprotein cholesterol) and MDA (malondialdehyde) in NASH models ( p < 0.05). BP increased the level of PPAR-α (Peroxisome proliferator-activated receptor α), and reduced the levels of SREBP-1c (sterol regulatory element binding protein-1c) and PNPLA-3 (Patatin-like phospholipase domain-containing protein 3) ( p < 0.05). BP reduced hepatic inflammation and apoptosis by affecting IL-6 (interleukin 6), TNF-α (Tumor necrosis factor α), caspase-3 and Bcl-2 in NASH models. Furthermore, PPAR-α inhibitor increased the level of SREBP-1c and PNPLA-3. Therefore, BP prevents NASH progression by affecting SREBP-1c/PNPLA-3 pathway via PPAR-α.

Usefulness of Cytokeratin-18M65 in Diagnosing Non-Alcoholic Steatohepatitis in Japanese Population.

PubMed

Hasegawa, Yutaka; Kim, Soo Ryang; Hatae, Takashi; Ohta, Mitsuhiro; Fujinami, Aya; Sugimoto, Kayo; Kim, Ke Ih; Imoto, Susumu; Tohyama, Madoka; Kim, Soo Ki; Ikura, Yoshihiro; Kudo, Masatoshi

2015-10-01

The aim of this study was to evaluate cytokeratin-18M65 (CK-18M65) for distinguishing between simple steatosis (SS) and non-alcoholic steatohepatitis (NASH) against healthy individuals (HIs) in Japanese population. The serum from 24 HIs, 21 patients with SS and 20 patients with NASH were examined. Serum CK-18M65 was measured by enzyme-linked immunosorbent assay. Aspartate aminotransferase was significantly different between NASH patients and HIs with p < 0.0001 (SS patients and HIs: p < 0.0001), as was alanine aminotransferase between NASH patients and HIs with p < 0.0001 (SS patients and HIs: p < 0.0001). Serum CK-18M65 increased in a stepwise fashion in HIs and also in SS and NASH patients. Multivariate logistic regression analysis revealed that NASH could be diagnosed with the use of CK-18M65 alone (p = 0.0285, OR 1.0038, 95% CI 1.0004-1.0073). At the optimal cut-off level of 548 U/l, CK-18M65 had an AUC value of 0.7369, 60.00% sensitivity and 85.70% specificity. In patients with NASH, no significant difference was observed between low fibrosis (Stage 0-1, 794.30 ± 454.41, n = 10) and high fibrosis (Stage 2-3, 809.70 ± 641.43, n = 10; p = 0.5967) and between slight steatosis (<33%, 512.89 ± 229.65, n = 9) and moderate steatosis (≥33%, 655.13 ± 480.78, n = 32) in patients with non-alcoholic fatty liver disease (NAFLD; p = 0.7647) with the use of CK-18M65. Serum CK-18M65 distinguished NASH from SS, but could not assess the severity of steatosis in NAFLD patients or the grade of fibrosis in NASH patients in Japanese population. © 2015 S. Karger AG, Basel.

A novel diagnostic biomarker panel for obesity-related nonalcoholic steatohepatitis (NASH).

PubMed

Younossi, Zobair M; Jarrar, Mohammed; Nugent, Clare; Randhawa, Manpreet; Afendy, Mariam; Stepanova, Maria; Rafiq, Nila; Goodman, Zachary; Chandhoke, Vikas; Baranova, Ancha

2008-11-01

Within the spectrum of nonalcoholic fatty liver disease (NAFLD), only patients with nonalcoholic steatohepatitis (NASH) show convincing evidence for progression. To date, liver biopsy remains the gold standard for the diagnosis of NASH; however, liver biopsy is expensive and associated with a small risk, emphasizing the urgent need for noninvasive diagnostic biomarkers. Recent findings suggest a role for apoptosis and adipocytokines in the pathogenesis of NASH. The aim of this study was to develop a noninvasive diagnostic biomarker for NASH. The study included 101 patients with liver biopsies who were tested with enzyme-linked immunosorbent assay (ELISA)-based assays. Of these, 69 were included in the biomarker development set and 32 were included in the biomarker validation set. Clinical data and serum samples were collected at the time of biopsy. Fasting serum samples were assayed for adiponectin, resistin, insulin, glucose, TNF-alpha, IL-6, IL-8, cytokeratin CK-18 (M65 antigen), and caspase-cleaved CK-18 (M30 antigen). Data analysis revealed that the levels of M30 antigen (cleaved CK-18) predicted histological NASH with 70% sensitivity and 83.7% specificity and area under the curve (AUC) = 0.711, p < 10(-4), whereas the predictive value of the levels of intact CK-18 (M65) was higher (63.6% sensitivity and 89.4% specificity and AUC = 0.814, p < 10(-4)). Histological NASH could be predicted by a combination of Cleaved CK-18, a product of the subtraction of Cleaved CK-18 level from intact CK-18 level, serum adiponectin, and serum resistin with a sensitivity of 95.45% sensitivity, specificity of 70.21%, and AUC of 0.908 (p < 10(-4)). Blinded validation of this model confirmed its reliability for separating NASH from simple steatosis. Four ELISA-based tests were combined to form a simple diagnostic biomarker for NASH.

Purinergic receptor X7 is a key modulator of metabolic oxidative stress-mediated autophagy and inflammation in experimental nonalcoholic steatohepatitis

PubMed Central

Das, Suvarthi; Seth, Ratanesh Kumar; Kumar, Ashutosh; Kadiiska, Maria B.; Michelotti, Gregory; Diehl, Anna Mae

2013-01-01

Recent studies indicate that metabolic oxidative stress, autophagy, and inflammation are hallmarks of nonalcoholic steatohepatitis (NASH) progression. However, the molecular mechanisms that link these important events in NASH remain unclear. In this study, we investigated the mechanistic role of purinergic receptor X7 (P2X7) in modulating autophagy and resultant inflammation in NASH in response to metabolic oxidative stress. The study uses two rodent models of NASH. In one of them, a CYP2E1 substrate bromodichloromethane is used to induce metabolic oxidative stress and NASH. Methyl choline-deficient diet feeding is used for the other NASH model. CYP2E1 and P2X7 receptor gene-deleted mice are used to establish their roles in regulating metabolic oxidative stress and autophagy. Autophagy gene expression, protein levels, confocal microscopy based-immunolocalization of lysosome-associated membrane protein (LAMP)2A and histopathological analysis were performed. CYP2E1-dependent metabolic oxidative stress induced increases in P2X7 receptor expression and chaperone-mediated autophagy markers LAMP2A and heat shock cognate 70 but caused depletion of light chain 3 isoform B (LC3B) protein levels. P2X7 receptor gene deletion significantly decreased LAMP2A and inflammatory indicators while significantly increasing LC3B protein levels compared with wild-type mice treated with bromodichloromethane. P2X7 receptor-deleted mice were also protected from NASH pathology as evidenced by decreased inflammation and fibrosis. Our studies establish that P2X7 receptor is a key regulator of autophagy induced by metabolic oxidative stress in NASH, thereby modulating hepatic inflammation. Furthermore, our findings presented here form a basis for P2X7 receptor as a potential therapeutic target in the treatment for NASH. PMID:24157968

Nash Social Welfare in Multiagent Resource Allocation

NASA Astrophysics Data System (ADS)

Ramezani, Sara; Endriss, Ulle

We study different aspects of the multiagent resource allocation problem when the objective is to find an allocation that maximizes Nash social welfare, the product of the utilities of the individual agents. The Nash solution is an important welfare criterion that combines efficiency and fairness considerations. We show that the problem of finding an optimal outcome is NP-hard for a number of different languages for representing agent preferences; we establish new results regarding convergence to Nash-optimal outcomes in a distributed negotiation framework; and we design and test algorithms similar to those applied in combinatorial auctions for computing such an outcome directly.

Deficiency of iNOS-derived NO accelerates lipid accumulation-independent liver fibrosis in non-alcoholic steatohepatitis mouse model.

PubMed

Nozaki, Yuichi; Fujita, Koji; Wada, Koichiro; Yoneda, Masato; Kessoku, Takaomi; Shinohara, Yoshiyasu; Imajo, Kento; Ogawa, Yuji; Nakamuta, Makoto; Saito, Satoru; Masaki, Naohiko; Nagashima, Yoji; Terauchi, Yasuo; Nakajima, Atsushi

2015-04-01

Although many of the factors and molecules closely associated with non-alcoholic steatohepatitis (NASH) have been reported, the role of inducible nitric oxide synthase (iNOS)-derived nitric oxide (NO) on the progression of NASH remains unclear. We therefore investigated the role of iNOS-derived NO in NASH pathogenesis with a long-term follow-up study using systemic iNOS-knockout mice under high-fat diet (HFD) conditions. iNOS-knockout and wild-type mice were fed a basal or HFD for 10 or 48 weeks. Lipid accumulation, fibrosis, and inflammation were evaluated, and various factors and molecules closely associated with NASH were analyzed. Marked fibrosis and inflammation (indicators of NASH) were observed in the livers of iNOS-knockout mice compared to wild-type mice after 48 weeks of a HFD; however, lipid accumulation in iNOS-knockout mice livers was less than in the wild-type. Increased expressions of various cytokines that are transcriptionally controlled by NF-kB in iNOS-deficient mice livers were observed during HFD conditions. iNOS-derived NO may play a protective role against the progression to NASH during an HFD by preventing fibrosis and inflammation, which are mediated by NF-kB activation in Kupffer cells. A lack of iNOS-derived NO accelerates progression to NASH without excessive lipid accumulation.

Teucrium polium reversed the MCD diet-induced liver injury in rats.

PubMed

Amini, Rahim; Yazdanparast, Razieh; Aghazadeh, Safiyeh; Ghaffari, Seyed H

2011-09-01

In the present study, we evaluated the ability of Teucrium polium ethyl acetate fraction, with high antioxidant activity, in the treatment of nonalcoholic steatohepatitis (NASH) in rats and its possible effect on factors involved in pathogenesis of the disease. To induce NASH, a methionine and choline deficient (MCD) diet was given to N-Mary rats for 8 weeks. After NASH development, MCD-fed rats were divided into 2 groups: NASH group that received MCD diet and NASH + T group which was fed MCD diet plus ethyl acetate fraction of T. polium orally for 3 weeks. Histopathological evaluations revealed that treatment with the extract has abated the severity of NASH among the MCD-fed rats. In addition, the fraction reduced the elevated levels of hepatic tumor necrosis factor-alpha (TNF-α) and transforming growth factor-beta (TGF-β) gene expression and also the elevated level of malondialdehyde (MDA). In addition, the extract increased the activities of superoxide dismutase (SOD), glutathione peroxidase (GPx) and enhanced the level of hepatic glutathione (GSH). Moreover, the fraction treatments lowered caspase-3 level and the phosphorylated form of C-Jun N-terminal kinase (JNK) and augmented the phosphorylated level of extracellular regulated kinase1/2 (ERK1/2). These results indicate that the ethyl acetate fraction of T. poium effectively reversed NASH, mainly due to its strong antioxidant and anti-inflammatory properties.

Pathophysiology of NASH: perspectives for a targeted treatment

PubMed Central

Marra, Fabio; Lotersztajn, Sophie

2013-01-01

Non alcoholic steatohepatitis (NASH) is the more severe form of nonalcoholic fatty liver disease. In NASH, fatty liver, hepatic inflammation, hepatocyte injury and fibrogenesis are associated, and thi condition may eventually lead to cirrhosis. Current treatment of NASH relies on the reduction of body weight and increase in physical activity, but there is no pharmacologic treatment approved as yet. Emerging data indicate that NASH progression results from parallel events originating from the liver as well as from the adipose tissue, the gut and the gastrointestinal tract. Thus, dysfunction of the adipose tissue through enhanced flow of free fatty acids and release of adipocytokines, and alterations in the gut microbiome generate proinflammatory signals that underly NASH progression. Additional ‘extrahepatic hits’ include dietary factors and gastrointestinal hormones. Within the liver, hepatocyte apoptosis, ER stress and oxidative stress are key contributors to hepatocellular injury. In addition, lipotoxic mediators and danger signals activate Kupffer cells which initiate and perpetuate the inflammatory response by releasing inflammatory mediators that contribute to inflammatory cell recruitment and development of fibrosis. Inflammatory and fibrogenic mediators include chemokines, the cannabinoid system, the inflammasome and activation of pattern-recognition receptors. Here we review the major mechanisms leading to appearance and progression of NASH, focusing on both extrahepatic signals and local inflammatory mechanisms, in an effort to identify the most promising molecular targets for the treatment of this condition. PMID:23394092

77 FR 10553 - Match-E-Be-Nash-She-Wish Band of Pottawatomi Indians (Gun Lake)-Amendment to Liquor Beverage...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-22

... DEPARTMENT OF THE INTERIOR Bureau of Indian Affairs Match-E-Be-Nash-She-Wish Band of Pottawatomi Indians (Gun Lake)-- Amendment to Liquor Beverage Control Ordinance AGENCY: Bureau of Indian Affairs, Interior. ACTION: Notice SUMMARY: This notice publishes the amendments to the Match-E-Be-Nash- She-Wish...

The Hopeful Traveler Jay Bryan Nash.

ERIC Educational Resources Information Center

Jessup, Harvey M., Comp.

This book is one of a series of publications preserving the best writing and speeches of outstanding leaders of the American Alliance for Health, Physical Education, Recreation and Dance. Jay Bryan Nash was one of the founders of the Alliance. The speeches and essays by Nash in this collection are, for the most part, appearing in published form…

Pre-Collegiate Teachers and Gary Nash

ERIC Educational Resources Information Center

Sesso, Gloria

2009-01-01

In this article, the author recalls the time she met Gary Nash at UCLA on July 13, 1992, when they began the work of creating the National Standards in History. Professor Nash was the leader in the development of the United States History Standards. In creating the Standards, they were to focus on Historical Thinking. They needed to organize the…

77 FR 43369 - Alumax Mill Products, Inc. Doing Business as Alcoa Mill Products Texarkana a Subsidiary of Alcoa...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-07-24

.... Doing Business as Alcoa Mill Products Texarkana a Subsidiary of Alcoa, Inc. Nash, TX; Amended... Mill Products Texarkana, a subsidiary of Alcoa, Inc., Nash, Texas, was separated is Alumax Mill... Alcoa Mill Products Texarkana, a subsidiary of Alcoa, Inc., Nash, Texas, who became totally or partially...

Evolutionary potential games on lattices

NASA Astrophysics Data System (ADS)

Szabó, György; Borsos, István

2016-04-01

Game theory provides a general mathematical background to study the effect of pair interactions and evolutionary rules on the macroscopic behavior of multi-player games where players with a finite number of strategies may represent a wide scale of biological objects, human individuals, or even their associations. In these systems the interactions are characterized by matrices that can be decomposed into elementary matrices (games) and classified into four types. The concept of decomposition helps the identification of potential games and also the evaluation of the potential that plays a crucial role in the determination of the preferred Nash equilibrium, and defines the Boltzmann distribution towards which these systems evolve for suitable types of dynamical rules. This survey draws parallel between the potential games and the kinetic Ising type models which are investigated for a wide scale of connectivity structures. We discuss briefly the applicability of the tools and concepts of statistical physics and thermodynamics. Additionally the general features of ordering phenomena, phase transitions and slow relaxations are outlined and applied to evolutionary games. The discussion extends to games with three or more strategies. Finally we discuss what happens when the system is weakly driven out of the "equilibrium state" by adding non-potential components representing games of cyclic dominance.

Nonalcoholic fatty liver disease: Update on pathogenesis, diagnosis, treatment and the role of S-adenosylmethionine

PubMed Central

Mato, José M; Lu, Shelly C

2015-01-01

Nonalcoholic fatty liver disease (NAFLD) is currently the most common liver disease worldwide affecting over one-third of the population in the U.S. It has been associated with obesity, type 2 diabetes, hyperlipidemia, and insulin resistance and is initiated by the accumulation of triglycerides in hepatocytes. Isolated hepatic steatosis (IHS) remains a benign process, while a subset develops superimposed inflammatory activity and progression to nonalcoholic steatohepatitis (NASH) with or without fibrosis. However, the molecular mechanisms underlying NAFLD progression are not completely understood. Liver biopsy is still required to differentiate IHS from NASH as easily accessible noninvasive biomarkers are lacking. In terms of treatments for NASH, pioglitazone, vitamin E, and obeticholic acid have shown some benefit. All of these agents have potential complications associated with long-term use. Nowadays, a complex hypothesis suggests that multiple parallel hits are involved in NASH development. However, the ‘key switch’ between IHS and NASH remains to be discovered. We have recently shown that knocking out enzymes involved in S-adenosylmethionine (SAMe) metabolism, the main biological methyl donor in humans that is abundant in the liver, will lead to NASH development in mice. This could be due to the fact that a normal SAMe level is required to establish the proper ratio of phosphatidylethanolamine to phosphatidylcholine that has been found to be important in NAFLD progression. New data from humans have also suggested that these enzymes play a role in the pathogenesis of NAFLD and that some of SAMe cycle metabolites may serve as noninvasive biomarkers of NASH. In this review, we discuss the evidence of the role of SAMe in animal models and humans with NAFLD and how studying this area may lead to the discovery of new noninvasive biomarkers and possibly personalized treatment for NASH. PMID:25873078

Docosahexaenoic Acid Attenuates Hepatic Inflammation, Oxidative Stress, and Fibrosis without Decreasing Hepatosteatosis in a Ldlr−/− Mouse Model of Western Diet-Induced Nonalcoholic Steatohepatitis123

PubMed Central

Depner, Christopher M.; Philbrick, Kenneth A.; Jump, Donald B.

2013-01-01

The incidence of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) has increased in parallel with the incidence of obesity. While both NAFLD and NASH are characterized by hepatosteatosis, NASH is characterized by hepatic damage, inflammation, oxidative stress, and fibrosis. We previously reported that feeding Ldlr−/− mice a high-fat, high-cholesterol diet containing menhaden oil attenuated several markers of NASH, including hepatosteatosis, inflammation, and fibrosis. Herein, we test the hypothesis that DHA [22:6 (n-3)] is more effective than EPA [20:5 (n-3)] at preventing Western diet (WD)-induced NASH in Ldlr−/− mice. Mice were fed the WD supplemented with either olive oil (OO), EPA, DHA, or EPA + DHA for 16 wk. WD + OO feeding induced a severe NASH phenotype, characterized by robust hepatosteatosis, inflammation, oxidative stress, and fibrosis. Whereas none of the C20–22 (n-3) fatty acid treatments prevented WD-induced hepatosteatosis, all 3 (n-3) PUFA-containing diets significantly attenuated WD-induced inflammation, fibrosis, and hepatic damage. The capacity of dietary DHA to suppress hepatic markers of inflammation (Clec4F, F4/80, Trl4, Trl9, CD14, Myd88), fibrosis (Procol1α1, Tgfβ1), and oxidative stress (NADPH oxidase subunits Nox2, p22phox, p40phox, p47phox, p67phox) was significantly greater than dietary EPA. The effects of DHA on these markers paralleled DHA-mediated suppression of hepatic Fads1 mRNA abundance and hepatic arachidonic acid content. Because DHA suppression of NASH markers does not require a reduction in hepatosteatosis, dietary DHA may be useful in combating NASH in obese humans. PMID:23303872

Impact of dietary fat on the development of non-alcoholic fatty liver disease in Ldlr−/− mice

PubMed Central

Jump, Donald B.; Depner, Christopher M.; Tripathy, Sasmita; Lytle, Kelli A.

2015-01-01

The prevalence of non-alcoholic fatty liver disease (NAFLD) has increased in parallel with central obesity and is now the most common chronic liver disease in developed countries. NAFLD is defined as excessive accumulation of lipid in the liver, i.e. hepatosteatosis. The severity of NAFLD ranges from simple fatty liver (steatosis) to non-alcoholic steatohepatitis (NASH). Simple steatosis is relatively benign until it progresses to NASH, which is characterised by hepatic injury, inflammation, oxidative stress and fibrosis. Hepatic fibrosis is a risk factor for cirrhosis and primary hepatocellular carcinoma. Our studies have focused on the impact of diet on the onset and progression of NASH. We developed a mouse model of NASH by feeding Ldlr−/− mice a western diet (WD), a diet moderately high in saturated and trans-fat, sucrose and cholesterol. The WD induced a NASH phenotype in Ldlr−/− mice that recapitulates many of the clinical features of human NASH. We also assessed the capacity of the dietary n-3 PUFA, i.e. EPA (20 : 5,n-3) and DHA (22 : 6,n-3), to prevent WD-induced NASH in Ldlr−/− mice. Histologic, transcriptomic, lipidomic and metabolomic analyses established that DHA was equal or superior to EPA at attenuating WD-induced dyslipidemia and hepatic injury, inflammation, oxidative stress and fibrosis. Dietary n-3 PUFA, however, had no significant effect on WD-induced changes in body weight, body fat or blood glucose. These studies provide a molecular and metabolic basis for understanding the strengths and weaknesses of using dietary n-3 PUFA to prevent NASH in human subjects. PMID:26282529

DOE Office of Scientific and Technical Information (OSTI.GOV)

Winkler, Sandra, E-mail: sandra.pelz@medizin.uni-leipzig.de; Borkham-Kamphorst, Erawan, E-mail: ekamphorst@ukaachen.de; Stock, Peggy, E-mail: peggy.stock@medizin.uni-leipzig.de

Non-alcoholic steatohepatitis (NASH) is a frequent clinical picture characterised by hepatic inflammation, lipid accumulation and fibrosis. When untreated, NASH bears a high risk of developing liver cirrhosis and consecutive hepatocellular carcinoma requiring liver transplantation in its end-stage. However, donor organ scarcity has prompted the search for alternatives, of which hepatocyte or stem cell-derived hepatocyte transplantation are regarded auspicious options of treatment. Mesenchymal stem cells (MSC) are able to differentiate into hepatocyte-like cells and thus may represent an alternative cell source to primary hepatocytes. In addition these cells feature anti-inflammatory and pro-regenerative characteristics, which might favour liver recovery from NASH. Themore » aim of this study was to investigate the potential benefit of hepatocyte-like cells derived from human bone marrow MSC in a mouse model of diet-induced NASH. Seven days post-transplant, human hepatocyte-like cells were found in the mouse liver parenchyma. Triglyceride depositions were lowered in the liver but restored to normal in the blood. Hepatic inflammation was attenuated as verified by decreased expression of the acute phase protein serum amyloid A, inflammation-associated markers (e.g. lipocalin 2), as well as the pro-inflammatory cytokine TNFα. Moreover, the proliferation of host hepatocytes that indicate the regenerative capacity in livers receiving cell transplants was enhanced. Transplantation of MSC-derived human hepatocyte-like cells corrects NASH in mice by restoring triglyceride depositions, reducing inflammation and augmenting the regenerative capacity of the liver. - Highlights: • First time to show NASH in an immune-deficient mouse model. • Human MSC attenuate NASH and improve lipid homeostasis. • MSC act anti-fibrotic and augment liver regeneration by stimulation of proliferation. • Pre-clinical assessment of human MSC for stem cell-based therapy of NASH.« less

Equilibrium theory of island biogeography: A review

Treesearch

Angela D. Yu; Simon A. Lei

2001-01-01

The topography, climatic pattern, location, and origin of islands generate unique patterns of species distribution. The equilibrium theory of island biogeography creates a general framework in which the study of taxon distribution and broad island trends may be conducted. Critical components of the equilibrium theory include the species-area relationship, island-...

Optimal strategies for electric energy contract decision making

NASA Astrophysics Data System (ADS)

Song, Haili

2000-10-01

The power industry restructuring in various countries in recent years has created an environment where trading of electric energy is conducted in a market environment. In such an environment, electric power companies compete for the market share through spot and bilateral markets. Being profit driven, electric power companies need to make decisions on spot market bidding, contract evaluation, and risk management. New methods and software tools are required to meet these upcoming needs. In this research, bidding strategy and contract pricing are studied from a market participant's viewpoint; new methods are developed to guide a market participant in spot and bilateral market operation. A supplier's spot market bidding decision is studied. Stochastic optimization is formulated to calculate a supplier's optimal bids in a single time period. This decision making problem is also formulated as a Markov Decision Process. All the competitors are represented by their bidding parameters with corresponding probabilities. A systematic method is developed to calculate transition probabilities and rewards. The optimal strategy is calculated to maximize the expected reward over a planning horizon. Besides the spot market, a power producer can also trade in the bilateral markets. Bidding strategies in a bilateral market are studied with game theory techniques. Necessary and sufficient conditions of Nash Equilibrium (NE) bidding strategy are derived based on the generators' cost and the loads' willingness to pay. The study shows that in any NE, market efficiency is achieved. Furthermore, all Nash equilibria are revenue equivalent for the generators. The pricing of "Flexible" contracts, which allow delivery flexibility over a period of time with a fixed total amount of electricity to be delivered, is analyzed based on the no-arbitrage pricing principle. The proposed algorithm calculates the price based on the optimality condition of the stochastic optimization formulation. Simulation examples illustrate the tradeoffs between prices and scheduling flexibility. Spot bidding and contract pricing are not independent decision processes. The interaction between spot bidding and contract evaluation is demonstrated with game theory equilibrium model and market simulation results. It leads to the conclusion that a market participant's contract decision making needs to be further investigated as an integrated optimization formulation.

Factors predicting non-alcoholic steatohepatitis (NASH) and advanced fibrosis in patients with non-alcoholic fatty liver disease (NAFLD).

PubMed

Tasneem, Abbas Ali; Luck, Nasir Hassan; Majid, Zain

2018-04-01

Introduction To determine the factors predicting non-alcoholic steatohepatitis (NASH) and advanced fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). Methodology All patients aged >18 years and having a fatty liver on abdominal ultrasound (US), presenting from January 2011 to January 2017, were included. A liver biopsy was performed on all the patients. Results Of 96 patients undergoing liver biopsy for non-alcoholic fatty liver disease (NAFLD), 76 (79.2%) were men. On liver US, diffuse fatty liver (DFL) was noted in 68 (70.8%) patients. Liver biopsy showed non-alcoholic steatohepatitis (NASH) in 78 (81.3%) patients. Factors associated with NASH were male gender, body mass index (BMI) > 27 kg/m 2 , DFL and raised alanine aminotransferase (ALT). A GULAB score (based on gender, US liver findings, lipid (fasting) levels, ALT level and BMI) of ≥5 predicted NASH with 82.05% sensitivity. Factors associated with advanced fibrosis in NAFLD were age >40 years, diabetes mellitus, AST/ALT ratio > 1 and raised GGT. Conclusion NASH is common in patients with male gender, high BMI, DFL on liver US, raised ALT and GULAB score ≥5.

Controversies in the Diagnosis and Management of NAFLD and NASH.

PubMed

Rinella, Mary E; Loomba, Rohit; Caldwell, Stephen H; Kowdley, Kris; Charlton, Michael; Tetri, Brent; Harrison, Stephen A

2014-04-01

Nonalcoholic fatty liver disease (NAFLD) is recognized as the most common cause of chronic liver disease in the United States. Nonalcoholic steatohepatitis (NASH) occurs in a subset of patients with NAFLD and is characterized by the presence of hepa-tocellular injury, which is progressive in a substantial proportion of cases and can lead to cirrhosis and all of its complications. Although the diagnosis of NAFLD can be made through imaging studies or liver biopsy, the diagnosis of NASH still requires histologic confirmation. Liver biopsy should be performed in the presence of risk factors for advanced disease. Measures aimed at promoting weight loss, a healthier lifestyle, and optimization of metabolic risk factors remain the cornerstone of management of NAFLD. Therapeutic agents that are presently considered the most promising in NAFLD are effective in less than 50% of patients. Among patients with biopsy-proven NASH, treatment with pharmacologic agents should be considered; however, the role of specific agents in NASH still needs further study. Despite a wealth of research over the past 15 years, many controversies remain with respect to the diagnosis and management of NAFLD and NASH as well as the influence of alcohol on liver disease progression in these patients.

Pathogenesis of Nonalcoholic Steatohepatitis: Interactions between Liver Parenchymal and Nonparenchymal Cells

PubMed Central

Magee, Nancy; Zou, An

2016-01-01

Nonalcoholic fatty liver disease (NAFLD) is the most common type of chronic liver disease in the Western countries, affecting up to 25% of the general population and becoming a major health concern in both adults and children. NAFLD encompasses the entire spectrum of fatty liver disease in individuals without significant alcohol consumption, ranging from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH) and cirrhosis. NASH is a manifestation of the metabolic syndrome and hepatic disorders with the presence of steatosis, hepatocyte injury (ballooning), inflammation, and, in some patients, progressive fibrosis leading to cirrhosis. The pathogenesis of NASH is a complex process and implicates cell interactions between liver parenchymal and nonparenchymal cells as well as crosstalk between various immune cell populations in liver. Lipotoxicity appears to be the central driver of hepatic cellular injury via oxidative stress and endoplasmic reticulum (ER) stress. This review focuses on the contributions of hepatocytes and nonparenchymal cells to NASH, assessing their potential applications to the development of novel therapeutic agents. Currently, there are limited pharmacological treatments for NASH; therefore, an increased understanding of NASH pathogenesis is pertinent to improve disease interventions in the future. PMID:27822476

Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States.

PubMed

Wong, Robert J; Aguilar, Maria; Cheung, Ramsey; Perumpail, Ryan B; Harrison, Stephen A; Younossi, Zobair M; Ahmed, Aijaz

2015-03-01

Nonalcoholic steatohepatitis (NASH) has been predicted to become the leading indication for liver transplantation (LT) in the United States. However, few studies have evaluated changes in the etiology of liver diseases among patients awaiting LT, and none have focused on the effects of NASH on liver transplant waitlists in the United States. We collected data from the United Network for Organ Sharing and Organ Procurement and Transplantation Network registry from 2004 through 2013, on liver transplant waitlist registrants with hepatitis C virus (HCV) infection, NASH, alcoholic liver disease (ALD), or a combination of HCV infection and ALD. We compared differences in survival within 90 days of registration (90-day survival) and probability of LT among patients with different diseases using Kaplan-Meier and multivariate logistic regression models. Between 2004 and 2013, new waitlist registrants with NASH increased by 170% (from 804 to 2174), with ALD increased by 45% (from 1400 to 2024), and with HCV increased by 14% (from 2887 to 3291); registrants with HCV and ALD decreased by 9% (from 880 to 803). In 2013, NASH became the second-leading disease among liver transplant waitlist registrants, after HCV. Patients with ALD had a significantly higher mean Model for End-Stage Liver Disease score at time of waitlist registration than other registrants. However, after multivariate adjustment, patients with ALD were less likely to die within 90 days when compared with patients with NASH (odds ratio [OR] = 0.77; 95% confidence interval [CI]: 0.67-0.89; P < .001); patients with HCV infection or HCV and ALD had similar odds for 90-day survival compared with NASH patients. Compared with patients with NASH, patients with HCV (OR = 1.45; 95% CI: 1.35-1.55; P < .001), ALD (OR = 1.15; 95% CI: 1.06-1.24; P < .001), or HCV and ALD (OR = 1.29; 95% CI: 1.18-1.42; P < .001) had higher odds for 90-day survival. Based on data from US adult LT databases, since 2004 the number of adults with NASH awaiting LTs has almost tripled. However, patients with NASH are less likely to undergo LT and less likely to survive for 90 days on the waitlist than patients with HCV, ALD, or HCV and ALD. Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.

Noninvasive Tests Do Not Accurately Differentiate Nonalcoholic Steatohepatitis From Simple Steatosis: A Systematic Review and Meta-analysis.

PubMed

Verhaegh, Pauline; Bavalia, Roisin; Winkens, Bjorn; Masclee, Ad; Jonkers, Daisy; Koek, Ger

2018-06-01

Nonalcoholic fatty liver disease is a rapidly increasing health problem. Liver biopsy analysis is the most sensitive test to differentiate between nonalcoholic steatohepatitis (NASH) and simple steatosis (SS), but noninvasive methods are needed. We performed a systematic review and meta-analysis of noninvasive tests for differentiating NASH from SS, focusing on blood markers. We performed a systematic search of the PubMed, Medline and Embase (1990-2016) databases using defined keywords, limited to full-text papers in English and human adults, and identified 2608 articles. Two independent reviewers screened the articles and identified 122 eligible articles that used liver biopsy as reference standard. If at least 2 studies were available, pooled sensitivity (sens p ) and specificity (spec p ) values were determined using the Meta-Analysis Package for R (metafor). In the 122 studies analyzed, 219 different blood markers (107 single markers and 112 scoring systems) were identified to differentiate NASH from simple steatosis, and 22 other diagnostic tests were studied. Markers identified related to several pathophysiological mechanisms. The markers analyzed in the largest proportions of studies were alanine aminotransferase (sens p , 63.5% and spec p , 74.4%) within routine biochemical tests, adiponectin (sensp, 72.0% and spec p , 75.7%) within inflammatory markers, CK18-M30 (sens p , 68.4% and spec p , 74.2%) within markers of cell death or proliferation and homeostatic model assessment of insulin resistance (sens p , 69.0% and spec p , 72.7%) within the metabolic markers. Two scoring systems could also be pooled: the NASH test (differentiated NASH from borderline NASH plus simple steatosis with 22.9% sens p and 95.3% spec p ) and the GlycoNASH test (67.1% sens p and 63.8% spec p ). In the meta-analysis, we found no test to differentiate NASH from SS with a high level of pooled sensitivity and specificity (≥80%). However, some blood markers, when included in scoring systems in single studies, identified patients with NASH with ≥80% sensitivity and specificity. Replication studies and more standardized study designs are urgently needed. At present, no marker or scoring system can be recommended for use in clinical practice to differentiate NASH from simple steatosis. Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.

Reversible shear-induced crystallization above equilibrium freezing temperature in a lyotropic surfactant system

PubMed Central

Rathee, Vikram; Krishnaswamy, Rema; Pal, Antara; Raghunathan, V. A.; Impéror-Clerc, Marianne; Pansu, Brigitte; Sood, A. K.

2013-01-01

We demonstrate a unique shear-induced crystallization phenomenon above the equilibrium freezing temperature in weakly swollen isotropic and lamellar mesophases with bilayers formed in a cationic-anionic mixed surfactant system. Synchrotron rheological X-ray diffraction study reveals the crystallization transition to be reversible under shear (i.e., on stopping the shear, the nonequilibrium crystalline phase melts back to the equilibrium mesophase). This is different from the shear-driven crystallization below , which is irreversible. Rheological optical observations show that the growth of the crystalline phase occurs through a preordering of the phase to an phase induced by shear flow, before the nucleation of the phase. Shear diagram of the phase constructed in the parameter space of shear rate vs. temperature exhibits and transitions above the equilibrium crystallization temperature , in addition to the irreversible shear-driven nucleation of in the phase below . In addition to revealing a unique class of nonequilibrium phase transition, the present study urges a unique approach toward understanding shear-induced phenomena in concentrated mesophases of mixed amphiphilic systems. PMID:23986497

Urinary metabolomics analysis identifies key biomarkers of different stages of nonalcoholic fatty liver disease

PubMed Central

Dong, Shu; Zhan, Zong-Ying; Cao, Hong-Yan; Wu, Chao; Bian, Yan-Qin; Li, Jian-Yuan; Cheng, Gen-Hong; Liu, Ping; Sun, Ming-Yu

2017-01-01

AIM To identify a panel of biomarkers that can distinguish between non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), and explore molecular mechanism involved in the process of developing NASH from NAFLD. METHODS Biomarkers may differ during stages of NAFLD. Urine and blood were obtained from non-diabetic subjects with NAFLD and steatosis, with normal liver function (n = 33), from patients with NASH, with abnormal liver function (n = 45), and from healthy age and sex-matched controls (n = 30). Samples were subjected to metabolomic analysis to identify potential non-invasive biomarkers. Differences in urinary metabolic profiles were analyzed using liquid chromatography tandem mass spectrometry with principal component analysis and partial least squares-discriminate analysis. RESULTS Compared with NAFLD patients, patients with NASH had abnormal liver function and high serum lipid concentrations. Urinary metabonomics found differences in 31 metabolites between these two groups, including differences in nucleic acids and amino acids. Pathway analysis based on overlapping metabolites showed that pathways of energy and amino acid metabolism, as well as the pentose phosphate pathway, were closely associated with pathological processes in NAFLD and NASH. CONCLUSION These findings suggested that a panel of biomarkers could distinguish between NAFLD and NASH, and could help to determine the molecular mechanism involved in the process of developing NASH from NAFLD. Urinary biomarkers may be diagnostic in these patients and could be used to assess responses to therapeutic interventions. PMID:28487615

Rising Rates of Hepatocellular Carcinoma Leading to Liver Transplantation in Baby Boomer Generation with Chronic Hepatitis C, Alcohol Liver Disease, and Nonalcoholic Steatohepatitis-Related Liver Disease.

PubMed

Cholankeril, George; Yoo, Eric R; Perumpail, Ryan B; Liu, Andy; Sandhu, Jeevin S; Nair, Satheesh; Hu, Menghan; Ahmed, Aijaz

2017-09-26

We aim to study the impact of the baby boomer (BB) generation, a birth-specific cohort (born 1945-1965) on hepatocellular carcinoma (HCC)-related liver transplantation (LT) in patients with chronic hepatitis C virus (HCV), alcoholic liver disease (ALD), and non-alcoholic steatohepatitis (NASH). We performed a retrospective analysis using the United Network for Organ Sharing (UNOS)/Organ Procurement Transplant Network (OPTN) database from 2003 to 2014 to compare HCC-related liver transplant surgery trends between two cohorts-the BB and non-BB-with a secondary diagnosis of HCV, ALD, or NASH. From 2003-2014, there were a total of 8313 liver transplant recipients for the indication of HCC secondary to HCV, ALD, or NASH. Of the total, 6658 (80.1%) HCC-related liver transplant recipients were BB. The number of liver transplant surgeries for the indication of HCC increased significantly in NASH (+1327%), HCV (+382%), and ALD (+286%) during the study period. The proportion of BB who underwent LT for HCC was the highest in HCV (84.7%), followed by NASH (70.3%) and ALD (64.7%). The recommendations for birth-cohort specific HCV screening stemmed from a greater understanding of the high prevalence of chronic HCV and HCV-related HCC within BB. The rising number of HCC-related LT among BB with ALD and NASH suggests the need for increased awareness and improved preventative screening/surveillance measures within NASH and ALD cohorts as well.

Bofutsushosan, a Japanese herbal (Kampo) medicine, attenuates progression of nonalcoholic steatohepatitis in mice.

PubMed

Ono, Masafumi; Ogasawara, Mitsunari; Hirose, Akira; Mogami, Sachiko; Ootake, Nobuhiro; Aritake, Kosuke; Higuchi, Takuma; Okamoto, Nobuto; Sakamoto, Shuji; Yamamoto, Masahiro; Urade, Yoshihiro; Saibara, Toshiji; Oben, Jude A

2014-06-01

Obesity-induced liver disease (nonalcoholic fatty liver disease, NAFLD) is now the commonest cause of chronic liver disease in affluent nations. There are presently no proven treatments for NAFLD or its more severe stage, nonalcoholic steatohepatitis (NASH). Bofutsushosan (BTS), a Japanese herbal (Kampo) medicine, long used as an anti-obesity medicine in Japan and other Asian countries, has been shown to reduce body weight and improve insulin resistance (IR) and hepatic steatosis. The precise mechanism of action of BTS, however, remains unclear. To evaluate the ability of BTS to prevent the development of NASH, and determine the mediators and pathways involved. C57BL/6 mice were injected intra-peritoneally with gold-thioglucose and fed a high-fat diet (HF) or HF diet admixed with either 2 or 5 % BTS for 12 weeks. The effectiveness of BTS in attenuating features of NASH and the mechanisms through which BTS attenuated NASH were then assayed through an assessment of the anthropometric, radiological, biochemical and histological parameters. BTS attenuated the progression of NASH through induction of adiponectin and its receptors along with an induction of PPAR-α and PPAR-γ, decreased expression of SREBP-1c, increased hepatic fatty acid oxidation and increased hepatic export of triglycerides. BTS moreover, reduced IR through phosphorylation of the protein kinase, Akt. BTS through induction of adiponectin signaling and Akt attenuated development of NASH. Identification of the active entity in BTS should allow development of novel treatments for NASH.

The xanthine oxidase inhibitor febuxostat suppresses development of nonalcoholic steatohepatitis in a rodent model.

PubMed

Nakatsu, Yusuke; Seno, Yasuyuki; Kushiyama, Akifumi; Sakoda, Hideyuki; Fujishiro, Midori; Katasako, Aya; Mori, Keiichi; Matsunaga, Yasuka; Fukushima, Toshiaki; Kanaoka, Ryuhei; Yamamotoya, Takeshi; Kamata, Hideaki; Asano, Tomoichiro

2015-07-01

Xanthine oxidase (XO) is an enzyme involved in the production of uric acid (UA) from purine nucleotides. Numerous recent studies have revealed the likelihood of metabolic syndrome including nonalcoholic fatty liver disease (NAFLD) or steatohepatitis (NASH) to be related to hyperuricemia. However, it remains unclear whether elevated serum UA during the development of NAFLD or NASH is a cause or a consequence of these diseases. In this study, the XO inhibitor febuxostat was administered to two types of NASH model mice. Febuxostat exerted a strong protective effect against NASH development induced by a high-fat diet containing trans fatty acid (HFDT). In contrast, methionine choline-deficient-diet-induced NASH development not accompanied by hyperuricemia showed no UA normalization, suggesting that the ameliorating effect of febuxostat occurs via the normalization of hyperuricemia itself and/or accompanying molecular mechanism(s) such as oxidative stress. In the HFDT-fed mice, hyperuricemia, elevated alanine aminotransferase, and increased Tunnel-positive cells in the liver were normalized by febuxostat administration. In addition, upregulation of fatty acid oxidation-related genes, fibrotic change, and increases in collagen deposition, inflammatory cytokine expressions, and lipid peroxidation in the HFDT-fed mice were also normalized by febuxostat administration. Taken together, these observations indicate that administration of febuxostat has a protective effect against HFDT-induced NASH development, suggesting the importance of XO in its pathogenesis. Thus XO inhibitors are potentially potent therapies for patients with NASH, particularly that associated with hyperuricemia. Copyright © 2015 the American Physiological Society.

Non-Alcoholic Steatohepatitis (NASH): Risk Factors in Morbidly Obese Patients

PubMed Central

Losekann, Alexandre; Weston, Antonio C.; de Mattos, Angelo A.; Tovo, Cristiane V.; de Carli, Luis A.; Espindola, Marilia B.; Pioner, Sergio R.; Coral, Gabriela P.

2015-01-01

The aim was to investigate the prevalence of non-alcoholic steatohepatitis (NASH) and risk factors for hepatic fibrosis in morbidly obese patients submitted to bariatric surgery. This retrospective study recruited all patients submitted to bariatric surgery from January 2007 to December 2012 at a reference attendance center of Southern Brazil. Clinical and biochemical data were studied as a function of the histological findings of liver biopsies done during the surgery. Steatosis was present in 226 (90.4%) and NASH in 176 (70.4%) cases. The diagnosis of cirrhosis was established in four cases (1.6%) and fibrosis in 108 (43.2%). Risk factors associated with NASH at multivariate analysis were alanine aminotransferase (ALT) >1.5 times the upper limit of normal (ULN); glucose ≥ 126 mg/dL and triglycerides ≥ 150 mg/dL. All patients with ALT ≥1.5 times the ULN had NASH. When the presence of fibrosis was analyzed, ALT > 1.5 times the ULN and triglycerides ≥ 150 mg/dL were risk factors, furthermore, there was an increase of 1% in the prevalence of fibrosis for each year of age increase. Not only steatosis, but NASH is a frequent finding in MO patients. In the present study, ALT ≥ 1.5 times the ULN identifies all patients with NASH, this finding needs to be further validated in other studies. Moreover, the presence of fibrosis was associated with ALT, triglycerides and age, identifying a subset of patients with more severe disease. PMID:26512661

Non-alcoholic fatty liver and the gut microbiota.

PubMed

Bashiardes, Stavros; Shapiro, Hagit; Rozin, Shachar; Shibolet, Oren; Elinav, Eran

2016-09-01

Non-alcoholic fatty liver (NAFLD) is a common, multi-factorial, and poorly understood liver disease whose incidence is globally rising. NAFLD is generally asymptomatic and associated with other manifestations of the metabolic syndrome. Yet, up to 25% of NAFLD patients develop a progressive inflammatory liver disease termed non-alcoholic steatohepatitis (NASH) that may progress towards cirrhosis, hepatocellular carcinoma, and the need for liver transplantation. In recent years, several lines of evidence suggest that the gut microbiome represents a significant environmental factor contributing to NAFLD development and its progression into NASH. Suggested microbiome-associated mechanisms contributing to NAFLD and NASH include dysbiosis-induced deregulation of the gut endothelial barrier function, which facilitates systemic bacterial translocation, and intestinal and hepatic inflammation. Furthermore, increased microbiome-modulated metabolites such as lipopolysaccharides, short chain fatty acids (SCFAs), bile acids, and ethanol, may affect liver pathology through multiple direct and indirect mechanisms. Herein, we discuss the associations, mechanisms, and clinical implications of the microbiome's contribution to NAFLD and NASH. Understanding these contributions to the development of fatty liver pathogenesis and its clinical course may serve as a basis for development of therapeutic microbiome-targeting approaches for treatment and prevention of NAFLD and NASH. Intestinal host-microbiome interactions play diverse roles in the pathogenesis and progression of NAFLD and NASH. Elucidation of the mechanisms driving these microbial effects on the pathogenesis of NAFLD and NASH may enable to identify new diagnostic and therapeutic targets of these common metabolic liver diseases. This article is part of a special issue on microbiota.

Pathology and biopsy assessment of non-alcoholic fatty liver disease.

PubMed

Straub, Beate Katharina; Schirmacher, Peter

2010-01-01

Non-alcoholic fatty liver disease (NAFLD) is one of the most prevalent liver diseases in Western industrialized countries with dramatically rising incidence. The diagnosis of NAFLD requires the existence of steatosis in the absence of significant alcohol consumption. In cases of relevant inflammation pathogenetically linked to steatosis, it is termed non-alcoholic steatohepatitis (NASH). While pure steatosis represents a relatively harmless and rapidly reversible condition without a significant tendency to progression, NASH carries a significant morbidity and progression risk. Noninvasive methods neither reliably establish the diagnosis nor define the extent of disease in NASH, making histopathology the diagnostic gold standard. Since current therapeutic options in NASH are limited, indication for biopsy is made in the clinical context, predominantly in unclear clinical constellations, prior to invasive measures, for follow-up purposes and in the context of clinical studies. Histological hallmarks of NASH are steatosis, hepatocellular ballooning (with and without Mallory-Denk bodies), necroinflammation, and progressing disease a characteristic with perisinusoidal fibrosis. For semiquantitative assessment of necroinflammation (grading) and fibrosis (staging), a score has recently been implemented. Although histology does not reliably distinguish alcoholic steatohepatitis/alcoholic fatty liver disease from NASH/NAFLD, it may give valuable hints. NASH has a tendency for more steatosis, the so-called glycogenated nuclei, and less necroinflammatory activity. Future development of biopsy diagnosis will be coupled to the development of differential systemic therapeutic approaches. Especially in the context of clinical studies, detailed histological evaluation should be considered for the detection of predictive parameters. Copyright 2010 S. Karger AG, Basel.

Susceptibility to gut leakiness: a possible mechanism for endotoxaemia in non-alcoholic steatohepatitis

PubMed Central

Farhadi, Ashkan; Gundlapalli, Sushama; Shaikh, Maliha; Frantzides, Constantine; Harrell, Laura; Kwasny, Mary M.; Keshavarzian, Ali

2014-01-01

Introduction One of the proposed second hit mechanisms in the pathophysiology of non-alcoholic steatohepatitis (NASH) is hepatic oxidative stress triggered by elevated levels of endotoxin. We investigated one possible mechanism for the endotoxaemia – disruption of intestinal barrier integrity. Methods We enrolled 16 subjects with fatty liver (10 NASH; 6 steatosis) and 12 healthy subjects. Steatosis and NASH were diagnosed by liver biopsy using the Brunt criteria. Gastrointestinal permeability was measured using urinary excretion of 5-h lactulose/mannitol (L/M) ratio and 24-h sucralose. Permeability testing was repeated after aspirin challenge. Results Groups had similar baseline urinary 0–5 h L/M ratio (small bowel permeability) and 0–24 h sucralose (whole-gut permeability). Aspirin increased 0–5 h urinary L/M in most subjects. In contrast, aspirin significantly increased whole-gut permeability only in NASH subjects. In fact, the major increase in the urinary sucralose occurred in the 6–24 h samples, which points towards the colon as the major site responsible for aspirin-induced leakiness in NASH patients. Serum endotoxin levels were significantly higher in NASH subjects. Discussion Our findings suggest that aspirin acts on the colon to unmask a susceptibility to gut leakiness in patients with NASH. This effect may be the underlying mechanism for increased serum endotoxin, which is the second hit (after altered lipid metabolism) that is required to initiate a necroinflammatory cascade in hepatocytes which are already primed with obesity-induced abnormal lipid homoeostasis. PMID:18397235

B cell-activating factor is associated with the histological severity of nonalcoholic fatty liver disease.

PubMed

Miyake, Teruki; Abe, Masanori; Tokumoto, Yoshio; Hirooka, Masashi; Furukawa, Shinya; Kumagi, Teru; Hamada, Maho; Kawasaki, Keitarou; Tada, Fujimasa; Ueda, Teruhisa; Hiasa, Yoichi; Matsuura, Bunzo; Onji, Morikazu

2013-06-01

B cell-activating factor (BAFF) is expressed in adipocytes and affects lipogenesis and insulin sensitivity. In addition, the BAFF receptor is expressed in visceral adipose tissue and liver. The aim of this study was to analyze serum BAFF levels in patients with nonalcoholic steatohepatitis (NASH) and simple steatosis (SS) and to compare their respective clinical and histological findings. A total of 96 patients with nonalcoholic fatty liver disease (20 with SS and 76 with NASH) were enrolled and their serum BAFF levels were analyzed. Comprehensive blood chemistry analysis and histological examination of liver samples were also conducted. Serum BAFF levels were higher in patients with NASH than in those with SS (p = 0.016). NASH patients with ballooning hepatocytes and advanced fibrosis had higher levels of BAFF in sera (p = 0.016 and p = 0.006, respectively). In addition, the prevalence of NASH increased significantly as the serum BAFF level increased (p = 0.004). Higher serum BAFF levels were found to be an independent risk factor for development of NASH (OR 1.003, 95% CI 1.0003-1.006; p = 0.047). Nonalcoholic steatohepatitis patients had higher levels of serum BAFF than patients with SS, and higher levels were associated with the presence of hepatocyte ballooning and advanced fibrosis. The serum BAFF level may be a useful tool for distinguishing NASH from SS.

A Game Theoretic Approach for Balancing Energy Consumption in Clustered Wireless Sensor Networks

PubMed Central

Lu, Yinzhi; Xiong, Lian; Tao, Yang; Zhong, Yuanchang

2017-01-01

Clustering is an effective topology control method in wireless sensor networks (WSNs), since it can enhance the network lifetime and scalability. To prolong the network lifetime in clustered WSNs, an efficient cluster head (CH) optimization policy is essential to distribute the energy among sensor nodes. Recently, game theory has been introduced to model clustering. Each sensor node is considered as a rational and selfish player which will play a clustering game with an equilibrium strategy. Then it decides whether to act as the CH according to this strategy for a tradeoff between providing required services and energy conservation. However, how to get the equilibrium strategy while maximizing the payoff of sensor nodes has rarely been addressed to date. In this paper, we present a game theoretic approach for balancing energy consumption in clustered WSNs. With our novel payoff function, realistic sensor behaviors can be captured well. The energy heterogeneity of nodes is considered by incorporating a penalty mechanism in the payoff function, so the nodes with more energy will compete for CHs more actively. We have obtained the Nash equilibrium (NE) strategy of the clustering game through convex optimization. Specifically, each sensor node can achieve its own maximal payoff when it makes the decision according to this strategy. Through plenty of simulations, our proposed game theoretic clustering is proved to have a good energy balancing performance and consequently the network lifetime is greatly enhanced. PMID:29149075

Prediction of Nonalcoholic Fatty Liver Disease Via a Novel Panel of Serum Adipokines

PubMed Central

Jamali, Raika; Arj, Abbas; Razavizade, Mohsen; Aarabi, Mohammad Hossein

2016-01-01

Abstract Considering limitations of liver biopsy for diagnosis of nonalcoholic liver disease (NAFLD), biomarkers’ panels were proposed. The aims of this study were to establish models based on serum adipokines for discriminating NAFLD from healthy individuals and nonalcoholic steatohepatitis (NASH) from simple steatosis. This case-control study was conducted in patients with persistent elevated serum aminotransferase levels and fatty liver on ultrasound. Individuals with evidence of alcohol consumption, hepatotoxic medication, viral hepatitis, and known liver disease were excluded. Liver biopsy was performed in the remaining patients to distinguish NAFLD/NASH. Histologic findings were interpreted using “nonalcoholic fatty liver activity score.” Control group consisted of healthy volunteers with normal physical examination, liver function tests, and liver ultrasound. Binary logistic regression analysis was applied to ascertain the effects of independent variables on the likelihood that participants have NAFLD/NASH. Decreased serum adiponectin and elevated serum visfatin, IL-6, TNF-a were associated with an increased likelihood of exhibiting NAFLD. NAFLD discriminant score was developed as the following: [(−0.298 × adiponectin) + (0.022 × TNF-a) + (1.021 × Log visfatin) + (0.709 × Log IL-6) + 1.154]. In NAFLD discriminant score, 86.4% of original grouped cases were correctly classified. Discriminant score threshold value of (−0.29) yielded a sensitivity and specificity of 91% and 83% respectively, for discriminating NAFLD from healthy controls. Decreased serum adiponectin and elevated serum visfatin, IL-8, TNF-a were correlated with an increased probability of NASH. NASH discriminant score was proposed as the following: [(−0.091 × adiponectin) + (0.044 × TNF-a) + (1.017 × Log visfatin) + (0.028 × Log IL-8) − 1.787] In NASH model, 84% of original cases were correctly classified. Discriminant score threshold value of (−0.22) yielded a sensitivity and specificity of 90% and 66% respectively, for separating NASH from simple steatosis. New discriminant scores were introduced for differentiating NAFLD/NASH patients with a high accuracy. If verified by future studies, application of suggested models for screening of NAFLD/NASH seems reasonable. PMID:26844476

Alpha-Fair Resource Allocation under Incomplete Information and Presence of a Jammer

NASA Astrophysics Data System (ADS)

Altman, Eitan; Avrachenkov, Konstantin; Garnaev, Andrey

In the present work we deal with the concept of alpha-fair resource allocation in the situation where the decision maker (in our case, the base station) does not have complete information about the environment. Namely, we develop a concept of α-fairness under uncertainty to allocate power resource in the presence of a jammer under two types of uncertainty: (a) the decision maker does not have complete knowledge about the parameters of the environment, but knows only their distribution, (b) the jammer can come into the environment with some probability bringing extra background noise. The goal of the decision maker is to maximize the α-fairness utility function with respect to the SNIR (signal to noise-plus-interference ratio). Here we consider a concept of the expected α-fairness utility function (short-term fairness) as well as fairness of expectation (long-term fairness). In the scenario with the unknown parameters of the environment the most adequate approach is a zero-sum game since it can also be viewed as a minimax problem for the decision maker playing against the nature where the decision maker has to apply the best allocation under the worst circumstances. In the scenario with the uncertainty about jamming being in the system the Nash equilibrium concept is employed since the agents have non-zero sum payoffs: the decision maker would like to maximize either the expected fairness or the fairness of expectation while the jammer would like to minimize the fairness if he comes in on the scene. For all the plots the equilibrium strategies in closed form are found. We have shown that for all the scenarios the equilibrium has to be constructed into two steps. In the first step the equilibrium jamming strategy has to be constructed based on a solution of the corresponding modification of the water-filling equation. In the second step the decision maker equilibrium strategy has to be constructed equalizing the induced by jammer background noise.

Models of supply function equilibrium with applications to the electricity industry

NASA Astrophysics Data System (ADS)

Aromi, J. Daniel

Electricity market design requires tools that result in a better understanding of incentives of generators and consumers. Chapter 1 and 2 provide tools and applications of these tools to analyze incentive problems in electricity markets. In chapter 1, models of supply function equilibrium (SFE) with asymmetric bidders are studied. I prove the existence and uniqueness of equilibrium in an asymmetric SFE model. In addition, I propose a simple algorithm to calculate numerically the unique equilibrium. As an application, a model of investment decisions is considered that uses the asymmetric SFE as an input. In this model, firms can invest in different technologies, each characterized by distinct variable and fixed costs. In chapter 2, option contracts are introduced to a supply function equilibrium (SFE) model. The uniqueness of the equilibrium in the spot market is established. Comparative statics results on the effect of option contracts on the equilibrium price are presented. A multi-stage game where option contracts are traded before the spot market stage is considered. When contracts are optimally procured by a central authority, the selected profile of option contracts is such that the spot market price equals marginal cost for any load level resulting in a significant reduction in cost. If load serving entities (LSEs) are price takers, in equilibrium, there is no trade of option contracts. Even when LSEs have market power, the central authority's solution cannot be implemented in equilibrium. In chapter 3, we consider a game in which a buyer must repeatedly procure an input from a set of firms. In our model, the buyer is able to sign long term contracts that establish the likelihood with which the next period contract is awarded to an entrant or the incumbent. We find that the buyer finds it optimal to favor the incumbent, this generates more intense competition between suppliers. In a two period model we are able to completely characterize the optimal mechanism.

Split-estate negotiations: the case of coal-bed methane

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hayley H. Chouinard; Christina Steinhoff

Coal-bed methane is an emerging contributor to the US energy supply. Split estates, where landowners control the surface and the energy companies lease the rights to the underground gas from the federal government, often impede successful negotiations for methane extraction. We provide an extensive form representation of the dynamic game of the negotiation process for subsurface access. We then solve for a set of Nash equilibrium outcomes associated with the split estate negotiations. By examining the optimal offers we can identify methods to improve the likelihood of negotiations that do not break down and result in the gas developer resortingmore » to the use of a bond. We examine how changes in transaction costs or entitlements will affect the outcomes, and support our finds with anecdotal evidence from actual negotiations for coal-bed methane access. 55 refs.« less

Optimal Power Control in Wireless Powered Sensor Networks: A Dynamic Game-Based Approach

PubMed Central

Xu, Haitao; Guo, Chao; Zhang, Long

2017-01-01

In wireless powered sensor networks (WPSN), it is essential to research uplink transmit power control in order to achieve throughput performance balancing and energy scheduling. Each sensor should have an optimal transmit power level for revenue maximization. In this paper, we discuss a dynamic game-based algorithm for optimal power control in WPSN. The main idea is to use the non-cooperative differential game to control the uplink transmit power of wireless sensors in WPSN, to extend their working hours and to meet QoS (Quality of Services) requirements. Subsequently, the Nash equilibrium solutions are obtained through Bellman dynamic programming. At the same time, an uplink power control algorithm is proposed in a distributed manner. Through numerical simulations, we demonstrate that our algorithm can obtain optimal power control and reach convergence for an infinite horizon. PMID:28282945

Seven rules to avoid the tragedy of the commons.

PubMed

Murase, Yohsuke; Baek, Seung Ki

2018-07-14

Cooperation among self-interested players in a social dilemma is fragile and easily interrupted by mistakes. In this work, we study the repeated n-person public-goods game and search for a strategy that forms a cooperative Nash equilibrium in the presence of implementation error with a guarantee that the resulting payoff will be no less than any of the co-players'. By enumerating strategic possibilities for n=3, we show that such a strategy indeed exists when its memory length m equals three. It means that a deterministic strategy can be publicly employed to stabilize cooperation against error with avoiding the risk of being exploited. We furthermore show that, for general n-person public-goods game, m ≥ n is necessary to satisfy the above criteria. Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.

A game-theoretical approach to multimedia social networks security.

PubMed

Liu, Enqiang; Liu, Zengliang; Shao, Fei; Zhang, Zhiyong

2014-01-01

The contents access and sharing in multimedia social networks (MSNs) mainly rely on access control models and mechanisms. Simple adoptions of security policies in the traditional access control model cannot effectively establish a trust relationship among parties. This paper proposed a novel two-party trust architecture (TPTA) to apply in a generic MSN scenario. According to the architecture, security policies are adopted through game-theoretic analyses and decisions. Based on formalized utilities of security policies and security rules, the choice of security policies in content access is described as a game between the content provider and the content requester. By the game method for the combination of security policies utility and its influences on each party's benefits, the Nash equilibrium is achieved, that is, an optimal and stable combination of security policies, to establish and enhance trust among stakeholders.

Competition and Cooperation of Distributed Generation and Power System

NASA Astrophysics Data System (ADS)

Miyake, Masatoshi; Nanahara, Toshiya

Advances in distributed generation technologies together with the deregulation of an electric power industry can lead to a massive introduction of distributed generation. Since most of distributed generation will be interconnected to a power system, coordination and competition between distributed generators and large-scale power sources would be a vital issue in realizing a more desirable energy system in the future. This paper analyzes competitions between electric utilities and cogenerators from the viewpoints of economic and energy efficiency based on the simulation results on an energy system including a cogeneration system. First, we examine best response correspondence of an electric utility and a cogenerator with a noncooperative game approach: we obtain a Nash equilibrium point. Secondly, we examine the optimum strategy that attains the highest social surplus and the highest energy efficiency through global optimization.

Quantum Barro-Gordon game in monetary economics

NASA Astrophysics Data System (ADS)

Samadi, Ali Hussein; Montakhab, Afshin; Marzban, Hussein; Owjimehr, Sakine

2018-01-01

Classical game theory addresses decision problems in multi-agent environment where one rational agent's decision affects other agents' payoffs. Game theory has widespread application in economic, social and biological sciences. In recent years quantum versions of classical games have been proposed and studied. In this paper, we consider a quantum version of the classical Barro-Gordon game which captures the problem of time inconsistency in monetary economics. Such time inconsistency refers to the temptation of weak policy maker to implement high inflation when the public expects low inflation. The inconsistency arises when the public punishes the weak policy maker in the next cycle. We first present a quantum version of the Barro-Gordon game. Next, we show that in a particular case of the quantum game, time-consistent Nash equilibrium could be achieved when public expects low inflation, thus resolving the game.

A Game-Theoretical Approach to Multimedia Social Networks Security

PubMed Central

Liu, Enqiang; Liu, Zengliang; Shao, Fei; Zhang, Zhiyong

2014-01-01

The contents access and sharing in multimedia social networks (MSNs) mainly rely on access control models and mechanisms. Simple adoptions of security policies in the traditional access control model cannot effectively establish a trust relationship among parties. This paper proposed a novel two-party trust architecture (TPTA) to apply in a generic MSN scenario. According to the architecture, security policies are adopted through game-theoretic analyses and decisions. Based on formalized utilities of security policies and security rules, the choice of security policies in content access is described as a game between the content provider and the content requester. By the game method for the combination of security policies utility and its influences on each party's benefits, the Nash equilibrium is achieved, that is, an optimal and stable combination of security policies, to establish and enhance trust among stakeholders. PMID:24977226

Cardiovascular risk across the histological spectrum and the clinical manifestations of non-alcoholic fatty liver disease: An update

PubMed Central

Athyros, Vasilios G; Tziomalos, Konstantinos; Katsiki, Niki; Doumas, Michael; Karagiannis, Asterios; Mikhailidis, Dimitri P

2015-01-01

Non-alcoholic fatty liver disease (NAFLD) is considered to be an independent cardiovascular disease (CVD) risk factor. However, simple steatosis has a benign clinical course without excess mortality. In contrast, the advanced form of NAFLD, non-alcoholic steatohepatitis (NASH) with liver fibrosis increases mortality by approximately 70%, due to an increase in CVD mortality by approximately 300%. Chronic kidney disease (CKD) may be caused by NAFLD/NASH and it substantially increases CVD risk, especially in the presence of type 2 diabetes mellitus. Moreover, CKD may trigger NAFLD/NASH deterioration in a vicious cycle. NAFLD/NASH is also related to increased arterial stiffness (AS), an independent CVD risk factor that further raises CVD risk. Diagnosis of advanced liver fibrosis (mainly by simple non-invasive tests), CKD, and increased AS should be made early in the course of NAFLD and treated appropriately. Lifestyle measures and statin treatment may help resolve NAFLD/NASH and beneficially affect the CVD risk factors mentioned above. PMID:26078558

Involvement of resistin-like molecule β in the development of methionine-choline deficient diet-induced non-alcoholic steatohepatitis in mice.

PubMed

Okubo, Hirofumi; Kushiyama, Akifumi; Sakoda, Hideyuki; Nakatsu, Yusuke; Iizuka, Masaki; Taki, Naoyuki; Fujishiro, Midori; Fukushima, Toshiaki; Kamata, Hideaki; Nagamachi, Akiko; Inaba, Toshiya; Nishimura, Fusanori; Katagiri, Hideki; Asahara, Takashi; Yoshida, Yasuto; Chonan, Osamu; Encinas, Jeffery; Asano, Tomoichiro

2016-01-28

Resistin-like molecule β (RELMβ) reportedly has multiple functions including local immune responses in the gut. In this study, we investigated the possible contribution of RELMβ to non-alcoholic steatohepatitis (NASH) development. First, RELMβ knock-out (KO) mice were shown to be resistant to methionine-choline deficient (MCD) diet-induced NASH development. Since it was newly revealed that Kupffer cells in the liver express RELMβ and that RELMβ expression levels in the colon and the numbers of RELMβ-positive Kupffer cells were both increased in this model, we carried out further experiments using radiation chimeras between wild-type and RELMβ-KO mice to distinguish between the contributions of RELMβ in these two organs. These experiments revealed the requirement of RELMβ in both organs for full manifestation of NASH, while deletion of each one alone attenuated the development of NASH with reduced serum lipopolysaccharide (LPS) levels. The higher proportion of lactic acid bacteria in the gut microbiota of RELMβ-KO than in that of wild-type mice may be one of the mechanisms underlying the lower serum LPS level the former. These data suggest the contribution of increases in RELMβ in the gut and Kupffer cells to NASH development, raising the possibility of RELMβ being a novel therapeutic target for NASH.

Plasma total and free fatty acids composition in human non-alcoholic steatohepatitis.

PubMed

de Almeida, I Tavares; Cortez-Pinto, H; Fidalgo, G; Rodrigues, D; Camilo, M E

2002-06-01

Non-alcoholic steatohepatitis (NASH), the association of steatosis with an inflammatory response, is a novel liver disease of unknown pathogenesis and prognosis. Triacylglycerols and their precursors, the fatty acids, are the likely candidates to accumulate in the hepatocyte. Disturbed fatty acid metabolism can be involved in the pathogenesis of NASH but there is no information concerning its plasma fatty acid profile. The aim of this study was to evaluate plasma total (esterified plus free) and free fatty acids concentrations to assess the association of NASH with plasma fatty acid accumulation. Overnight fasting blood samples from 22 biopsy-proven NASH patients and of 6 matched age healthy controls were studied. NASH patients had significantly higher concentration of total and free fatty acids than controls (P<0.05), higher total saturated and monounsaturated levels in both studied lipid fractions (P<0.05), mainly due to the increase of hexadecanoic, hexadecenoic and octadecenoic acids. Absolute polyunsaturated fatty acids (PUFA) concentrations were similar in both groups. The C20:4/C18:2 and the C18:1/C18:0 ratios as well as the peroxidability index were not significantly different. In overweight/obese patients NASH is associated with deranged fatty acid metabolism which may be involved in its pathogenesis and/or progression.

Rising Rates of Hepatocellular Carcinoma Leading to Liver Transplantation in Baby Boomer Generation with Chronic Hepatitis C, Alcohol Liver Disease, and Nonalcoholic Steatohepatitis-Related Liver Disease

PubMed Central

Cholankeril, George; Perumpail, Ryan B.; Liu, Andy; Sandhu, Jeevin S.; Nair, Satheesh; Hu, Menghan; Ahmed, Aijaz

2017-01-01

We aim to study the impact of the baby boomer (BB) generation, a birth-specific cohort (born 1945–1965) on hepatocellular carcinoma (HCC)-related liver transplantation (LT) in patients with chronic hepatitis C virus (HCV), alcoholic liver disease (ALD), and non-alcoholic steatohepatitis (NASH). We performed a retrospective analysis using the United Network for Organ Sharing (UNOS)/Organ Procurement Transplant Network (OPTN) database from 2003 to 2014 to compare HCC-related liver transplant surgery trends between two cohorts—the BB and non-BB—with a secondary diagnosis of HCV, ALD, or NASH. From 2003–2014, there were a total of 8313 liver transplant recipients for the indication of HCC secondary to HCV, ALD, or NASH. Of the total, 6658 (80.1%) HCC-related liver transplant recipients were BB. The number of liver transplant surgeries for the indication of HCC increased significantly in NASH (+1327%), HCV (+382%), and ALD (+286%) during the study period. The proportion of BB who underwent LT for HCC was the highest in HCV (84.7%), followed by NASH (70.3%) and ALD (64.7%). The recommendations for birth-cohort specific HCV screening stemmed from a greater understanding of the high prevalence of chronic HCV and HCV-related HCC within BB. The rising number of HCC-related LT among BB with ALD and NASH suggests the need for increased awareness and improved preventative screening/surveillance measures within NASH and ALD cohorts as well. PMID:28954412

Follow-up CT findings of tamoxifen-induced non-alcoholic steatohepatitis (NASH) of breast cancer patients treated with bezafibrate.

PubMed

Ogawa, Yasuhiro; Murata, Yoriko; Saibara, Toshiji; Nishioka, Akihito; Kariya, Shinji; Yoshida, Shoji

2003-01-01

One-third of the breast cancer patients who underwent tamoxifen intake showed less than 0.9 of their liver/spleen CT (computed tomography) ratio on their annual CT study, and were diagnosed as having fatty liver (hepatic steatosis). Among them, patients who showed a lower liver/spleen CT ratio of less than 0.5 were recommended to undergo needle biopsy of the liver in order to obtain histopathological confirmation of non-alcoholic steatohepatitis (NASH), with 15 patients undergoing needle biopsy of the liver. As a result, 14 out of the 15 patients were diagnosed as having NASH, and these patients were additionally administered bezafibrate in order to prevent possible progressive changes of NASH into liver cirrhosis. In this study, we show the changes of follow-up CT findings of 6 patients with histopathologically-proven NASH who continued to undergo bezafibrate intake after the diagnosis of NASH. Two patients showed almost complete improvement as indicated by the liver/spleen CT ratio several months after completion of a tamoxifen intake of 5 years, and another 3 showed partial improvement on their liver/spleen CT ratio by bezafibrate intake in spite of continuing tamoxifen intake. Another patient with diabetes mellitus (type II) showed a continually decreasing liver/spleen CT ratio during adjuvant tamoxifen in spite of bezafibrate intake. Therefore, we concluded that the progression of NASH could be prevented by bezafibrate without any interruption of adjuvant tamoxifen treatment. For patients with diabetes mellitus, critical follow-up using CT study and laboratory tests is considered essential.

Protective role of endogenous plasmalogens against hepatic steatosis and steatohepatitis in mice.

PubMed

Jang, Jung Eun; Park, Han-Sol; Yoo, Hyun Ju; Baek, In-Jeoung; Yoon, Ji Eun; Ko, Myoung Seok; Kim, Ah-Ram; Kim, Hyoun Sik; Park, Hye-Sun; Lee, Seung Eun; Kim, Seung-Whan; Kim, Su Jung; Leem, Jaechan; Kang, Yu Mi; Jung, Min Kyo; Pack, Chan-Gi; Kim, Chong Jai; Sung, Chang Ohk; Lee, In-Kyu; Park, Joong-Yeol; Fernández-Checa, José C; Koh, Eun Hee; Lee, Ki-Up

2017-08-01

Free cholesterol (FC) accumulation in the liver is an important pathogenic mechanism of nonalcoholic steatohepatitis (NASH). Plasmalogens, key structural components of the cell membrane, act as endogenous antioxidants and are primarily synthesized in the liver. However, the role of hepatic plasmalogens in metabolic liver disease is unclear. In this study, we found that hepatic levels of docosahexaenoic acid (DHA)-containing plasmalogens, expression of glyceronephosphate O-acyltransferase (Gnpat; the rate-limiting enzyme in plasmalogen biosynthesis), and expression of Pparα were lower in mice with NASH caused by accumulation of FC in the liver. Cyclodextrin-induced depletion of FC transactivated Δ-6 desaturase by increasing sterol regulatory element-binding protein 2 expression in cultured hepatocytes. DHA, the major product of Δ-6 desaturase activation, activated GNPAT, thereby explaining the association between high hepatic FC and decreased Gnpat expression. Gnpat small interfering RNA treatment significantly decreased peroxisome proliferator-activated receptor α (Pparα) expression in cultured hepatocytes. In addition to GNPAT, DHA activated PPARα and increased expression of Pparα and its target genes, suggesting that DHA in the DHA-containing plasmalogens contributed to activation of PPARα. Accordingly, administration of the plasmalogen precursor, alkyl glycerol (AG), prevented hepatic steatosis and NASH through a PPARα-dependent increase in fatty acid oxidation. Gnpat +/- mice were more susceptible to hepatic lipid accumulation and less responsive to the preventive effect of fluvastatin on NASH development, suggesting that endogenous plasmalogens prevent hepatic steatosis and NASH. Increased hepatic FC in animals with NASH decreased plasmalogens, thereby sensitizing animals to hepatocyte injury and NASH. Our findings uncover a novel link between hepatic FC and plasmalogen homeostasis through GNPAT regulation. Further study of AG or other agents that increase hepatic plasmalogen levels may identify novel therapeutic strategies against NASH. (Hepatology 2017;66:416-431). © 2017 by the American Association for the Study of Liver Diseases.

A long-acting FGF21 alleviates hepatic steatosis and inflammation in NASH mice partly through an FGF21- adiponectin- IL17A axis.

PubMed

Bao, Lichen; Yin, Jun; Gao, Wen; Wang, Qun; Yao, Wenbing; Gao, Xiangdong

2018-06-02

NASH is the most severe form of NAFLD and is a serious public health problem around the world. There are currently no approved treatments for NASH. FGF21 has recently emerged as a promising drug candidate for metabolic diseases. However, the challenges in developing FGF21 as a novel medicine include its short plasma half-life and poor drug-like properties. Here, we explored the therapeutic effects of PsTag600-FGF21, an engineered long-acting FGF21 fusion protein, in NASH mice and revealed some of the mechanisms responsible for this activity. A long-acting FGF21 was prepared by genetic fusion with a 600 residues polypeptide (PsTag600). We conducted our studies using a choline-deficient high-fat diet (CD-HFD) induced NASH mouse model. In NASH mice, the effects on body weight, insulin sensitivity, inflammation and levels of hormones and metabolites were studied first. We further investigated whether PsTag600-FGF21 attenuated inflammation through the Th17-IL17A axis and the associated mechanisms. PsTag600-FGF21 dose-dependently reduced body weight, blood glucose, insulin and lipid levels and reversed hepatic steatosis. PsTag600-FGF21 enhanced fatty acid activation and mitochondrial β-oxidation in the liver. The profound reduction in hepatic inflammation in NASH mice was associated with PsTag600-FGF21 inhibition of IL17A expression in Th17 cells. Furthermore, PsTag600-FGF21 depended on adiponectin to exert its suppression effects on Th17 cell differentiation and IL17A expression. Our data begin to uncover the indirect mechanism by which PsTag600-FGF21 suppresses hepatic inflammation and further suggest that PsTag600-FGF21 could be an effective approach in NASH treatment. This article is protected by copyright. All rights reserved.

NASH resolution is associated with improvements in HDL and triglyceride levels but not improvement in LDL or non-HDL-C levels.

PubMed

Corey, K E; Vuppalanchi, R; Wilson, L A; Cummings, O W; Chalasani, N

2015-02-01

Nonalcoholic steatohepatitis (NASH) is associated with dyslipidemia and cardiovascular disease (CVD). To determine the relationship between resolution of NASH and dyslipidemia. Individuals in the Pioglitazone vs. Vitamin E vs. Placebo for the Treatment of Nondiabetic Patients with Nonalcoholic Steatohepatitis (PIVENS) trial with paired liver biopsies and fasting lipid levels were included (N = 222). In the PIVENS trial individuals were randomised to pioglitazone 30 mg, vitamin E 800 IU or placebo for 96 weeks. Change in lipid levels at 96 weeks was compared between those with and without NASH resolution. Dyslipidemia at baseline was frequent, with low high-density lipoprotein (HDL) (<40 mg/dL in men or <50 mg/dL in women) in 63%, hypertriglyceridaemia (≥150 mg/dL) in 46%, hypercholesterolaemia (≥200 mg/dL) in 47% and triglycerides (TG)/HDL >5.0 in 25%. Low-density lipoprotein (LD) ≥160 mg/dL was found in 16% and elevated non-HDL cholesterol (non-HDL-C) (≥130 mg/dL) in 73%. HDL increased with NASH resolution but decreased in those without resolution (2.9 mg/dL vs. -2.5 mg/dL, P < 0.001). NASH resolution was associated with significant decreases in TG and TG/HDL ratio compared to those without resolution (TG: -21.1 vs. -2.3 mg/dL, P = 0.03 and TG/HDL: -0.7 vs. 0.1, P = 0.003). Non-HDL-C, LDL and cholesterol decreased over 96 weeks in both groups, but there was no significant difference between groups. Treatment group did not impact lipids. NASH resolution is associated with improvements in TG and HDL but not in other cardiovascular disease risk factors including LDL and non-HDL-C levels. Individuals with resolution of NASH may still be at increased risk of cardiovascular disease. ClinicalTrials.gov identifier: NCT00063622. © 2014 John Wiley & Sons Ltd.

NLRP3 inflammasome blockade reduces liver inflammation and fibrosis in experimental NASH in mice.

PubMed

Mridha, Auvro R; Wree, Alexander; Robertson, Avril A B; Yeh, Matthew M; Johnson, Casey D; Van Rooyen, Derrick M; Haczeyni, Fahrettin; Teoh, Narci C-H; Savard, Christopher; Ioannou, George N; Masters, Seth L; Schroder, Kate; Cooper, Matthew A; Feldstein, Ariel E; Farrell, Geoffrey C

2017-05-01

NOD-like receptor protein 3 (NLRP3) inflammasome activation occurs in Non-alcoholic fatty liver disease (NAFLD). We used the first small molecule NLRP3 inhibitor, MCC950, to test whether inflammasome blockade alters inflammatory recruitment and liver fibrosis in two murine models of steatohepatitis. We fed foz/foz and wild-type mice an atherogenic diet for 16weeks, gavaged MCC950 or vehicle until 24weeks, then determined NAFLD phenotype. In mice fed an methionine/choline deficient (MCD) diet, we gavaged MCC950 or vehicle for 6weeks and determined the effects on liver fibrosis. In vehicle-treated foz/foz mice, hepatic expression of NLRP3, pro-IL-1β, active caspase-1 and IL-1β increased at 24weeks, in association with cholesterol crystal formation and NASH pathology; plasma IL-1β, IL-6, MCP-1, ALT/AST all increased. MCC950 treatment normalized hepatic caspase 1 and IL-1β expression, plasma IL-1β, MCP-1 and IL-6, lowered ALT/AST, and reduced the severity of liver inflammation including designation as NASH pathology, and liver fibrosis. In vitro, cholesterol crystals activated Kupffer cells and macrophages to release IL-1β; MCC950 abolished this, and the associated neutrophil migration. MCD diet-fed mice developed fibrotic steatohepatitis; MCC950 suppressed the increase in hepatic caspase 1 and IL-1β, lowered numbers of macrophages and neutrophils in the liver, and improved liver fibrosis. MCC950, an NLRP3 selective inhibitor, improved NAFLD pathology and fibrosis in obese diabetic mice. This is potentially attributable to the blockade of cholesterol crystal-mediated NLRP3 activation in myeloid cells. MCC950 reduced liver fibrosis in MCD-fed mice. Targeting NLRP3 is a logical direction in pharmacotherapy of NASH. Fatty liver disease caused by being overweight with diabetes and a high risk of heart attack, termed non-alcoholic steatohepatitis (NASH), is the most common serious liver disease with no current treatment. There could be several causes of inflammation in NASH, but activation of a protein scaffold within cells termed the inflammasome (NLRP3) has been suggested to play a role. Here we show that cholesterol crystals could be one pathway to activate the inflammasome in NASH. We used a drug called MCC950, which has already been shown to block NLRP3 activation, in an attempt to reduce liver injury in NASH. This drug partly reversed liver inflammation, particularly in obese diabetic mice that most closely resembles the human context of NASH. In addition, such dampening of liver inflammation in NASH achieved with MCC950 partly reversed liver scarring, the process that links NASH to the development of cirrhosis. Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Enhanced free cholesterol, SREBP-2 and StAR expression in human NASH.

PubMed

Caballero, Francisco; Fernández, Anna; De Lacy, Antonio M; Fernández-Checa, Jose C; Caballería, Juan; García-Ruiz, Carmen

2009-04-01

Non-alcoholic fatty liver disease (NAFLD) pathogenesis remains unknown. Due to the emerging role of free cholesterol (FC) in NAFLD, our aim was to examine the correlation between FC accumulation in patients with NAFLD and the expression of enzymes that regulate cholesterol homeostasis. Filipin staining, indicative of FC accumulation, and real-time PCR analyses were performed in 31 NAFLD patients and in seven controls. All NASH patients (n=14) and 4 out of 17 patients with steatosis exhibited filipin staining compared to controls (0 out of 7 subjects with normal liver histology and BMI). Sterol regulatory element-binding protein-2 (SREBP-2) mRNA levels were 7- and 3-fold higher in NASH and steatosis patients, respectively, compared to controls. Since hydroxymethylglutaryl-CoA (HMG-CoA) reductase is the key enzyme in cholesterol synthesis and transcriptionally controlled by SREBP-2 we measured its mRNA levels, being 3- to 4-fold higher in NAFLD compared to controls, without any difference between NASH and steatosis patients. Fatty acid synthase (FAS) and SREBP-1c expression were not significantly induced in NAFLD, while ATP-binding cassette sub-family G member 1 (ABCG1), a transporter involved in cholesterol egress, and acyl-CoA-cholesterol acyltransferase mRNA levels were modestly increased (1.5- to 2.5-fold, p<0.05), regardless of fibrosis. Interestingly, mRNA levels of steroidogenic acute regulatory protein (StAR), a mitochondrial-cholesterol transporting polypeptide, increased 7- and 15-fold in steatosis and NASH patients, respectively, compared to controls. FC increases in NASH and correlates with SREBP-2 induction. Moreover, StAR overexpression in NASH suggests that mitochondrial FC may be a player in disease progression and a novel target for intervention.

The severity of NAFLD is associated with gut dysbiosis and shift in the metabolic function of the gut microbiota

PubMed Central

Boursier, Jérôme; Mueller, Olaf; Barret, Matthieu; Machado, Mariana; Fizanne, Lionel; Araujo-Perez, Felix; Guy, Cynthia D.; Seed, Patrick C.; Rawls, John F.; David, Lawrence A.; Hunault, Gilles; Oberti, Frédéric; Calès, Paul; Diehl, Anna Mae

2016-01-01

Background & aims Several animal studies have emphasized the role of gut microbiota in non-alcoholic fatty liver disease (NAFLD). However, data about gut dysbiosis in human NAFLD remains scarce in the literature, especially studies including the whole spectrum of NAFLD lesions. We aimed to evaluate the association between gut dysbiosis and severe NAFLD lesions, i.e. non-alcoholic steatohepatitis (NASH) and fibrosis, in a well-characterized population of adult NAFLD. Methods 57 patients with biopsy-proven NAFLD were enrolled. The taxonomic composition of gut microbiota was determined using 16S ribosomal RNA gene sequencing of stool samples. Results 30 patients had F0/1 fibrosis stage at liver biopsy (10 with NASH), and 27 patients had significant F≥2 fibrosis (25 with NASH). Bacteroides abundance was significantly increased in NASH and F≥2 patients, whereas Prevotella abundance was decreased. Ruminococcus abundance was significantly higher in F≥2 patients. By multivariate analysis, Bacteroides abundance was independently associated with NASH and Ruminococcus with F≥2 fibrosis. Stratification according to the abundance of these 2 bacteria generated 3 patient subgroups with increasing severity of NAFLD lesions. Based on imputed metagenomic profiles, KEGG pathways significantly related to NASH and fibrosis F≥2 were mostly related to carbohydrate, lipid, and amino acid metabolism. Conclusion NAFLD severity associates with gut dysbiosis and a shift in metabolic function of the gut microbiota. We identified Bacteroides as independently associated with NASH and Ruminococcus with significant fibrosis. Thus, gut microbiota analysis adds information to classical predictors of NAFLD severity and suggests novel metabolic targets for pre/probiotics therapies. PMID:26600078

HCV genotype 3 and squamous cell carcinoma antigen (SCCA)-IgM are independently associated with histological features of NASH in HCV-infected patients.

PubMed

Martini, A; Fattovich, G; Guido, M; Bugianesi, E; Biasiolo, A; Ieluzzi, D; Gallotta, A; Fassina, G; Merkel, C; Gatta, A; Negro, F; Pontisso, P

2015-10-01

Nonalcoholic steatohepatitis (NASH) enhances the risk of progressive liver disease. In chronic hepatitis C (CHC), liver steatosis is frequent, especially in genotype 3, but its clinical significance is debated. As squamous cell carcinoma antigen (SCCA)-IgM has been associated with advanced liver disease and risk of tumour development, we evaluated its occurrence in CHC and the possible relation with NASH at liver biopsy. Using a validated ELISA, serum SCCA-IgM was measured in 91 patients with CHC at the time of liver biopsy performed before antiviral treatment, at the end of treatment and 6 months thereafter, and in 93 HCV-negative patients with histological diagnosis of nonalcoholic fatty liver disease, as controls. SCCA-IgM was detected in 33% of CHC patients and in 4% of controls. This biomarker was found more elevated in CHC patients with histological NASH, and at multivariate analysis, SCCA-IgM and HCV genotype 3 were independently associated with NASH [OR (95% CI): 6.94 (1.21-40) and 27.02 (4.44-166.6)]. As predictors of NASH, HCV genotype 3 and SCCA-IgM had a specificity and a sensitivity of 97% and 44%, and of 95% and 27%, respectively. PPV and NPV were 80% and 86% for HCV genotype 3 vs 73% and 72% for SCCA-IgM. In patients with sustained virologic response to therapy, SCCA-IgM levels decreased significantly, while these remained unchanged in nonresponders. In conclusion, SCCA-IgM is detectable in one-third of patients with CHC and significantly correlates with histological NASH. © 2015 John Wiley & Sons Ltd.

Challenges and Management of Liver Cirrhosis: Practical Issues in the Therapy of Patients with Cirrhosis due to NAFLD and NASH.

PubMed

Traussnigg, Stefan; Kienbacher, Christian; Halilbasic, Emina; Rechling, Christian; Kazemi-Shirazi, Lili; Hofer, Harald; Munda, Petra; Trauner, Michael

2015-01-01

Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome and comprises a liver disease spectrum ranging from steatosis to nonalcoholic steatohepatitis (NASH) with risk of progression to liver cirrhosis and hepatocellular carcinoma (HCC). Associated metabolic conditions and comorbidities such as obesity, diabetes and cardiovascular diseases are common and require concerted management. Adiponutrin (PNPLA3) variants may help to identify NAFLD patients at higher risk for liver disease progression towards advanced fibrosis and HCC. The therapeutic options in NAFLD/NASH include lifestyle modification, pharmacological treatment, bariatric surgery for patients with morbid obesity and treatment of complications of liver cirrhosis and HCC, including liver transplantation. Insulin sensitizers and antioxidative treatment strategies with vitamin E are among the best-established pharmacological approaches, but both drugs have long-term safety issues and there is limited evidence in cirrhotic patients. Treatment of concomitant/underlying metabolic conditions with statins or metformin may also have beneficial effects on portal hypertension, complications of liver cirrhosis and HCC prevention. The bile acid receptor FXR may be a promising novel therapeutic target for the treatment of NAFLD/NASH, fibrosis and portal hypertension, but the prognostic implications of associated changes in low- and high-density lipoprotein cholesterol require further studies. Morbidly obese NASH patients can benefit from bariatric surgery which may reduce liver fibrosis but carries a risk of decompensation in patients with advanced liver cirrhosis. When carefully selected, patients with NASH cirrhosis undergoing liver transplantation have a good outcome. This review summarizes recent progress in the management of patients with liver cirrhosis due to NASH. © 2015 S. Karger AG, Basel.

Clinical features and treatment of nonalcoholic fatty liver disease across the Asia Pacific region-the GO ASIA initiative.

PubMed

Chan, W-K; Treeprasertsuk, S; Imajo, K; Nakajima, A; Seki, Y; Kasama, K; Kakizaki, S; Fan, J-G; Song, M J; Yoon, S K; Dan, Y-Y; Lesmana, L; Ho, K-Y; Goh, K-L; Wong, V W-S

2018-03-01

The Gut and Obesity Asia (GO ASIA) workgroup was formed to study the relationships between obesity and gastrointestinal diseases in the Asia Pacific region. To study factors associated with nonalcoholic steatohepatitis (NASH) and advanced fibrosis, and medical treatment of biopsy-proven nonalcoholic fatty liver disease (NAFLD) patients. Retrospective study of biopsy-proven NAFLD patients from centres in the GO ASIA Workgroup. Independent factors associated with NASH and with advanced fibrosis on binary logistic regression analyses in a training cohort were used for the development of their corresponding risk score, which were validated in a validation cohort. We included 1008 patients from nine centres across eight countries (NASH 62.9%, advanced fibrosis 17.2%). Independent predictors of NASH were body mass index ≥30 kg/m 2 , diabetes mellitus, dyslipidaemia, alanine aminotransferase ≥88 U/L and aspartate aminotransferase ≥38 U/L, constituting the Asia Pacific NASH risk score. A high score has a positive predictive value of 80%-83% for NASH. Independent predictors of advanced fibrosis were age ≥55 years, diabetes mellitus and platelet count <150 × 10 9 /L, constituting the Asia-Pacific NAFLD advanced fibrosis risk score. A low score has a negative predictive value of 95%-96% for advanced fibrosis. Only 1.7% of patients were referred for structured lifestyle program, 4.2% were on vitamin E, and 2.4% were on pioglitazone. More severe liver disease can be suspected or ruled out based on factors identified in this study. Utilisation of structured lifestyle program, vitamin E and pioglitazone was limited despite this being a cohort of biopsy-proven NAFLD patients with majority of patients having NASH. © 2018 John Wiley & Sons Ltd.

PNPLA3 genotype increases susceptibility of nonalcoholic steatohepatitis among obese patients with nonalcoholic fatty liver disease.

PubMed

Tai, Chi-Ming; Huang, Chih-Kun; Tu, Hung-Pin; Hwang, Jau-Chung; Chang, Chi-Yang; Yu, Ming-Lung

2015-01-01

The patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409 variant is associated with histologic disease severity in patients with nonalcoholic fatty liver disease (NAFLD); however, whether the PNPLA3 genotype has an effect on susceptibility of nonalcoholic steatohepatitis (NASH) from NAFLD among severely obese patients remains unclear. The objective of this study was to investigate the role of the PNPLA3 genotype on NASH in severely obese Asian patients with NAFLD. The PNPLA3 rs738409 genotype was determined in 181 severely obese patients who underwent bariatric surgery. The diagnosis of NASH and the NAFLD activity score (NAS) were determined by liver histopathology. Of the 181 patients, 29 (16.0%), 60 (33.2%), and 92 (50.8%) were in the non-NAFLD, steatosis, and NASH groups, respectively. The PNPLA3 rs738409 GG genotype was associated with higher liver enzymes and a higher risk for NASH (odds ratio [OR], 3.72; 95% CI, 1.25-11.05). The GG genotype was also associated with histologic severity of NAFLD, including higher steatosis grade (OR, 9.94; 95% CI, 2.20-44.83 for patients with grade 3 steatosis) and NAS (OR, 11.49; 95% CI, 2.50-52.83 for patients with a NAS ≥5). Finally, multiple logistic regression also showed that the GG genotype was an independent risk factor for NASH (OR, 3.58; 95% CI, 1.15-11.12) in NAFLD patients. The PNPLA3 rs738409 GG genotype increases susceptibility of NASH in severely obese Asians with NAFLD and correlates to histologic severity of NAFLD. Copyright © 2015 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.

Total body weight loss of ≥ 10 % is associated with improved hepatic fibrosis in patients with nonalcoholic steatohepatitis.

PubMed

Glass, Lisa M; Dickson, Rolland C; Anderson, Joseph C; Suriawinata, Arief A; Putra, Juan; Berk, Brian S; Toor, Arifa

2015-04-01

Given the rising epidemics of obesity and metabolic syndrome, nonalcoholic steatohepatitis (NASH) is now the most common cause of liver disease in the developed world. Effective treatment for NASH, either to reverse or prevent the progression of hepatic fibrosis, is currently lacking. To define the predictors associated with improved hepatic fibrosis in NASH patients undergoing serial liver biopsies at prolonged biopsy interval. This is a cohort study of 45 NASH patients undergoing serial liver biopsies for clinical monitoring in a tertiary care setting. Biopsies were scored using the NASH Clinical Research Network guidelines. Fibrosis regression was defined as improvement in fibrosis score ≥1 stage. Univariate analysis utilized Fisher's exact or Student's t test. Multivariate regression models determined independent predictors for regression of fibrosis. Forty-five NASH patients with biopsies collected at a mean interval of 4.6 years (±1.4) were included. The mean initial fibrosis stage was 1.96, two patients had cirrhosis and 12 patients (26.7 %) underwent bariatric surgery. There was a significantly higher rate of fibrosis regression among patients who lost ≥10 % total body weight (TBW) (63.2 vs. 9.1 %; p = 0.001) and who underwent bariatric surgery (47.4 vs. 4.5 %; p = 0.003). Factors such as age, gender, glucose intolerance, elevated ferritin, and A1AT heterozygosity did not influence fibrosis regression. On multivariate analysis, only weight loss of ≥10 % TBW predicted fibrosis regression [OR 8.14 (CI 1.08-61.17)]. Results indicate that regression of fibrosis in NASH is possible, even in advanced stages. Weight loss of ≥10 % TBW predicts fibrosis regression.

Hepatocyte nuclear receptor SHP suppresses inflammation and fibrosis in a mouse model of nonalcoholic steatohepatitis.

PubMed

Zou, An; Magee, Nancy; Deng, Fengyan; Lehn, Sarah; Zhong, Cuncong; Zhang, Yuxia

2018-06-01

Nonalcoholic fatty liver disease (NAFLD) is a burgeoning health problem worldwide, ranging from nonalcoholic fatty liver (NAFL, steatosis without hepatocellular injury) to the more aggressive nonalcoholic steatohepatitis (NASH, steatosis with ballooning, inflammation, or fibrosis). Although many studies have greatly contributed to the elucidation of NAFLD pathogenesis, the disease progression from NAFL to NASH remains incompletely understood. Nuclear receptor small heterodimer partner (Nr0b2, SHP ) is a transcriptional regulator critical for the regulation of bile acid, glucose, and lipid metabolism. Here, we show that SHP levels are decreased in the livers of patients with NASH and in diet-induced mouse NASH. Exposing primary mouse hepatocytes to palmitic acid and lipopolysaccharide in vitro , we demonstrated that the suppression of Shp expression in hepatocytes is due to c-Jun N-terminal kinase (JNK) activation, which stimulates c-Jun-mediated transcriptional repression of Shp Interestingly, in vivo induction of hepatocyte-specific SHP in steatotic mouse liver ameliorated NASH progression by attenuating liver inflammation and fibrosis, but not steatosis. Moreover, a key mechanism linking the anti-inflammatory role of hepatocyte-specific SHP expression to inflammation involved SHP-induced suppression of NF-κB p65-mediated induction of chemokine (C-C motif) ligand 2 (CCL2), which activates macrophage proinflammatory polarization and migration. In summary, our results indicate that a JNK/SHP/NF-κB/CCL2 regulatory network controls communications between hepatocytes and macrophages and contributes to the disease progression from NAFL to NASH. Our findings may benefit the development of new management or prevention strategies for NASH. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

 The product of triglycerides and glucose as biomarker for screening simple steatosis and NASH in asymptomatic women.

PubMed

Simental-Mendía, Luis E; Simental-Mendía, Esteban; Rodríguez-Hernández, Heriberto; Rodríguez-Morán, Martha; Guerrero-Romero, Fernando

2016-01-01

 Introduction and aim. Given that early identification of non-alcoholic fatty liver disease (NAFLD) is an important issue for primary prevention of hepatic disease, the objectives of this study were to evaluate the efficacy of the product of triglyceride and glucose levels (TyG) for screening simple steatosis and non-alcoholic steatohepatitis (NASH) in asymptomatic women, and to compare its efficacy vs. other biomarkers for recognizing NAFLD. Asymptomatic women aged 20 to 65 years were enrolled into a cross-sectional study. The optimal values of TyG, for screening simple steatosis and NASH were established on a Receiver Operating Characteristic scatter plot; the sensitivity, specificity, and likelihood ratios of TyG index were estimated versus liver biopsy. According sensitivity and specificity, the efficacy of TyG was compared versus the well-known clinical biomarkers for recognizing NAFLD. A total of 50 asymptomatic women were enrolled. The best cutoff point of TyG for screening simple steatosis was 4.58 (sensitivity 0.94, specificity 0.69); in addition, the best cutoff point of TyG index for screening NASH was 4.59 (sensitivity 0.87, specificity 0.69). The positive and negative likelihood ratios were 3.03 and 0.08 for simple steatosis, and 2.80 and 0.18 for NASH. As compared versus SteatoTest, NashTest, Fatty liver index, and Algorithm, the TyG showed to be the best test for screening. TyG has high sensitivity and low negative likelihood ratio; as compared with other clinical biomarkers, the TyG showed to be the best test for screening simple steatosis and NASH.

Mixed Nash equilibria in Eisert-Lewenstein-Wilkens (ELW) games

NASA Astrophysics Data System (ADS)

Bolonek-Lasoń, Katarzyna; Kosiński, Piotr

2017-01-01

The classification of all mixed Nash equilibria for the original ELW game is presented. It is based on the quaternionic form of the game proposed by Landsburg (Proc. Am. Math. Soc. 139 (2011), 4423; Rochester Working Paper No 524 (2006); Wiley Encyclopedia of Operations Research and Management Science (Wiley and Sons, New York, (2011)). This approach allows to reduce the problem of finding the Nash equilibria to relatively simple analysis of the extrema of certain quadratic forms.

Utility of the ELF Test for Detecting Steatohepatitis in Morbid Obese Patients with Suspicion of Nonalcoholic Fatty Liver Disease.

PubMed

López, Iria Cebreiros; Aroca, Florentina Guzmán; Bernal, Maria Dolores Frutos; Mompeán, Juan Antonio Luján; Bernal, Águeda Bas; Martínez, Antonio Miguel Hernández; Barba, Enrique Martínez; Velasco, Jose Antonio Noguera; Paricio, Pascual Parilla

2017-09-01

Morbid obese patients have a high rate of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). NASH is related to the progression and poor evolution of chronic hepatopathy in NAFLD, so that its detection makes it possible to identify the subjects who are most at risk in order to prioritize treatment. The ELF test (Enhanced Liver Fibrosis test; Siemens Diagnostics, NY, USA) has been assessed for its capacity to detect fibrosis in patients with NAFLD, but its capacity for diagnosing NASH has not been checked. Our objective is to determine the utility of the ELF test for detecting NASH in morbid obese patients with suspected NAFLD. ELF values were determined in a cohort of obese patients who underwent bariatric surgery with suspected NAFLD. Liver biopsy was used as the reference standard. The values of ELF were significantly higher in patients with NASH (p = 0.002) and in those who presented with metabolic syndrome (p = 0.047). An ELF cut-off point of 8.72 allows the detection of patients with NASH with a sensitivity of 71.4% and a specificity of 74.1% (AUC = 0.742, p = 0.002). The ELF test is efficient for the identification of obese patients with NAFLD and early signs of steatohepatitis and fibrosis.

Involvement of resistin-like molecule β in the development of methionine-choline deficient diet-induced non-alcoholic steatohepatitis in mice

PubMed Central

Okubo, Hirofumi; Kushiyama, Akifumi; Sakoda, Hideyuki; Nakatsu, Yusuke; Iizuka, Masaki; Taki, Naoyuki; Fujishiro, Midori; Fukushima, Toshiaki; Kamata, Hideaki; Nagamachi, Akiko; Inaba, Toshiya; Nishimura, Fusanori; Katagiri, Hideki; Asahara, Takashi; Yoshida, Yasuto; Chonan, Osamu; Encinas, Jeffery; Asano, Tomoichiro

2016-01-01

Resistin-like molecule β (RELMβ) reportedly has multiple functions including local immune responses in the gut. In this study, we investigated the possible contribution of RELMβ to non-alcoholic steatohepatitis (NASH) development. First, RELMβ knock-out (KO) mice were shown to be resistant to methionine-choline deficient (MCD) diet-induced NASH development. Since it was newly revealed that Kupffer cells in the liver express RELMβ and that RELMβ expression levels in the colon and the numbers of RELMβ-positive Kupffer cells were both increased in this model, we carried out further experiments using radiation chimeras between wild-type and RELMβ-KO mice to distinguish between the contributions of RELMβ in these two organs. These experiments revealed the requirement of RELMβ in both organs for full manifestation of NASH, while deletion of each one alone attenuated the development of NASH with reduced serum lipopolysaccharide (LPS) levels. The higher proportion of lactic acid bacteria in the gut microbiota of RELMβ-KO than in that of wild-type mice may be one of the mechanisms underlying the lower serum LPS level the former. These data suggest the contribution of increases in RELMβ in the gut and Kupffer cells to NASH development, raising the possibility of RELMβ being a novel therapeutic target for NASH. PMID:26818807

Nonalcoholic steatohepatitis (NASH) after pancreaticoduodenectomy: association of pancreatic exocrine deficiency and infection.

PubMed

Murata, Yasuhiro; Mizuno, Shugo; Kato, Hiroyuki; Kishiwada, Masashi; Ohsawa, Ichiro; Hamada, Takashi; Usui, Masanobu; Sakurai, Hiroyuki; Tabata, Masami; Nishimura, Keisuke; Fukutome, Kazuo; Isaji, Shuji

2011-08-01

Previous clinical study has demonstrated that 30-40% of patients undergoing pancreaticoduodenectomy (PD) developed hepatic steatosis. However, nonalcoholic steatohepatitis (NASH) is a little-known complication after PD. Recently we encountered two patients with PD who later developed NASH diagnosed by liver biopsy. Case 1 was a 79-year-old woman who underwent PD for intraductal papillary mucinous neoplasm (IPMN). She had postoperative severe diarrhea due to pseudomembranous enterocolitis. Severe liver dysfunction was observed on the 31st postoperative day. Abdominal computed tomography (CT) on the 32nd day showed remarkably decreased hepatic CT value of 6 HU. Immediate liver biopsy revealed NASH (Brunt criteria: grade 2, stage 2). Case 2 was a 71-year-old woman who underwent PD for IPMN. Liver biopsy on 70th postoperative day, which was performed for assessment of moderate liver dysfunction and decreased hepatic CT value of 44 HU, demonstrated simple steatosis. In the 21st postoperative month, she developed severe urinary tract infection together with marked liver dysfunction. Immediate liver biopsy revealed NASH (Brunt criteria: grade 1, stage 1). For each patient, treatment of infection and high-dose pancreatic enzyme supplements improved liver dysfunction and liver steatosis. Clinical features of our cases seem to support the current leading hypothesis of the pathogenesis of NASH, i.e., the two-hit theory.

Autoimmune Hepatitis

MedlinePlus

... Living with a Liver Transplant Clinical Trials Nonalcoholic Fatty Liver Disease & NASH Definition & Facts Symptoms & Causes Diagnosis Treatment Eating, Diet, & Nutrition Clinical Trials Nonalcoholic Fatty Liver Disease & NASH in Children Definition & Facts Symptoms & Causes ...

Redox nanoparticles as a novel treatment approach for inflammation and fibrosis associated with nonalcoholic steatohepatitis

PubMed Central

Eguchi, Akiko; Yoshitomi, Toru; Lazic, Milos; Johnson, Casey D; Vong, Long Binh; Wree, Alexander; Povero, Davide; Papouchado, Bettina G; Nagasaki, Yukio; Feldstein, Ariel E

2015-01-01

Aim: Oxidative stress (OS) is largely thought to be a central mechanism responsible for liver damage, inflammation and fibrosis in nonalcoholic steatohepatitis (NASH). Our aim was to investigate whether suppression of OS in the liver via redox nanoparticles (RNPs) reduces liver damage in a mouse model of NASH. Materials & methods: RNPs were prepared by self-assembly of redox polymers possessing antioxidant nitroxide radicals and were orally administered by daily gavage for 4 weeks. Results: The redox polymer was delivered to the liver after disintegration of nanoparticle in the stomach. RNP treatment in NASH mice via gavage led to a reduction of liver OS, improvement of fibrosis, and significant reduction of inflammation. Conclusion: These findings uncover RNP as a novel potential NASH therapy. PMID:26020857

Non-alcoholic steatohepatitis pathogenesis: sublethal hepatocyte injury as a driver of liver inflammation

PubMed Central

Ibrahim, Samar H; Hirsova, Petra; Gores, Gregory J

2018-01-01

A subset of patients with non-alcoholic fatty liver disease develop an inflammatory condition, termed nonalcoholic steatohepatitis (NASH). NASH is characterised by hepatocellular injury, innate immune cell-mediated inflammation and progressive liver fibrosis. The mechanisms whereby hepatic inflammation occurs in NASH remain incompletely understood, but appear to be linked to the proinflammatory microenvironment created by toxic lipid-induced hepatocyte injury, termed lipotoxicity. In this review, we discuss the signalling pathways induced by sublethal hepatocyte lipid overload that contribute to the pathogenesis of NASH. Furthermore, we will review the role of proinflammatory, proangiogenic and profibrotic hepatocyte-derived extracellular vesicles as disease biomarkers and pathogenic mediators during lipotoxicity. We also review the potential therapeutic strategies to block the feed-forward loop between sublethal hepatocyte injury and liver inflammation. PMID:29367207

Quantitative imaging of fibrotic and morphological changes in liver of non-alcoholic steatohepatitis (NASH) model mice by second harmonic generation (SHG) and auto-fluorescence (AF) imaging using two-photon excitation microscopy (TPEM).

PubMed

Yamamoto, Shin; Oshima, Yusuke; Saitou, Takashi; Watanabe, Takao; Miyake, Teruki; Yoshida, Osamu; Tokumoto, Yoshio; Abe, Masanori; Matsuura, Bunzo; Hiasa, Yoichi; Imamura, Takeshi

2016-12-01

Non-alcoholic steatohepatitis (NASH) is a common liver disorder caused by fatty liver. Because NASH is associated with fibrotic and morphological changes in liver tissue, a direct imaging technique is required for accurate staging of liver tissue. For this purpose, in this study we took advantage of two label-free optical imaging techniques, second harmonic generation (SHG) and auto-fluorescence (AF), using two-photon excitation microscopy (TPEM). Three-dimensional ex vivo imaging of tissues from NASH model mice, followed by image processing, revealed that SHG and AF are sufficient to quantitatively characterize the hepatic capsule at an early stage and parenchymal morphologies associated with liver disease progression, respectively.

Modelling inter-supply chain competition with resource limitation and demand disruption

NASA Astrophysics Data System (ADS)

Chen, Zhaobo; Teng, Chunxian; Zhang, Ding; Sun, Jiayi

2016-05-01

This paper proposes a comprehensive model for studying supply chain versus supply chain competition with resource limitation and demand disruption. We assume that there are supply chains with heterogeneous supply network structures that compete at multiple demand markets. Each supply chain is comprised of internal and external firms. The internal firms are coordinated in production and distribution and share some common but limited resources within the supply chain, whereas the external firms are independent and do not share the internal resources. The supply chain managers strive to develop optimal strategies in terms of production level and resource allocation in maximising their profit while facing competition at the end market. The Cournot-Nash equilibrium of this inter-supply chain competition is formulated as a variational inequality problem. We further study the case when there is demand disruption in the plan-execution phase. In such a case, the managers need to revise their planned strategy in order to maximise their profit with the new demand under disruption and minimise the cost of change. We present a bi-criteria decision-making model for supply chain managers and develop the optimal conditions in equilibrium, which again can be formulated by another variational inequality problem. Numerical examples are presented for illustrative purpose.

Dynamics of quality as a strategic variable in complex food supply chain network competition: The case of fresh produce

NASA Astrophysics Data System (ADS)

Nagurney, Anna; Besik, Deniz; Yu, Min

2018-04-01

In this paper, we construct a competitive food supply chain network model in which the profit-maximizing producers decide not only as to the volume of fresh produce produced and distributed using various supply chain network pathways, but they also decide, with the associated costs, on the initial quality of the fresh produce. Consumers, in turn, respond to the various producers' product outputs through the prices that they are willing to pay, given also the average quality associated with each producer or brand at the retail outlets. The quality of the fresh produce is captured through explicit formulae that incorporate time, temperature, and other link characteristics with links associated with processing, shipment, storage, etc. Capacities on links are also incorporated as well as upper bounds on the initial product quality of the firms at their production/harvesting sites. The governing concept of the competitive supply chain network model is that of Nash Equilibrium, for which alternative variational inequality formulations are derived, along with existence results. An algorithmic procedure, which can be interpreted as a discrete-time tatonnement process, is then described and applied to compute the equilibrium produce flow patterns and accompanying link Lagrange multipliers in a realistic case study, focusing on peaches, which includes disruptions.

Closed set of the uniqueness conditions and bifurcation criteria in generalized coupled thermoplasticity for small deformations

NASA Astrophysics Data System (ADS)

Śloderbach, Zdzisław

2016-05-01

This paper reports the results of a study into global and local conditions of uniqueness and the criteria excluding the possibility of bifurcation of the equilibrium state for small strains. The conditions and criteria are derived on the basis of an analysis of the problem of uniqueness of a solution involving the basic incremental boundary problem of coupled generalized thermo-elasto-plasticity. This work forms a follow-up of previous research (Śloderbach in Bifurcations criteria for equilibrium states in generalized thermoplasticity, IFTR Reports, 1980, Arch Mech 3(35):337-349, 351-367, 1983), but contains a new derivation of global and local criteria excluding a possibility of bifurcation of an equilibrium state regarding a comparison body dependent on the admissible fields of stress rate. The thermal elasto-plastic coupling effects, non-associated laws of plastic flow and influence of plastic strains on thermoplastic properties of a body were taken into account in this work. Thus, the mathematical problem considered here is not a self-conjugated problem.

Self-organization in a distributed coordination game through heuristic rules

NASA Astrophysics Data System (ADS)

Agarwal, Shubham; Ghosh, Diptesh; Chakrabarti, Anindya S.

2016-12-01

In this paper, we consider a distributed coordination game played by a large number of agents with finite information sets, which characterizes emergence of a single dominant attribute out of a large number of competitors. Formally, N agents play a coordination game repeatedly, which has exactly N pure strategy Nash equilibria, and all of the equilibria are equally preferred by the agents. The problem is to select one equilibrium out of N possible equilibria in the least number of attempts. We propose a number of heuristic rules based on reinforcement learning to solve the coordination problem. We see that the agents self-organize into clusters with varying intensities depending on the heuristic rule applied, although all clusters but one are transitory in most cases. Finally, we characterize a trade-off in terms of the time requirement to achieve a degree of stability in strategies versus the efficiency of such a solution.

Instrumenting Beliefs in Threshold Public Goods

PubMed Central

2016-01-01

Understanding the causal impact of beliefs on contributions in Threshold Public Goods (TPGs) is particularly important since the social optimum can be supported as a Nash Equilibrium and best-response contributions are a function of beliefs. Unfortunately, investigations of the impact of beliefs on behavior are plagued with endogeneity concerns. We create a set of instruments by cleanly and exogenously manipulating beliefs without deception. Tests indicate that the instruments are valid and relevant. Perhaps surprisingly, we fail to find evidence that beliefs are endogenous in either the one-shot or repeated-decision settings. TPG allocations are determined by a base contribution and beliefs in a one shot-setting. In the repeated-decision environment, once we instrument for first-round allocations, we find that second-round allocations are driven equally by beliefs and history. Moreover, we find that failing to instrument prior decisions overstates their importance. PMID:26859492

An incentive-based distributed mechanism for scheduling divisible loads in tree networks

DOE Office of Scientific and Technical Information (OSTI.GOV)

Carroll, T. E.; Grosu, D.

The underlying assumption of Divisible Load Scheduling (DLS) theory is that the pro-cessors composing the network are obedient, i.e., they do not “cheat” the scheduling algorithm. This assumption is unrealistic if the processors are owned by autonomous, self-interested organizations that have no a priori motivation for cooperation and they will manipulate the algorithm if it is beneficial to do so. In this paper, we address this issue by designing a distributed mechanism for scheduling divisible loads in tree net-works, called DLS-T, which provides incentives to processors for reporting their true processing capacity and executing their assigned load at full processingmore » capacity. We prove that the DLS-T mechanism computes the optimal allocation in an ex post Nash equilibrium. Finally, we simulate and study the mechanism under various network structures and processor parameters.« less

Optimizing pricing and ordering strategies in a three-level supply chain under return policy

NASA Astrophysics Data System (ADS)

Noori-daryan, Mahsa; Taleizadeh, Ata Allah

2018-03-01

This paper develops an economic production quantity model in a three-echelon supply chain composing of a supplier, a manufacturer and a wholesaler under two scenarios. As the first scenario, we consider a return contract between the outside supplier and the supplier and also between the manufacturer and the wholesaler, but in the second one, the return policy between the manufacturer and the wholesaler is not applied. Here, it is assumed that shortage is permitted and demand is price-sensitive. The principal goal of the research is to maximize the total profit of the chain by optimizing the order quantity of the supplier and the selling prices of the manufacturer and the wholesaler. Nash-equilibrium approach is considered between the chain members. In the end, a numerical example is presented to clarify the applicability of the introduced model and compare the profit of the chain under two scenarios.

Infrared and Visible Image Fusion Based on Different Constraints in the Non-Subsampled Shearlet Transform Domain.

PubMed

Huang, Yan; Bi, Duyan; Wu, Dongpeng

2018-04-11

There are many artificial parameters when fuse infrared and visible images, to overcome the lack of detail in the fusion image because of the artifacts, a novel fusion algorithm for infrared and visible images that is based on different constraints in non-subsampled shearlet transform (NSST) domain is proposed. There are high bands and low bands of images that are decomposed by the NSST. After analyzing the characters of the bands, fusing the high level bands by the gradient constraint, the fused image can obtain more details; fusing the low bands by the constraint of saliency in the images, the targets are more salient. Before the inverse NSST, the Nash equilibrium is used to update the coefficient. The fused images and the quantitative results demonstrate that our method is more effective in reserving details and highlighting the targets when compared with other state-of-the-art methods.

Three-player quantum Kolkata restaurant problem under decoherence

NASA Astrophysics Data System (ADS)

Ramzan, M.

2013-01-01

Effect of quantum decoherence in a three-player quantum Kolkata restaurant problem is investigated using tripartite entangled qutrit states. Different qutrit channels such as, amplitude damping, depolarizing, phase damping, trit-phase flip and phase flip channels are considered to analyze the behaviour of players payoffs. It is seen that Alice's payoff is heavily influenced by the amplitude damping channel as compared to the depolarizing and flipping channels. However, for higher level of decoherence, Alice's payoff is strongly affected by depolarizing noise. Whereas the behaviour of phase damping channel is symmetrical around 50% decoherence. It is also seen that for maximum decoherence ( p = 1), the influence of amplitude damping channel dominates over depolarizing and flipping channels. Whereas, phase damping channel has no effect on the Alice's payoff. Therefore, the problem becomes noiseless at maximum decoherence in case of phase damping channel. Furthermore, the Nash equilibrium of the problem does not change under decoherence.

Quantum Locality in Game Strategy

NASA Astrophysics Data System (ADS)

Melo-Luna, Carlos A.; Susa, Cristian E.; Ducuara, Andrés F.; Barreiro, Astrid; Reina, John H.

2017-03-01

Game theory is a well established branch of mathematics whose formalism has a vast range of applications from the social sciences, biology, to economics. Motivated by quantum information science, there has been a leap in the formulation of novel game strategies that lead to new (quantum Nash) equilibrium points whereby players in some classical games are always outperformed if sharing and processing joint information ruled by the laws of quantum physics is allowed. We show that, for a bipartite non zero-sum game, input local quantum correlations, and separable states in particular, suffice to achieve an advantage over any strategy that uses classical resources, thus dispensing with quantum nonlocality, entanglement, or even discord between the players’ input states. This highlights the remarkable key role played by pure quantum coherence at powering some protocols. Finally, we propose an experiment that uses separable states and basic photon interferometry to demonstrate the locally-correlated quantum advantage.

Game Theory Based Trust Model for Cloud Environment

PubMed Central

Gokulnath, K.; Uthariaraj, Rhymend

2015-01-01

The aim of this work is to propose a method to establish trust at bootload level in cloud computing environment. This work proposes a game theoretic based approach for achieving trust at bootload level of both resources and users perception. Nash equilibrium (NE) enhances the trust evaluation of the first-time users and providers. It also restricts the service providers and the users to violate service level agreement (SLA). Significantly, the problem of cold start and whitewashing issues are addressed by the proposed method. In addition appropriate mapping of cloud user's application to cloud service provider for segregating trust level is achieved as a part of mapping. Thus, time complexity and space complexity are handled efficiently. Experiments were carried out to compare and contrast the performance of the conventional methods and the proposed method. Several metrics like execution time, accuracy, error identification, and undecidability of the resources were considered. PMID:26380365

Manipulating Scrip Systems: Sybils and Collusion

NASA Astrophysics Data System (ADS)

Kash, Ian A.; Friedman, Eric J.; Halpern, Joseph Y.

Game-theoretic analyses of distributed and peer-to-peer systems typically use the Nash equilibrium solution concept, but this explicitly excludes the possibility of strategic behavior involving more than one agent. We examine the effects of two types of strategic behavior involving more than one agent, sybils and collusion, in the context of scrip systems where agents provide each other with service in exchange for scrip. Sybils make an agent more likely to be chosen to provide service, which generally makes it harder for agents without sybils to earn money and decreases social welfare. Surprisingly, in certain circumstances it is possible for sybils to make all agents better off. While collusion is generally bad, in the context of scrip systems it actually tends to make all agents better off, not merely those who collude. These results also provide insight into the effects of allowing agents to advertise and loan money.

Off-Policy Integral Reinforcement Learning Method to Solve Nonlinear Continuous-Time Multiplayer Nonzero-Sum Games.

PubMed

Song, Ruizhuo; Lewis, Frank L; Wei, Qinglai

2017-03-01

This paper establishes an off-policy integral reinforcement learning (IRL) method to solve nonlinear continuous-time (CT) nonzero-sum (NZS) games with unknown system dynamics. The IRL algorithm is presented to obtain the iterative control and off-policy learning is used to allow the dynamics to be completely unknown. Off-policy IRL is designed to do policy evaluation and policy improvement in the policy iteration algorithm. Critic and action networks are used to obtain the performance index and control for each player. The gradient descent algorithm makes the update of critic and action weights simultaneously. The convergence analysis of the weights is given. The asymptotic stability of the closed-loop system and the existence of Nash equilibrium are proved. The simulation study demonstrates the effectiveness of the developed method for nonlinear CT NZS games with unknown system dynamics.

Quantum Locality in Game Strategy

PubMed Central

Melo-Luna, Carlos A.; Susa, Cristian E.; Ducuara, Andrés F.; Barreiro, Astrid; Reina, John H.

2017-01-01

Game theory is a well established branch of mathematics whose formalism has a vast range of applications from the social sciences, biology, to economics. Motivated by quantum information science, there has been a leap in the formulation of novel game strategies that lead to new (quantum Nash) equilibrium points whereby players in some classical games are always outperformed if sharing and processing joint information ruled by the laws of quantum physics is allowed. We show that, for a bipartite non zero-sum game, input local quantum correlations, and separable states in particular, suffice to achieve an advantage over any strategy that uses classical resources, thus dispensing with quantum nonlocality, entanglement, or even discord between the players’ input states. This highlights the remarkable key role played by pure quantum coherence at powering some protocols. Finally, we propose an experiment that uses separable states and basic photon interferometry to demonstrate the locally-correlated quantum advantage. PMID:28327567

Infrared and Visible Image Fusion Based on Different Constraints in the Non-Subsampled Shearlet Transform Domain

PubMed Central

Huang, Yan; Bi, Duyan; Wu, Dongpeng

2018-01-01

There are many artificial parameters when fuse infrared and visible images, to overcome the lack of detail in the fusion image because of the artifacts, a novel fusion algorithm for infrared and visible images that is based on different constraints in non-subsampled shearlet transform (NSST) domain is proposed. There are high bands and low bands of images that are decomposed by the NSST. After analyzing the characters of the bands, fusing the high level bands by the gradient constraint, the fused image can obtain more details; fusing the low bands by the constraint of saliency in the images, the targets are more salient. Before the inverse NSST, the Nash equilibrium is used to update the coefficient. The fused images and the quantitative results demonstrate that our method is more effective in reserving details and highlighting the targets when compared with other state-of-the-art methods. PMID:29641505

Security-Oriented and Load-Balancing Wireless Data Routing Game in the Integration of Advanced Metering Infrastructure Network in Smart Grid

DOE Office of Scientific and Technical Information (OSTI.GOV)

He, Fulin; Cao, Yang; Zhang, Jun Jason

Ensuring flexible and reliable data routing is indispensable for the integration of Advanced Metering Infrastructure (AMI) networks, we propose a secure-oriented and load-balancing wireless data routing scheme. A novel utility function is designed based on security routing scheme. Then, we model the interactive security-oriented routing strategy among meter data concentrators or smart grid meters as a mixed-strategy network formation game. Finally, such problem results in a stable probabilistic routing scheme with proposed distributed learning algorithm. One contributions is that we studied that different types of applications affect the routing selection strategy and the strategy tendency. Another contributions is that themore » chosen strategy of our mixed routing can adaptively to converge to a new mixed strategy Nash equilibrium (MSNE) during the learning process in the smart grid.« less

Pigouvian taxation of energy for flow and stock externalities and strategic, noncompetitive energy pricing

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wirl, F.

1994-01-01

The literature on energy and carbon taxes is by and large concerned about the derivation of (globally) efficient strategies. In contrast, this paper considers the dynamic interactions between cartelized energy suppliers and a consumers' government that collectively taxes energy carriers for Pigouvian motives. Two different kinds of external costs are associated with energy consumption: flow (e.g., acid rain) and stock externalities (e.g., global warming). The dynamic interactions between a consumers' government and a producers' cartel are modeled as a differential game with a subgame perfect Nash equilibrium in linear and nonlinear Markov strategies. The major implications are that the nonlinearmore » solutions are Pareto-inferior to the linear strategies and energy suppliers may preempt energy taxation and thereby may raise the price at front; however, this effect diminishes over time because the producers' price declines, while taxes increase. 22 refs., 5 figs., 1 tab.« less

A Brinkmanship Game Theory Model of Terrorism

NASA Astrophysics Data System (ADS)

Melese, Francois

This study reveals conditions under which a world leader might credibly issue a brinkmanship threat of preemptive action to deter sovereign states or transnational terrorist organizations from acquiring weapons of mass destruction (WMD). The model consists of two players: the United Nations (UN) “Principal,” and a terrorist organization “Agent.” The challenge in issuing a brinkmanship threat is that it needs to be sufficiently unpleasant to deter terrorists from acquiring WMD, while not being so repugnant to those that must carry it out that they would refuse to do so. Two “credibility constraints” are derived. The first relates to the unknown terrorist type (Hard or Soft), and the second to acceptable risks (“blowback”) to the World community. Graphing the incentive-compatible Nash equilibrium solutions reveals when a brinkmanship threat is credible, and when it is not - either too weak to be effective, or unacceptably dangerous to the World community.

Interdependent Network Recovery Games.

PubMed

Smith, Andrew M; González, Andrés D; Dueñas-Osorio, Leonardo; D'Souza, Raissa M

2017-10-30

Recovery of interdependent infrastructure networks in the presence of catastrophic failure is crucial to the economy and welfare of society. Recently, centralized methods have been developed to address optimal resource allocation in postdisaster recovery scenarios of interdependent infrastructure systems that minimize total cost. In real-world systems, however, multiple independent, possibly noncooperative, utility network controllers are responsible for making recovery decisions, resulting in suboptimal decentralized processes. With the goal of minimizing recovery cost, a best-case decentralized model allows controllers to develop a full recovery plan and negotiate until all parties are satisfied (an equilibrium is reached). Such a model is computationally intensive for planning and negotiating, and time is a crucial resource in postdisaster recovery scenarios. Furthermore, in this work, we prove this best-case decentralized negotiation process could continue indefinitely under certain conditions. Accounting for network controllers' urgency in repairing their system, we propose an ad hoc sequential game-theoretic model of interdependent infrastructure network recovery represented as a discrete time noncooperative game between network controllers that is guaranteed to converge to an equilibrium. We further reduce the computation time needed to find a solution by applying a best-response heuristic and prove bounds on ε-Nash equilibrium, where ε depends on problem inputs. We compare best-case and ad hoc models on an empirical interdependent infrastructure network in the presence of simulated earthquakes to demonstrate the extent of the tradeoff between optimality and computational efficiency. Our method provides a foundation for modeling sociotechnical systems in a way that mirrors restoration processes in practice. © 2017 Society for Risk Analysis.

Jay B. Nash.

ERIC Educational Resources Information Center

Jable, J. Thomas

1985-01-01

Jay B. Nash's accomplishments and professional service have long been recognized by physical educators. This article examines the major forces and events that made him one of the most important leaders in American physical education. (MT)

Auction-based distributed efficient economic operations of microgrid systems

NASA Astrophysics Data System (ADS)

Zou, Suli; Ma, Zhongjing; Liu, Xiangdong

2014-12-01

This paper studies the economic operations of the microgrid in a distributed way such that the operational schedule of each of the units, like generators, load units, storage units, etc., in a microgrid system, is implemented by autonomous agents. We apply and generalise the progressive second price (PSP) auction mechanism which was proposed by Lazar and Semret to efficiently allocate the divisible network resources. Considering the economic operation for the microgrid systems, the generators play as sellers to supply energy and the load units play as the buyers to consume energy, while a storage unit, like battery, super capacitor, etc., may transit between buyer and seller, such that it is a buyer when it charges and becomes a seller when it discharges. Furthermore in a connected mode, each individual unit competes against not only the other individual units in the microgrid but also the exogenous main grid possessing fixed electricity price and infinite trade capacity; that is to say, the auctioneer assigns the electricity among all individual units and the main grid with respect to the submitted bid strategies of all individual units in the microgrid in an economic way. Due to these distinct characteristics, the underlying auction games are distinct from those studied in the literature. We show that under mild conditions, the efficient economic operation strategy is a Nash equilibrium (NE) for the PSP auction games, and propose a distributed algorithm under which the system can converge to an NE. We also show that the performance of worst NE can be bounded with respect to the system parameters, say the energy trading price with the main grid, and based upon that, the implemented NE is unique and efficient under some conditions.

Relationship between obstructive sleep apnea and liver abnormalities in morbidly obese patients: a prospective study.

PubMed

Jouët, Pauline; Sabaté, Jean-Marc; Maillard, Dominique; Msika, Simon; Mechler, Charlotte; Ledoux, Séverine; Harnois, Florence; Coffin, Benoit

2007-04-01

Morbid obesity is a risk factor of nonalcoholic steatohepatitis (NASH). Obstructive sleep apnea (OSA) could also be an independent risk factor for elevated liver enzymes and NASH. The relationships between liver injuries and OSA in morbidly obese patients requiring bariatric surgery were studied prospectively. Every consecutive morbidly obese patient (BMI > or =40 kg/m2 or > or =35 kg/m2 with severe comorbidities) requiring bariatric surgery was included between January 2003 and October 2004. Polygraphic recording, serum aminotransferases (ALT, AST), gamma-glutamyltransferase (GGT) and liver biopsy were systematically performed. OSA was present when the apnea-hypopnea index (AHI) was >10/h. 62 patients (54 F; age 38.5 +/- 11.0 (SD) yrs; BMI 47.8 +/- 8.4 kg/m2) were included. Liver enzymes (AST, ALT or GGT) were increased in 46.6%. NASH was present in 34.4% and OSA in 84.7%. Patients with OSA were significantly older (P = 0.015) and had a higher BMI (P = 0.003). In multivariate analysis, risk factors for elevated liver enzymes were the presence of OSA and male sex. The presence of NASH was similar in patients with or without OSA (32.7% vs 44.4% of patients, P = 0.76). In this cohort of morbidly obese patients requiring bariatric surgery, one-third of patients had NASH, a prevalence similar to previous studies. OSA was found to be a risk factor for elevated liver enzymes but not for NASH.

Sorafenib prevents liver fibrosis in a non-alcoholic steatohepatitis (NASH) rodent model

PubMed Central

Stefano, J.T.; Pereira, I.V.A.; Torres, M.M.; Bida, P.M.; Coelho, A.M.M.; Xerfan, M.P.; Cogliati, B.; Barbeiro, D.F.; Mazo, D.F.C.; Kubrusly, M.S.; D'Albuquerque, L.A.C.; Souza, H.P.; Carrilho, F.J.; Oliveira, C.P.

2015-01-01

Liver fibrosis occurring as an outcome of non-alcoholic steatohepatitis (NASH) can precede the development of cirrhosis. We investigated the effects of sorafenib in preventing liver fibrosis in a rodent model of NASH. Adult Sprague-Dawley rats were fed a choline-deficient high-fat diet and exposed to diethylnitrosamine for 6 weeks. The NASH group (n=10) received vehicle and the sorafenib group (n=10) received 2.5 mg·kg-1·day-1 by gavage. A control group (n=4) received only standard diet and vehicle. Following treatment, animals were sacrificed and liver tissue was collected for histologic examination, mRNA isolation, and analysis of mitochondrial function. Genes related to fibrosis (MMP9, TIMP1, TIMP2), oxidative stress (HSP60, HSP90, GST), and mitochondrial biogenesis (PGC1α) were evaluated by real-time quantitative polymerase chain reaction (RT-qPCR). Liver mitochondrial oxidation activity was measured by a polarographic method, and cytokines by enzyme-linked immunosorbent assay (ELISA). Sorafenib treatment restored mitochondrial function and reduced collagen deposition by nearly 63% compared to the NASH group. Sorafenib upregulated PGC1α and MMP9 and reduced TIMP1 and TIMP2 mRNA and IL-6 and IL-10 protein expression. There were no differences in HSP60, HSP90 and GST expression. Sorafenib modulated PGC1α expression, improved mitochondrial respiration and prevented collagen deposition. It may, therefore, be useful in the treatment of liver fibrosis in NASH. PMID:25714891

Cholesterol-lowering drugs cause dissolution of cholesterol crystals and disperse Kupffer cell crown-like structures during resolution of NASH

PubMed Central

Ioannou, George N.; Van Rooyen, Derrick M.; Savard, Christopher; Haigh, W. Geoffrey; Yeh, Matthew M.; Teoh, Narci C.; Farrell, Geoffrey C.

2015-01-01

Cholesterol crystals form within hepatocyte lipid droplets in human and experimental nonalcoholic steatohepatitis (NASH) and are the focus of crown-like structures (CLSs) of activated Kupffer cells (KCs). Obese, diabetic Alms1 mutant (foz/foz) mice were a fed high-fat (23%) diet containing 0.2% cholesterol for 16 weeks and then assigned to four intervention groups for 8 weeks: a) vehicle control, b) ezetimibe (5 mg/kg/day), c) atorvastatin (20 mg/kg/day), or d) ezetimibe and atorvastatin. Livers of vehicle-treated mice developed fibrosing NASH with abundant cholesterol crystallization within lipid droplets calculated to extend over 3.3% (SD, 2.2%) of liver surface area. Hepatocyte lipid droplets with prominent cholesterol crystallization were surrounded by TNFα-positive (activated) KCs forming CLSs (≥3 per high-power field). KCs that formed CLSs stained positive for NLRP3, implicating activation of the NLRP3 inflammasome in response to cholesterol crystals. In contrast, foz/foz mice treated with ezetimibe and atorvastatin showed near-complete resolution of cholesterol crystals [0.01% (SD, 0.02%) of surface area] and CLSs (0 per high-power field), with amelioration of fibrotic NASH. Ezetimibe or atorvastatin alone had intermediate effects on cholesterol crystallization, CLSs, and NASH. These findings are consistent with a causative link between exposure of hepatocytes and KCs to cholesterol crystals and with the development of NASH possibly mediated by NLRP3 activation. PMID:25520429

Pharmacological cholesterol lowering reverses fibrotic NASH in obese, diabetic mice with metabolic syndrome.

PubMed

Van Rooyen, Derrick M; Gan, Lay T; Yeh, Matthew M; Haigh, W Geoffrey; Larter, Claire Z; Ioannou, George; Teoh, Narci C; Farrell, Geoffrey C

2013-07-01

We have recently showed that hyperinsulinemia promotes hepatic free cholesterol (FC) accumulation in obese, insulin-resistant Alms1 mutant (foz/foz) mice with NASH. Here we tested whether cholesterol-lowering drugs reduce stress-activated c-Jun N-terminal kinase (JNK) activation, hepatocyte injury/apoptosis, inflammation, and fibrosis in this metabolic syndrome NASH model. Female foz/foz and WT mice were fed HF (0.2% cholesterol) 16 weeks, before adding ezetimibe (5 mg/kg), atorvastatin (20 mg/kg), or both to diet, another 8 weeks. Hepatic lipidomic analysis, ALT, liver histology, Sirius Red morphometry, hepatic mRNA and protein expression and immunohistochemistry (IHC) for apoptosis (M30), macrophages (F4/80), and polymorphs (myeloperoxidase) were determined. In mice with NASH, ezetimibe/atorvastatin combination normalized hepatic FC but did not alter saturated free fatty acids (FFA) and had minimal effects on other lipids; ezetimibe and atorvastatin had similar but less profound effects. Pharmacological lowering of FC abolished JNK activation, improved serum ALT, apoptosis, liver inflammation/NAFLD activity score, designation as "NASH", macrophage chemotactic protein-1 expression, reduced macrophage and polymorph populations, and liver fibrosis. Cholesterol lowering with ezetimibe/atorvastatin combination reverses hepatic FC but not saturated FFA accumulation. This dampens JNK activation, ALT release, hepatocyte apoptosis, and inflammatory recruitment, with reversal of steatohepatitis pathology and liver fibrosis. Ezetimibe/statin combination is a potent, mechanism-based treatment that could reverse NASH and liver fibrosis. Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Cholesterol-lowering drugs cause dissolution of cholesterol crystals and disperse Kupffer cell crown-like structures during resolution of NASH.

PubMed

Ioannou, George N; Van Rooyen, Derrick M; Savard, Christopher; Haigh, W Geoffrey; Yeh, Matthew M; Teoh, Narci C; Farrell, Geoffrey C

2015-02-01

Cholesterol crystals form within hepatocyte lipid droplets in human and experimental nonalcoholic steatohepatitis (NASH) and are the focus of crown-like structures (CLSs) of activated Kupffer cells (KCs). Obese, diabetic Alms1 mutant (foz/foz) mice were a fed high-fat (23%) diet containing 0.2% cholesterol for 16 weeks and then assigned to four intervention groups for 8 weeks: a) vehicle control, b) ezetimibe (5 mg/kg/day), c) atorvastatin (20 mg/kg/day), or d) ezetimibe and atorvastatin. Livers of vehicle-treated mice developed fibrosing NASH with abundant cholesterol crystallization within lipid droplets calculated to extend over 3.3% (SD, 2.2%) of liver surface area. Hepatocyte lipid droplets with prominent cholesterol crystallization were surrounded by TNFα-positive (activated) KCs forming CLSs (≥ 3 per high-power field). KCs that formed CLSs stained positive for NLRP3, implicating activation of the NLRP3 inflammasome in response to cholesterol crystals. In contrast, foz/foz mice treated with ezetimibe and atorvastatin showed near-complete resolution of cholesterol crystals [0.01% (SD, 0.02%) of surface area] and CLSs (0 per high-power field), with amelioration of fibrotic NASH. Ezetimibe or atorvastatin alone had intermediate effects on cholesterol crystallization, CLSs, and NASH. These findings are consistent with a causative link between exposure of hepatocytes and KCs to cholesterol crystals and with the development of NASH possibly mediated by NLRP3 activation.

[Metabolic parameters in patients with steatosis non alcoholic liver and controlled diabetes type 2 versus uncontrolled diabetes type 2].

PubMed

Miranda Manrique, Gonzalo

2016-01-01

Non-alcoholic fatty liver (NASH) is widely distributed around the world and is more common in subjects with dyslipidemia, metabolic syndrome obese and DM2 (34-74%). However, the prevalence of cirrhosis by NASH in general population is unknown which is still subject of research. To determine if there are significant differences between metabolic parameters of non-alcoholic fatty liver in controlled versus uncontrolled diabetes type 2 of recent diagnosis. retrospective case-control study, performed in the Hospital Guillermo Almenara Irigoyen, Lima, Peru from November 2014 to February 2015.This study included 231 patients: 147 patients (NASH with DM2 of recent diagnosis and poor control) and 84 patients (NASH with DM2 ofrecent diagnosis and adequate control). Levene test for evaluating homogeneity of variances intra groups and parametric test for independent samples. After applying Levene test of homogeneity and student test, significant metabolic parameters were the triglycerides, HbA1C level, metformin dose and gender. It is important in diabetic patients to diagnose NASH early for a tighter control, not only of glucose but other metabolic parameters mainly triglycerides which strongly supports existing concept of "multiple hits" which considers NASH affects glucose homeostasis, and it could be the starting point of new research to improve interventions for decreasing progression from to cirrhosis in diabetic patients and also to delay progression of diabetes mellitus in patients with non alcoholic steatohepatitis.

Nonalcoholic steatohepatitis in bariatric patients with a diagnosis of obstructive sleep apnea.

PubMed

Weingarten, Toby N; Mantilla, Carlos B; Swain, James M; Kendrick, Michael L; Oberhansley, Jeff M; Burcham, Robert J; Ribeiro, Tarsila C R; Watt, Kymberly D; Schroeder, Darrell R; Narr, Bradly J; Sprung, Juraj

2012-01-01

To study a possible association between obstructive sleep apnea (OSA) severity, managed with noninvasive ventilation, and nonalcoholic steatohepatitis (NASH) in bariatric surgical patients. Medical records of 218 bariatric surgical patients who underwent liver biopsy were reviewed. OSA severity was determined from preoperative polysomnography (apnea-hypopnea index (AHI) ≤ 15 no/mild OSA vs. AHI ≥ 16 moderate/severe OSA). Patients diagnosed with OSA were prescribed noninvasive ventilation. Patients were categorized according to liver histopathology into 3 groups: (i) no liver disease or simple steatosis, (ii) mild NASH (steatosis with necroinflammation and mild fibrosis (stage 0-1)), and iii) advanced NASH (steatosis with necroinflammation and more advanced fibrosis (stage ≥ 2)). 125 patients (57%) had no/mild OSA, and 93 (43%) had moderate/severe OSA. There was no difference in serum aminotransferases between patients by OSA severity classification. There was a high prevalence of hepatic histopathological abnormalities: 84% patients had steatosis, 57% had necroinflammation, 34% had fibrotic changes, and 14% had advanced NASH. There was no association between severity of NASH and severity of OSA. There is no association between stage of steatohepatitis and OSA severity among morbidly obese patients managed with noninvasive ventilation.

Gender and racial differences in nonalcoholic fatty liver disease.

PubMed

Pan, Jen-Jung; Fallon, Michael B

2014-05-27

Due to the worldwide epidemic of obesity, nonalcoholic fatty liver disease (NAFLD) has become the most common cause of elevated liver enzymes. NAFLD represents a spectrum of liver injury ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) which may progress to advanced fibrosis and cirrhosis. Individuals with NAFLD, especially those with metabolic syndrome, have higher overall mortality, cardiovascular mortality, and liver-related mortality compared with the general population. According to the population-based studies, NAFLD and NASH are more prevalent in males and in Hispanics. Both the gender and racial ethnic differences in NAFLD and NASH are likely attributed to interaction between environmental, behavioral, and genetic factors. Using genome-wide association studies, several genetic variants have been identified to be associated with NAFLD/NASH. However, these variants account for only a small amount of variation in hepatic steatosis among ethnic groups and may serve as modifiers of the natural history of NAFLD. Alternatively, these variants may not be the causative variants but simply markers representing a larger body of genetic variations. In this article, we provide a concise review of the gender and racial differences in the prevalence of NAFLD and NASH in adults. We also discuss the possible mechanisms for these disparities.

Melatonin ameliorates methionine- and choline-deficient diet-induced nonalcoholic steatohepatitis in rats.

PubMed

Tahan, Veysel; Atug, Ozlen; Akin, Hakan; Eren, Fatih; Tahan, Gulgun; Tarcin, Ozlem; Uzun, Hafize; Ozdogan, Osman; Tarcin, Orhan; Imeryuz, Nese; Ozguner, Fehmi; Celikel, Cigdem; Avsar, Erol; Tozun, Nurdan

2009-05-01

Nonalcoholic steatohepatitis (NASH) may progress to advanced fibrosis and cirrhosis. Mainly, oxidative stress and excessive hepatocyte apoptosis are implicated in the pathogenesis of progressive NASH. Melatonin is not only a powerful antioxidant but also an anti-inflammatory and anti-apoptotic agent. We aimed to evaluate the effects of melatonin on methionine- and choline-deficient diet (MCDD)-induced NASH in rats. Thirty-two male Wistar rats were divided into four groups. Two groups were fed with MCDD while the other two groups were fed a control diet, pair-fed. One of the MCDD groups and one of the control diet groups were administered melatonin 50 mg/kg/day intraperitoneally, and the controls were given a vehicle. After 1 month the liver tissue oxidative stress markers, proinflammatory cytokines and hepatocyte apoptosis were studied by commercially available kits. For grading and staging histological lesions, Brunt et al.'s system was used. Melatonin decreased oxidative stress, proinflammatory cytokines and hepatocyte apoptosis. The drug ameliorated the grade of NASH. The present study suggests that melatonin functions as a potent antioxidant, anti-inflammatory and antiapoptotic agent in NASH and may be a therapeutic option.

Equilibrium points, stability and numerical solutions of fractional-order predator-prey and rabies models

NASA Astrophysics Data System (ADS)

Ahmed, E.; El-Sayed, A. M. A.; El-Saka, H. A. A.

2007-01-01

In this paper we are concerned with the fractional-order predator-prey model and the fractional-order rabies model. Existence and uniqueness of solutions are proved. The stability of equilibrium points are studied. Numerical solutions of these models are given. An example is given where the equilibrium point is a centre for the integer order system but locally asymptotically stable for its fractional-order counterpart.

Different approaches for centralized and decentralized water system management in multiple decision makers' problems

NASA Astrophysics Data System (ADS)

Anghileri, D.; Giuliani, M.; Castelletti, A.

2012-04-01

There is a general agreement that one of the most challenging issues related to water system management is the presence of many and often conflicting interests as well as the presence of several and independent decision makers. The traditional approach to multi-objective water systems management is a centralized management, in which an ideal central regulator coordinates the operation of the whole system, exploiting all the available information and balancing all the operating objectives. Although this approach allows to obtain Pareto-optimal solutions representing the maximum achievable benefit, it is based on assumptions which strongly limits its application in real world contexts: 1) top-down management, 2) existence of a central regulation institution, 3) complete information exchange within the system, 4) perfect economic efficiency. A bottom-up decentralized approach seems therefore to be more suitable for real case applications since different reservoir operators may maintain their independence. In this work we tested the consequences of a change in the water management approach moving from a centralized toward a decentralized one. In particular we compared three different cases: the centralized management approach, the independent management approach where each reservoir operator takes the daily release decision maximizing (or minimizing) his operating objective independently from each other, and an intermediate approach, leading to the Nash equilibrium of the associated game, where different reservoir operators try to model the behaviours of the other operators. The three approaches are demonstrated using a test case-study composed of two reservoirs regulated for the minimization of flooding in different locations. The operating policies are computed by solving one single multi-objective optimal control problem, in the centralized management approach; multiple single-objective optimization problems, i.e. one for each operator, in the independent case; using techniques related to game theory for the description of the interaction between the two operators, in the last approach. Computational results shows that the Pareto-optimal control policies obtained in the centralized approach dominate the control policies of both the two cases of decentralized management and that the so called price of anarchy increases moving toward the independent management approach. However, the Nash equilibrium solution seems to be the most promising alternative because it represents a good compromise in maximizing management efficiency without limiting the behaviours of the reservoir operators.

Screening for therapeutic trials and treatment indication in clinical practice: MACK-3, a new blood test for the diagnosis of fibrotic NASH.

PubMed

Boursier, J; Anty, R; Vonghia, L; Moal, V; Vanwolleghem, T; Canivet, C M; Michalak, S; Bonnafous, S; Michielsen, P; Oberti, F; Iannelli, A; Van Gaal, L; Patouraux, S; Blanchet, O; Verrijken, A; Gual, P; Rousselet, M-C; Driessen, A; Hunault, G; Bertrais, S; Tran, A; Calès, P; Francque, S

2018-05-01

The composite histological endpoint comprising nonalcoholic steatohepatitis (NASH) and NAFLD activity score ≥4 and advanced fibrosis (F ≥ 2) ("fibrotic NASH") is becoming an important diagnostic target in NAFLD: it is currently used to select patients for inclusion in phase III therapeutic trials and will ultimately be used to indicate treatment in clinical practice once the new drugs are approved. To develop a new blood test specifically dedicated for this new diagnostic target of interest. Eight Hundred and forty-six biopsy-proven NAFLD patients from three centres (Angers, Nice, Antwerp) were randomised into derivation and validation sets. The blood fibrosis tests BARD, NFS and FIB4 had poor accuracy for fibrotic NASH with respective AUROC: 0.566 ± 0.023, 0.654 ± 0.023, 0.732 ± 0.021. In the derivation set, fibrotic NASH was independently predicted by AST, HOMA and CK18; all three were combined in the new blood test MACK-3 (hoMa, Ast, CK18) for which 90% sensitivity and 95% specificity cut-offs were calculated. In the validation set, MACK-3 had a significantly higher AUROC (0.847 ± 0.030, P ≤ 0.002) than blood fibrosis tests. Using liver biopsy in the grey zone between the two cut-offs (36.0% of the patients), MACK-3 provided excellent accuracy for the diagnosis of fibrotic NASH with 93.3% well-classified patients, sensitivity: 90.0%, specificity: 94.2%, positive predictive value: 81.8% and negative predictive value: 97.0%. The new blood test MACK-3 accurately diagnoses fibrotic NASH. This new test will facilitate patient screening and inclusion in NAFLD therapeutic trials and will enable the identification of patients who will benefit from the treatments once approved. © 2018 John Wiley & Sons Ltd.

Fatty acids in non-alcoholic steatohepatitis: Focus on pentadecanoic acid.

PubMed

Yoo, Wonbeak; Gjuka, Donjeta; Stevenson, Heather L; Song, Xiaoling; Shen, Hong; Yoo, Suk Young; Wang, Jing; Fallon, Michael; Ioannou, George N; Harrison, Stephen A; Beretta, Laura

2017-01-01

Non-alcoholic fatty liver disease (NAFLD) is the most common form of liver disease and ranges from isolated steatosis to NASH. To determine whether circulating fatty acids could serve as diagnostic markers of NAFLD severity and whether specific fatty acids could contribute to the pathogenesis of NASH, we analyzed two independent NAFLD patient cohorts and used the methionine- and choline-deficient diet (MCD) NASH mouse model. We identified six fatty acids that could serve as non-invasive markers of NASH in patients with NAFLD. Serum levels of 15:0, 17:0 and 16:1n7t negatively correlated with NAFLD activity scores and hepatocyte ballooning scores, while 18:1n7c serum levels strongly correlated with fibrosis stage and liver inflammation. Serum levels of 15:0 and 17:0 also negatively correlated with fasting glucose and AST, while 16:1n7c and 18:1n7c levels positively correlated with AST and ferritin, respectively. Inclusion of demographic and clinical parameters improved the performance of the fatty acid panels in detecting NASH in NAFLD patients. The panel [15:0, 16:1n7t, 18:1n7c, 22:5n3, age, ferritin and APRI] predicted intermediate or advanced fibrosis in NAFLD patients, with 82% sensitivity at 90% specificity [AUROC = 0.92]. 15:0 and 18:1n7c were further selected for functional studies in vivo. Mice treated with 15:0-supplemented MCD diet showed reduced AST levels and hepatic infiltration of ceroid-laden macrophages compared to MCD-treated mice, suggesting that 15:0 deficiency contributes to liver injury in NASH. In contrast, 18:1n7c-supplemented MCD diet didn't affect liver pathology. In conclusion, 15:0 may serve as a promising biomarker or therapeutic target in NASH, opening avenues for the integration of diagnosis and treatment.

The selective peroxisome proliferator–activated receptor‐delta agonist seladelpar reverses nonalcoholic steatohepatitis pathology by abrogating lipotoxicity in diabetic obese mice

PubMed Central

Haczeyni, Fahrettin; Wang, Hans; Barn, Vanessa; Mridha, Auvro R.; Yeh, Matthew M.; Haigh, W. Geoffrey; Ioannou, George N.; Choi, Yun‐Jung; McWherter, Charles A.; Teoh, Narcissus C.‐H.

2017-01-01

Lipotoxicity associated with insulin resistance is central to nonalcoholic steatohepatitis (NASH) pathogenesis. To date, only weight loss fully reverses NASH pathology, but mixed peroxisome proliferator–activated receptor‐alpha/delta (PPAR‐α/δ) agonists show some efficacy. Seladelpar (MBX‐8025), a selective PPAR‐δ agonist, improves atherogenic dyslipidemia. We therefore used this agent to test whether selective PPAR‐δ activation can reverse hepatic lipotoxicity and NASH in an obese, dyslipidemic, and diabetic mouse model. From weaning, female Alms1 mutant (foz/foz) mice and wild‐type littermates were fed an atherogenic diet for 16 weeks; groups (n = 8‐12) were then randomized to receive MBX‐8025 (10 mg/kg) or vehicle (1% methylcellulose) by gavage for 8 weeks. Despite minimally altering body weight, MBX‐8025 normalized hyperglycemia, hyperinsulinemia, and glucose disposal in foz/foz mice. Serum alanine aminotransferase ranged 300‐600 U/L in vehicle‐treated foz/foz mice; MBX‐8025 reduced alanine aminotransferase by 50%. In addition, MBX‐8025 normalized serum lipids and hepatic levels of free cholesterol and other lipotoxic lipids that were increased in vehicle‐treated foz/foz versus wild‐type mice. This abolished hepatocyte ballooning and apoptosis, substantially reduced steatosis and liver inflammation, and improved liver fibrosis. In vehicle‐treated foz/foz mice, the mean nonalcoholic fatty liver disease activity score was 6.9, indicating NASH; MBX‐8025 reversed NASH in all foz/foz mice (nonalcoholic fatty liver disease activity score 3.13). Conclusion: Seladelpar improves insulin sensitivity and reverses dyslipidemia and hepatic storage of lipotoxic lipids to improve NASH pathology in atherogenic diet–fed obese diabetic mice. Selective PPAR‐δ agonists act independently of weight reduction, but counter lipotoxicity related to insulin resistance, thereby providing a novel therapy for NASH. (Hepatology Communications 2017;1:663–674) PMID:29404484

Modeling NAFLD Disease Burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016-2030.

PubMed

Estes, Chris; Anstee, Quentin M; Arias-Loste, Maria Teresa; Bantel, Heike; Bellentani, Stefeno; Caballeria, Joan; Colombo, Massimo; Craxi, Antonio; Crespo, Javier; Day, Christopher P; Geier, Andreas; Kondili, Loreta A; Lazarus, Jeffrey V; Loomba, Rohit; Manns, Michael P; Marchesini, Giulio; Negro, Francesco; Petta, Salvatore; Ratziu, Vlad; Romero-Gomez, Manuel; Sanyal, Arun; Schattenberg, Jörn M; Tacke, Frank; Trautwein, Christian; Wei, Lai; Zeuzem, Stefan; Razavi, Homie

2018-06-07

Nonalcoholic fatty liver disease (NAFLD) with resulting nonalcoholic steatohepatitis (NASH) are increasingly a cause of cirrhosis and hepatocellular carcinoma (HCC) globally. This burden is expected to increase as epidemics of obesity, diabetes and metabolic syndrome continue to grow. The goal of this analysis was to use a Markov model to forecast NAFLD disease burden using currently available data. A model was used to estimate NAFLD and NASH disease progression in 8 countries based on data for adult prevalence of obesity and type 2 diabetes mellitus (DM). Published estimates and expert consensus were used to build and validate the model projections. If obesity and DM level off in the future, we project a modest growth in total NAFLD cases (0-30%), between 2016-2030, with the highest growth in China as result of urbanization and the lowest growth in Japan as result of a shrinking population. However, at the same time, NASH prevalence will increase 15-56%, while liver mortality and advanced liver disease will more than double as result of an aging/increasing population. NAFLD and NASH represent a large and growing public health problem and efforts to understand this epidemic and to mitigate the disease burden are needed. If obesity and DM continue to increase at current and historical rates, both NAFLD and NASH prevalence are expected to increase. Since both are reversible, public health campaigns to increase awareness and diagnosis, and to promote diet and exercise can help manage the growth in future disease burden. Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) can lead to advanced liver disease, and are occurring in increasing numbers in tandem with epidemics of obesity and diabetes. A mathematical model was built to understand how the disease burden associated with NAFLD and NASH will change over time. Results suggest increasing numbers of cases of advanced liver disease and liver-related mortality in the coming years. Copyright © 2018. Published by Elsevier B.V.

Probiotics in Nonalcoholic Fatty Liver Disease, Nonalcoholic Steatohepatitis, and Cirrhosis.

PubMed

Qamar, Amir A

2015-01-01

With the growing epidemic of obesity, the incidence of both nonalcoholic fatty liver disease (NAFL) and nonalcoholic steatohepatitis (NASH) is increasing. The intestinal microbiota differs between individuals who are obese or have normal body mass indices. Animal studies have shown increased intestinal permeability in NAFL, NASH, and cirrhosis. This increases the risk of oxidative and inflammatory injury to the liver from intestinal microbacteria. It may also increase the risk of fatty acid injury and fatty deposition. Bacterial translocation is associated with increased portal hypertension and hepatic encephalopathy in cirrhosis. By preventing bacterial adhesion and translocation, probiotics may have a role in the management of patients with NAFL, NASH, and cirrhosis. Multiple small studies have suggested that probiotics improve some of the clinical markers of activity in patients with NAFL and NASH. Controlled studies have also shown improved outcomes in patients with cirrhosis who were treated with probiotics.

Activation of the Nrf2-ARE Pathway in Hepatocytes Protects Against Steatosis in Nutritionally Induced Non-alcoholic Steatohepatitis in Mice

PubMed Central

Lee, Lung-Yi; Köhler, Ulrike A.; Zhang, Li; Roenneburg, Drew; Werner, Sabine; Johnson, Jeffrey A.; Foley, David P.

2014-01-01

Oxidative stress is implicated in the development of non-alcoholic steatohepatitis (NASH). The Nrf2-antioxidant response element pathway protects cells from oxidative stress. Studies have shown that global Nrf2 deficiency hastens the progression of NASH. The purpose of this study was to determine whether long-term hepatocyte-specific activation of Nrf2 mitigates NASH progression. Transgenic mice expressing a constitutively active Nrf2 construct in hepatocytes (AlbCre+/caNrf2+) and littermate controls were generated. These mice were fed standard or methionine-choline-deficient (MCD) diet, a diet used to induce NASH development in rodents. After 28 days of MCD dietary feeding, mice developed significant increases in steatosis, inflammation, oxidative stress, and HSC activation compared with those mice on standard diet. AlbCre+/caNrf2+ animals had significantly decreased serum transaminases and reduced steatosis when compared with the AlbCre+/caNrf2− animals. This significant reduction in steatosis was associated with increased expression of genes involved in triglyceride export (MTTP) and β-oxidation (CPT2). However, there were no differences in the increased oxidative stress, inflammation, and HSC activation from MCD diet administration between the AlbCre+/caNrf2− and AlbCre+/caNrf2+ animals. We conclude that hepatocyte-specific activation of Nrf2-mediated gene expression decreased hepatocellular damage and steatosis in a dietary model of NASH. However, hepatocyte-specific induction of Nrf2-mediated gene expression alone is insufficient to mitigate inflammation, oxidative stress, and HSC activation in this nutritional NASH model. PMID:25294219

Long term highly saturated fat diet does not induce NASH in Wistar rats

PubMed Central

Romestaing, Caroline; Piquet, Marie-Astrid; Bedu, Elodie; Rouleau, Vincent; Dautresme, Marianne; Hourmand-Ollivier, Isabelle; Filippi, Céline; Duchamp, Claude; Sibille, Brigitte

2007-01-01

Background Understanding of nonalcoholic steatohepatitis (NASH) is hampered by the lack of a suitable model. Our aim was to investigate whether long term high saturated-fat feeding would induce NASH in rats. Methods 21 day-old rats fed high fat diets for 14 weeks, with either coconut oil or butter, and were compared with rats feeding a standard diet or a methionine choline-deficient (MCD) diet, a non physiological model of NASH. Results MCDD fed rats rapidly lost weight and showed NASH features. Rats fed coconut (86% of saturated fatty acid) or butter (51% of saturated fatty acid) had an increased caloric intake (+143% and +30%). At the end of the study period, total lipid ingestion in term of percentage of energy intake was higher in both coconut (45%) and butter (42%) groups than in the standard (7%) diet group. No change in body mass was observed as compared with standard rats at the end of the experiment. However, high fat fed rats were fattier with enlarged white and brown adipose tissue (BAT) depots, but they showed no liver steatosis and no difference in triglyceride content in hepatocytes, as compared with standard rats. Absence of hepatic lipid accumulation with high fat diets was not related to a higher lipid oxidation by isolated hepatocytes (unchanged ketogenesis and oxygen consumption) or hepatic mitochondrial respiration but was rather associated with a rise in BAT uncoupling protein UCP1 (+25–28% vs standard). Conclusion Long term high saturated fat feeding led to increased "peripheral" fat storage and BAT thermogenesis but did not induce hepatic steatosis and NASH. PMID:17313679

Histological improvement of non-alcoholic steatohepatitis with a prebiotic: a pilot clinical trial.

PubMed

Bomhof, Marc R; Parnell, Jill A; Ramay, Hena R; Crotty, Pam; Rioux, Kevin P; Probert, Chris S; Jayakumar, Saumya; Raman, Maitreyi; Reimer, Raylene A

2018-05-19

In obesity and diabetes the liver is highly susceptible to abnormal uptake and storage of fat. In certain individuals hepatic steatosis predisposes to the development of non-alcoholic steatohepatitis (NASH), a disease marked by hepatic inflammation and fibrosis. Although the precise pathophysiology of NASH is unknown, it is believed that the gut microbiota-liver axis influences the development of this disease. With few treatment strategies available for NASH, exploration of gut microbiota-targeted interventions is warranted. We investigated the therapeutic potential of a prebiotic supplement to improve histological parameters of NASH. In a placebo-controlled, randomized pilot trial, 14 individuals with liver-biopsy-confirmed NASH [non-alcoholic fatty liver activity score (NAS) ≥ 5] were randomized to receive oligofructose (8 g/day for 12 weeks followed by 16 g/day for 24 weeks) or isocaloric placebo for 9 months. The primary outcome measure was the change in liver biopsy NAS score and the secondary outcomes included changes in body weight, body composition, glucose tolerance, inflammatory markers, and gut microbiota. Independent of weight loss, oligofructose improved liver steatosis relative to placebo and improved overall NAS score (P = 0.016). Bifidobacterium was enhanced by oligofructose, whereas bacteria within Clostridium cluster XI and I were reduced with oligofructose (P < 0.05). There were no adverse side effects that deterred individuals from consuming oligofructose for treatment of this disease. Independent of other lifestyle changes, prebiotic supplementation reduced histologically-confirmed steatosis in patients with NASH. Larger follow-up studies are warranted. This trial was registered at Clinicaltrials.com as NCT03184376.

78 FR 72611 - Proposal for Hospital/Medical/Infectious Waste Incinerator Negative Declaration for Designated...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-12-03

[email protected] . 3. Fax: (312) 692-2543. 4. Mail: Carlton T. Nash, Chief, Toxics and Global Atmosphere... Boulevard, Chicago, Illinois 60604. 5. Hand Delivery: Carlton T. Nash, Chief, Toxics and Global Atmosphere...

Exercise Reduces Liver Lipids and Visceral Adiposity in Patients With Nonalcoholic Steatohepatitis in a Randomized Controlled Trial.

PubMed

Houghton, David; Thoma, Christian; Hallsworth, Kate; Cassidy, Sophie; Hardy, Timothy; Burt, Alastair D; Tiniakos, Dina; Hollingsworth, Kieren G; Taylor, Roy; Day, Christopher P; McPherson, Stuart; Anstee, Quentin M; Trenell, Michael I

2017-01-01

Pharmacologic treatments for nonalcoholic steatohepatitis (NASH) are limited. Lifestyle interventions are believed to be effective in reducing features of NASH, although the effect of regular exercise, independent of dietary change, is unclear. We performed a randomized controlled trial to study the effect of exercise on hepatic triglyceride content (HTGC) and biomarkers of fibrosis in patients with NASH. Twenty-four patients (mean age, 52 ± 14 y; body mass index, 33 ± 6 kg/m 2 ) with sedentary lifestyles (<60 min/wk of moderate-vigorous activity) and biopsy-proven NASH were assigned randomly to groups that exercised (n = 12) or continued standard care (controls, n = 12) for 12 weeks while maintaining their weight. The exercise (cycling and resistance training) was supervised at an accredited sports center and supervised by a certified exercise specialist and recorded 3 times per week on nonconsecutive days. We measured HTGC, body composition, circulating markers of inflammation, fibrosis, and glucose tolerance at baseline and at 12 weeks. Compared with baseline, exercise significantly reduced HTGC (reduction of 16% ± 24% vs an increase of 9% ± 15% for controls; P < .05), visceral fat (reduction of 22 ± 33 cm 2 vs an increase of 14 ± 48 cm 2 for controls; P < .05), plasma triglycerides (reduction of 0.5 ± 1.0 mmol/L vs an increase of 0.3 ± 0.4 mmol/L for controls; P < .05), and γ-glutamyltransferase (reduction of 10 ± 28 U/L - 1 vs a reduction of 17 ± 38 U/L -1 for controls; P < .05). There were no effects of exercise on liver enzyme levels, metabolic parameters, circulatory markers of inflammation (levels of interleukin 6, tumor necrosis factor-α, or C-reactive protein) and fibrosis. In a randomized controlled trial, 12 weeks of exercise significantly reduced HTGC, visceral fat, and plasma triglyceride levels in patients with NASH, but did not affect circulating markers of inflammation or fibrosis. Exercise without weight loss therefore affects some but not all factors associated with NASH. Clinical care teams should consider exercise as part of a management strategy of NASH, but weight management strategies should be included. Larger and longer-term studies are required to determine the effects of exercise in patients with NASH. ISRCTN registry.com: ISRCTN16070927. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

Non-equilibrium thermodynamics, maximum entropy production and Earth-system evolution.

PubMed

Kleidon, Axel

2010-01-13

The present-day atmosphere is in a unique state far from thermodynamic equilibrium. This uniqueness is for instance reflected in the high concentration of molecular oxygen and the low relative humidity in the atmosphere. Given that the concentration of atmospheric oxygen has likely increased throughout Earth-system history, we can ask whether this trend can be generalized to a trend of Earth-system evolution that is directed away from thermodynamic equilibrium, why we would expect such a trend to take place and what it would imply for Earth-system evolution as a whole. The justification for such a trend could be found in the proposed general principle of maximum entropy production (MEP), which states that non-equilibrium thermodynamic systems maintain steady states at which entropy production is maximized. Here, I justify and demonstrate this application of MEP to the Earth at the planetary scale. I first describe the non-equilibrium thermodynamic nature of Earth-system processes and distinguish processes that drive the system's state away from equilibrium from those that are directed towards equilibrium. I formulate the interactions among these processes from a thermodynamic perspective and then connect them to a holistic view of the planetary thermodynamic state of the Earth system. In conclusion, non-equilibrium thermodynamics and MEP have the potential to provide a simple and holistic theory of Earth-system functioning. This theory can be used to derive overall evolutionary trends of the Earth's past, identify the role that life plays in driving thermodynamic states far from equilibrium, identify habitability in other planetary environments and evaluate human impacts on Earth-system functioning. This journal is © 2010 The Royal Society

Slope-Velocity-Equilibrium and evolution of surface roughness on a stony hillslope

USDA-ARS?s Scientific Manuscript database

Slope-velocity equilibrium is hypothesized as a state that evolves naturally over time due to the interaction between overland flow and bed morphology, wherein steeper areas develop a relative increase in physical and hydraulic roughness such that flow velocity is a unique function of overland flow ...

77 FR 24451 - Direct Final Approval of Hospital/Medical/Infectious Waste Incinerators State Plan for Designated...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-04-24

...) 886-6030. 4. Mail: Carlton T. Nash, Chief, Toxics and Global Atmosphere Section, Air Toxics and..., Illinois 60604. 5. Hand Delivery: Carlton T. Nash, Chief, Toxics and Global Atmosphere Section, Air Toxics...

78 FR 34973 - Proposal for Sewage Sludge Incinerators State Plan for Designated Facilities and Pollutants; Indiana

Federal Register 2010, 2011, 2012, 2013, 2014

2013-06-11

[email protected] . 3. Fax: (312) 692-2543. 4. Mail: Carlton T. Nash, Chief, Toxics and Global Atmosphere... Boulevard, Chicago, Illinois 60604. 5. Hand Delivery: Carlton T. Nash, Chief, Toxics and Global Atmosphere...

A Graphical Analysis of the Cournot-Nash and Stackelberg Models.

ERIC Educational Resources Information Center

Fulton, Murray

1997-01-01

Shows how the Cournot-Nash and Stackelberg equilibria can be represented in the familiar supply-demand graphical framework, allowing a direct comparison with the monopoly, competitive, and industrial organization models. This graphical analysis is represented throughout the article. (MJP)

Evolving Concepts in the Pathogenesis of NASH: Beyond Steatosis and Inflammation

PubMed Central

Peverill, William; Powell, Lawrie W.; Skoien, Richard

2014-01-01

Non-alcoholic steatohepatitis (NASH) is characterised by hepatic steatosis and inflammation and, in some patients, progressive fibrosis leading to cirrhosis. An understanding of the pathogenesis of NASH is still evolving but current evidence suggests multiple metabolic factors critically disrupt homeostasis and induce an inflammatory cascade and ensuing fibrosis. The mechanisms underlying these changes and the complex inter-cellular interactions that mediate fibrogenesis are yet to be fully elucidated. Lipotoxicity, in the setting of excess free fatty acids, obesity, and insulin resistance, appears to be the central driver of cellular injury via oxidative stress. Hepatocyte apoptosis and/or senescence contribute to activation of the inflammasome via a variety of intra- and inter-cellular signalling mechanisms leading to fibrosis. Current evidence suggests that periportal components, including the ductular reaction and expansion of the hepatic progenitor cell compartment, may be involved and that the Th17 response may mediate disease progression. This review aims to provide an overview of the pathogenesis of NASH and summarises the evidence pertaining to key mechanisms implicated in the transition from steatosis and inflammation to fibrosis. Currently there are limited treatments for NASH although an increasing understanding of its pathogenesis will likely improve the development and use of interventions in the future. PMID:24830559

Monosodium glutamate (MSG): a villain and promoter of liver inflammation and dysplasia.

PubMed

Nakanishi, Yuko; Tsuneyama, Koichi; Fujimoto, Makoto; Salunga, Thucydides L; Nomoto, Kazuhiro; An, Jun-Ling; Takano, Yasuo; Iizuka, Seiichi; Nagata, Mitsunobu; Suzuki, Wataru; Shimada, Tsutomu; Aburada, Masaki; Nakano, Masayuki; Selmi, Carlo; Gershwin, M Eric

2008-01-01

Chronic inflammation is a common theme in a variety of disease pathways, including autoimmune diseases. The pathways of chronic inflammation are well illustrated by nonalcoholic steatohepatitis (NASH), which is of a serious concern due to its increasing prevalence in the westernized world and its direct correlation with lifestyle factors, particularly diet. Importantly, NASH may ultimately lead to the development of hepatocellular carcinoma. We previously reported that injection of monosodium glutamate (MSG) in ICR mice leads to the development of significant inflammation, central obesity, and type 2 diabetes. To directly address the long-term consequences of MSG on inflammation, we have performed serial analysis of MSG-injected mice and focused in particular on liver pathology. By 6 and 12 months of age, all MSG-treated mice developed NAFLD and NASH-like histology, respectively. In particular, the murine steatohepatitis at 12 months was virtually undistinguishable from human NASH. Further, dysplastic nodular lesions were detected in some cases within the fibrotic liver parenchyma. We submit that MSG treatment of mice induces obesity and diabetes with steatosis and steatohepatitis resembling human NAFLD and NASH with pre-neoplastic lesions. These results take on considerable significance in light of the widespread usage of dietary MSG and we suggest that MSG should have its safety profile re-examined and be potentially withdrawn from the food chain.

Hepatic Transcriptome Profiles of Mice with Diet-Induced Nonalcoholic Steatohepatitis Treated with Astaxanthin and Vitamin E

PubMed Central

Kobori, Masuko; Takahashi, Yumiko; Sakurai, Mutsumi; Ni, Yinhua; Chen, Guanliang; Nagashimada, Mayumi; Kaneko, Shuichi; Ota, Tsuguhito

2017-01-01

Astaxanthin alleviates hepatic lipid accumulation and peroxidation, inflammation, and fibrosis in mice with high-cholesterol, high-cholate, and high-fat (CL) diet-induced nonalcoholic steatohepatitis (NASH). It has been proposed as a potential new treatment to inhibit the progression of NASH in humans. In this study, we compared hepatic gene expression profiles after treatment with astaxanthin or the antioxidant vitamin E in mice with CL diet-induced NASH. Comprehensive gene expression analyses of the livers of mice fed a standard, CL, or CL diet containing astaxanthin or vitamin E for 12 weeks were performed using a DNA microarray. Both astaxanthin and vitamin E effectively improved gene expression associated with eukaryotic initiation factor-2 (EIF2) signaling, which is suppressed in NASH by endoplasmic reticulum (ER) stress in the liver. However, astaxanthin did not improve the expression of genes associated with mitochondrial dysfunction. Astaxanthin, but not vitamin E, was predicted to suppress the actions of ligand-dependent nuclear receptors peroxisome proliferator-activated receptors, (PPAR) α (PPARA) and PPARδ (PPARD), and to affect related molecules. Establishing a new therapy using astaxanthin will require elucidation of astaxanthin’s molecular action on the functions of PPARα and related molecules in the livers of mice with diet-induced NASH. PMID:28282876

Clinical Model for NASH and Advanced Fibrosis in Adult Patients With Diabetes and NAFLD: Guidelines for Referral in NAFLD

PubMed Central

Bazick, Jessica; Donithan, Michele; Neuschwander-Tetri, Brent A.; Kleiner, David; Brunt, Elizabeth M.; Wilson, Laura; Doo, Ed; Lavine, Joel; Tonascia, James

2015-01-01

OBJECTIVE Approximately 18 million people in the U.S. have coexisting type 2 diabetes and nonalcoholic fatty liver disease (NAFLD). It is not known who among these patients has nonalcoholic steatohepatitis (NASH) with advanced fibrosis. Therefore, we aimed to determine factors that are associated with both NASH and advanced fibrosis in patients with diabetes and NAFLD in order to identify who should be prioritized for referral to a hepatologist for further diagnostic evaluation and treatment. RESEARCH DESIGN AND METHODS This study was derived from the NASH Clinical Research Network studies and included 1,249 patients with biopsy-proven NAFLD (including a model development cohort of 346 patients and an independent validation cohort of 100 patients with type 2 diabetes as defined by the American Diabetes Association criteria). Outcome measures were presence of NASH or advanced fibrosis (stage 3 or 4) using cross-validated, by jackknife method, multivariable-adjusted area under the receiver operating characteristic curve (AUROC) and 95% CI. RESULTS The mean ± SD age and BMI of patients with diabetes and NAFLD was 52.5 ± 10.3 years and 35.8 ± 6.8 kg/m2, respectively. The prevalence of NASH and advanced fibrosis was 69.2% and 41.0%, respectively. The model for NASH included white race, BMI, waist, alanine aminotransferase (ALT), Aspartate aminotransferase (AST), albumin, HbA1c, HOMA of insulin resistance, and ferritin with an AUROC of 0.80 (95% CI 0.75–0.84, P = 0.007). The specificity, sensitivity, negative predictive values (NPVs), and positive predictive values (PPVs) were 90.0%, 56.8%, 47.7%, and 93.2%, respectively, and the model correctly classified 67% of patients as having NASH. The model for predicting advanced fibrosis included age, Hispanic ethnicity, BMI, waist-to-hip ratio, hypertension, ALT-to-AST ratio, alkaline phosphatase, isolated abnormal alkaline phosphatase, bilirubin (total and direct), globulin, albumin, serum insulin, hematocrit, international normalized ratio, and platelet count with an AUROC of 0.80 (95% CI 0.76–0.85, P < 0.001). The specificity, sensitivity, NPV, and PPV were 90.0%, 57%, 75.1%, and 80.2%, respectively, and the model correctly classified 76.6% of patients as having advanced fibrosis. Results remained consistent for both models in the validation cohort. The proposed model performed better than the NAFLD fibrosis score in detecting advanced fibrosis. CONCLUSIONS Routinely available clinical variables can be used to quantify the likelihood of NASH or advanced fibrosis in adult diabetic patients with NAFLD. The clinical models presented can be used to guide clinical decision making about referrals of patients with diabetes and NAFLD to hepatologists. PMID:25887357

Apnoeic-hypopnoeic episodes during obstructive sleep apnoea are associated with histological nonalcoholic steatohepatitis.

PubMed

Mishra, Poonam; Nugent, Clarke; Afendy, Arian; Bai, Chunhong; Bhatia, Priya; Afendy, Mariam; Fang, Yun; Elariny, Hazem; Goodman, Zachary; Younossi, Zobair M

2008-09-01

Nonalcoholic fatty liver disease (NAFLD) and obstructive sleep apnoea are associated with metabolic syndrome and atherosclerotic heart disease. This study evaluates the potential association between the NAFLD subtypes and a number of polysomnographical (PSG) parameters. This study included patients undergoing bariatric surgery with extensive clinical and histological data for whom complete PSG data before surgery were also available. Excess alcohol intake and other causes of liver disease were excluded. Apnoea, hypopnoea and apnoea-hypopnoea index (AHI) were calculated as described previously. In this study, a total of 101 patients [77 nonalcoholic steatohepatitis (NASH) and 22 non-NASH controls] with PSG data were included (age 42.9 +/- 11.4 years, body mass index 51.6 +/- 9.5 kg/m(2), fasting serum glucose 117.4 +/- 53.4 mg/dl, fasting serum triglycerides 171.3 +/- 82.9 mg/dl, 58% hypertension and 33% diabetes mellitus). Subjects with histological NASH had significantly lower lowest desaturation (77 vs. 85%, P=0.006), lower mean nocturnal oxygen saturation (91 vs. 93%, P=0.05), higher AHI (35 vs. 22, P=0.03), higher respiratory disturbance index (46 vs. 21, P=0.02) and higher alanine aminotransferase/aspartate aminotransferase ratio (1.4 vs. 1.3, P=0.05) compared with non-NASH controls. In multivariate analysis, the lowest desaturation (P=0.04) was independently associated with histological NASH. Lowest desaturation and mean nocturnal oxygen saturation were significantly lower in subjects with fibrosis (76 vs. 85%, P=0.004 and 90.4 vs. 93.0%, P=0.02). Our results suggest that the frequent nocturnal hypoxic episodes in NAFLD patients may be a risk factor for developing NASH. Additional studies are needed to study the effect of optimizing sleep apnoea management on the outcomes of patients with NAFLD.

Curcumin reduces the risk of chronic kidney damage in mice with nonalcoholic steatohepatitis by modulating endoplasmic reticulum stress and MAPK signaling.

PubMed

Afrin, Mst Rejina; Arumugam, Somasundaram; Rahman, Md Azizur; Karuppagounder, Vengadeshprabhu; Harima, Meilei; Suzuki, Hiroshi; Miyashita, Shizuka; Suzuki, Kenji; Ueno, Kazuyuki; Yoneyama, Hiroyuki; Watanabe, Kenichi

2017-08-01

Developing confirmation recommends that in patients with dynamic type of NAFLD, particularly nonalcoholic steatohepatitis (NASH) may have the pathogenic parts in the advancement of kidney damage. In this study we have examined the impact of curcumin on NASH instigated chronic kidney damage (CKD) and the putative mechanisms. To prepare this NASH model, neonatal C57BL/6J male mice were exposed to low-dose streptozotocin (STZ) and were fed high-fat diet (HFD) at the age of 4weeks and continued up to 14weeks, curcumin was given at 100mg/kg dose by oral gavage daily after 10weeks of STZ injection and continued for 4weeks along with HFD feeding. NASH incited mice demonstrated nephrotoxicity as proved by declining renal capacity, which was evaluated by measuring blood urea nitrogen and creatinine in serum and histopathological variations from the norm. These progressions were switched by curcumin treatment, which brought about huge change in renal capacity. Furthermore, curcumin markedly decreased NAD(P)H oxidase subunits (p67phox, p47phox, p22phox), nitrotyrosine and CYP2E1 renal protein expression as well as reduced pro-inflammatory cytokine expression (TNFα, IL-1β, IFNγ). Renal protein expression of mitogen activated protein kinases (MAPKs) (p-JNK, p-ERK1/2) and glucose regulated protein 78, CHOP were increased in NASH induced mice and curcumin treatment attenuated these increased expressions. In addition, curcumin treatment also decreased the apoptosis signaling proteins (cleaved caspase-3, cleaved caspase-12) in the NASH kidney. Taken together, our results suggest that curcumin preserves the renal function, probably by attenuating the ER stress mediated MAPK signaling. Copyright © 2017 Elsevier B.V. All rights reserved.

Deletion of Smad4 attenuates the hepatic inflammation and fibrogenesis during nonalcoholic steatohepatitis progression.

PubMed

Qin, Geng; Wang, Guo Zhen; Guo, Dan Dan; Bai, Ru-Xue; Wang, Miao; Du, Shi Yu

2018-04-25

To explore the effects of Smad4 deletion on inflammation and fibrogenesis during nonalcoholic steatohepatitis (NASH) progression. We collected 56 liver tissues from NASH patients (NASH group) and 60 normal liver tissues from patients received liver resection for trauma (control group). Smad4 Co/Co mice and wild-type (WT) mice were used to construct NASH model by high-fat diet (HFD) or methionine- and choline-deficient (MCD) diet. Hematoxylin and eosin (HE) staining and Tunnel assay were performed to observe pathological changes and apoptosis of liver tissues, respectively, quantitative real-time polymerase chain reaction (qRT-PCR) to detect expressions of inflammatory, fibrogenesis and apoptosis-related genes, and immunohistochemistry to determine proteins expressions of Smad4, MCP-1 and α-SMA. Smad4 protein expression was significantly increased in NASH patients as compared with Control group. Besides, in terms of HFD- and MCD- fed mice, those in Smad4 Co/Co group showed reduction of hepatic steatosis, inflammatory, liver apoptosis and NAS scores, and presented a decrease in glucose, TG, FFAs, AST and ALT, a great up-regulation in adiponectin. Besides, as compared with the WT mice fed with HFD and MCD, Smad4 Co/Co decreased the expressions of inflammatory markers (TNF-α, MCP-1, IFN-γ), fibrogenesis markers (COL1A1, α-SMA and TGF-β1), lipogenic genes (SREBP1c, FAS and ACC) and proapoptotic genes (Bax and caspase 3) in liver tissues, but increased the expressions of β-oxidation genes (PPARα, CPT1 and ACO) and antiapoptotic gene Bcl-2. Smad4 deletion may inhibit lipogenesis, stimulateβ-oxidation, ameliorate lipid metabolism and liver function, alleviate inflammation, fibrosis, and reduce liver apoptosis during NASH. This article is protected by copyright. All rights reserved.

Silymarin suppresses hepatic stellate cell activation in a dietary rat model of non-alcoholic steatohepatitis: Analysis of isolated hepatic stellate cells

PubMed Central

KIM, MINA; YANG, SU-GEUN; KIM, JOON MI; LEE, JIN-WOO; KIM, YOUNG SOO; LEE, JUNG IL

2012-01-01

Non-alcoholic steatohepatitis (NASH) is characterized by hepatocellular injury and initial fibrosis severity has been suggested as an important prognostic factor of NASH. Silymarin was reported to improve carbon tetrachloride-induced liver fibrosis and reduce the activation of hepatic stellate cells (HSC). We investigated whether silymarin could suppress the activation of HSCs in NASH induced by methionine- and choline-deficient (MCD) diet fed to insulin-resistant rats. NASH was induced by feeding MCD diet to obese diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Non-diabetic Long-Evans Tokushima Otsuka (LETO) rats were fed with standard chow and served as the control. OLETF rats were fed on either standard laboratory chow, or MCD diet or MCD diet mixed with silymarin. Histological analysis of the liver showed improved non-alcoholic fatty liver disease (NAFLD) activity score in silymarin-fed MCD-induced NASH. Silymarin reduced the activation of HSCs, evaluated by counting α-smooth muscle actin (SMA)-positive cells and measuring α-SMA mRNA expression in the liver lysates as well as in HSCs isolated from the experimental animals. Although silymarin decreased α1-procollagen mRNA expression in isolated HSCs, the anti-fibrogenic effect of silymarin was not prominent so as to show significant difference under histological analysis. Silymarin increased the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and decreased tumor necrosis factor (TNF)-α mRNA expression in the liver. Our study suggested that the possible protective effect of silymarin in diet induced NASH by suppressing the activation of HSCs and disturbing the role of the inflammatory cytokine TNF-α. PMID:22710359

Effects of dark chocolate on NOX-2-generated oxidative stress in patients with non-alcoholic steatohepatitis.

PubMed

Loffredo, L; Del Ben, M; Perri, L; Carnevale, R; Nocella, C; Catasca, E; Baratta, F; Ceci, F; Polimeni, L; Gozzo, P; Violi, F; Angelico, F

2016-08-01

Activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is considered a pathogenetic mechanism determining fibrosis and disease progression in non-alcoholic steatohepatitis (NASH). Polyphenols exert antioxidant action and inhibit NADPH oxidase in humans. To analyse the effect of cocoa polyphenols on NADPH oxidase isoform 2 (NOX2) activation, oxidative stress and hepatocyte apoptosis in a population affected by NASH. In a cross-sectional study comparing 19 NASH and 19 controls, oxidative stress, as assessed by serum NOX2 activity and F2-isoprostanes, and hepatocyte apoptosis, as assessed by serum cytokeratin-18 (CK-18) levels, were measured. Furthermore, the 19 NASH patients were randomly allocated in a crossover design to 40 g/day of dark chocolate (>85% cocoa) or 40 g/day of milk chocolate (<35% cocoa), for 2 weeks. sNOX2-dp, serum isoprostanes and CK-18 were assessed at baseline and after 2 weeks of chocolate intake. Compared to controls, NASH patients had higher sNOX2-dp, serum isoprostanes and CK-18 levels. A significant difference for treatments was found in subjects with respect to sNOX2-dp, serum isoprostanes and serum CK-18. The pairwise comparisons showed that, compared to baseline, after 14 days of dark chocolate intake, a significant reduction in sNOX2-dp serum isoprostanes and CK-18 M30 was found. No change was observed after milk chocolate ingestion. A simple linear regression analysis showed that ∆ of sNOX2-dp was associated with ∆ of serum isoprostanes. Cocoa polyphenols exert an antioxidant activity via NOX2 down-regulation in NASH patients. © 2016 John Wiley & Sons Ltd.

Design and rationale for a real-world observational cohort of patients with nonalcoholic fatty liver disease: The TARGET-NASH study.

PubMed

Barritt, A S; Gitlin, Norman; Klein, Samuel; Lok, Anna S; Loomba, Rohit; Malahias, Laura; Powell, Margaret; Vos, Miriam B; Weiss, L Michael; Cusi, Kenneth; Neuschwander-Tetri, Brent A; Sanyal, Arun

2017-10-01

Nonalcoholic fatty liver disease (NAFLD) is highly prevalent and can lead to cirrhosis, hepatocellular carcinoma, and end-stage liver disease. NAFLD comprises the spectrum from simple steatosis (nonalcoholic fatty liver, NAFL), to steatosis with inflammation (nonalcoholic steatohepatitis, NASH). Current primary therapy recommended for NAFLD is weight loss induced by lifestyle modification. The difficulty in achieving this has led to robust pharmacological therapy development. While new drugs may show efficacy in selected phase II/III clinical trial populations, their real-world effectiveness is unknown. TARGET-NASH is a 5-year, longitudinal, observational study of patients with NAFLD designed to evaluate the effectiveness of clinical practice interventions and provide practical information unobtainable in registration trials. A biological specimen repository is included in TARGET-NASH for translational studies of genomics and biomarkers of disease activity. Patients are enrolling at adult and pediatric sites representing multiple specialties. All patients being managed for NAFLD are eligible, whereas those in other NASH registries or clinical trials will be excluded. Enrolled patients range in age from 6 and up and will have 3years of clinical data reviewed. Patient comorbidities, concomitant medications, disease progression and off-label interventions will be assessed, and adverse outcomes, monitored. Confirming the use, safety and effectiveness of NAFLD interventions in children and adults and establishing pragmatic methods of assessing disease progression under real-world conditions are key study outcomes. Ultimately, TARGET-NASH will establish a large, diverse registry of NAFLD patients at academic and community practices to be leveraged to improve health and reduce development of cirrhosis and hepatocellular carcinoma. Copyright © 2017 Elsevier Inc. All rights reserved.

Alisol A 24-acetate ameliorates nonalcoholic steatohepatitis by inhibiting oxidative stress and stimulating autophagy through the AMPK/mTOR pathway.

PubMed

Wu, Chenqu; Jing, Menghui; Yang, Lijuan; Jin, Lei; Ding, Yicun; Lu, Juan; Cao, Qin; Jiang, Yuanye

2018-06-05

Alisol A 24-acetate (AA), a natural triterpenoid isolated from the traditional Chinese medicine Rhizoma Alismatis, has various therapeutic effects. We investigated the anti-nonalcoholic steatohepatitis (NASH) effect of AA and its underlying mechanisms in vitro and in vivo. C57BL/6 mice were fed a methionine and choline-deficient (MCD) diet for 4 weeks to induce NASH. The mice were simultaneously treated with a daily dose of AA (15, 30, and 60 mg kg -1 , ig) for 4 weeks. On the last day, the animals were sacrificed and plasma and liver tissue were collected. Serum and liver tissue biochemical analyses and histological observation were performed. The human hepatic stellate cell line LX-2 was used to build NASH models by culturing with conditioned medium from WRL-68 liver cells after exposure to MCD medium in vitro. Liver oxidative stress and inflammatory indices and autophagy markers were examined. The results showed that AA suppressed reactive oxygen species (ROS) and inflammation in a NASH mouse model and inhibited the expression of inflammatory cytokines and ROS in LX-2 cells in MCD medium. Furthermore, we found AA stimulated autophagy in mice liver and LX-2, which could be the underlying mechanism of AA in NASH. To further investigate the role of autophagy in LX-2 cells, we found that AA regulated autophagy via the AMPK/mTOR/ULK1 pathway and dorsomorphin, a selective AMPK inhibitor, led to the suppression of AA-induced autophagy. Taken together, our results indicate that AA could be a possible therapy for NASH by inhibiting oxidative stress and stimulating autophagy. Copyright © 2018. Published by Elsevier B.V.

Hepatocellular carcinoma in a mouse model fed a choline-deficient, L-amino acid-defined, high-fat diet.

PubMed

Ikawa-Yoshida, Ayae; Matsuo, Saori; Kato, Atsuhiko; Ohmori, Yusuke; Higashida, Atsuko; Kaneko, Eiji; Matsumoto, Masahiko

2017-08-01

Hepatocellular carcinoma (HCC) is a common cancer worldwide and represents the outcome of the natural history of chronic liver disease. The growing rates of HCC may be partially attributable to increased numbers of people with non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). However, details of the liver-specific molecular mechanisms responsible for the NAFLD-NASH-HCC progression remain unclear, and mouse models that can be used to explore the exact factors that influence the progression of NAFLD/NASH to the more chronic stages of liver disease and subsequent HCC are not yet fully established. We have previously reported a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) as a dietary NASH model with rapidly progressive liver fibrosis in mice. The current study in C57BL/6J mice fed CDAHFD provided evidence for the chronic persistence of advanced hepatic fibrosis in NASH and disease progression towards HCC in a period of 36 weeks. When mice fed CDAHFD were switched back to a standard diet, hepatic steatosis was normalized and NAFLD activity score improved, but HCC incidence increased and the phenotype of fibrosis-associated HCC development was observed. Moreover, when mice continued to be fed CDAHFD for 60 weeks, HCC further developed without severe body weight loss or carcinogenesis in other organs. The autochthonous tumours showed a variety of histological features and architectural patterns including trabecular, pseudoglandular and solid growth. The CDAHFD mouse model might be a useful tool for studying the development of HCC from NAFLD/NASH, and potentially useful for better understanding pathological changes during hepatocarcinogenesis. © 2017 The Authors. International Journal of Experimental Pathology published by John Wiley & Sons Ltd on behalf of Company of the International Journal of Experimental Pathology (CIJEP).

Farnesoid X receptor deficiency induces nonalcoholic steatohepatitis in low-density lipoprotein receptor-knockout mice fed a high-fat diet.

PubMed

Kong, Bo; Luyendyk, James P; Tawfik, Ossama; Guo, Grace L

2009-01-01

Nonalcoholic steatohepatitis (NASH) comprises dysregulation of lipid metabolism and inflammation. Identification of the various genetic and environmental susceptibility factors for NASH may provide novel treatments to limit inflammation and fibrosis in patients. This study utilized a mouse model of hypercholesterolemia, low-density lipoprotein receptor knockout (LDLr(-/-)) mice fed a high-fat diet for 5 months, to test the hypothesis that farnesoid X receptor (FXR) deficiency contributed to NASH development. Either the high-fat diet or FXR deficiency increased serum alanine aminotransferase activity, whereas only FXR deficiency increased bile acid and alkaline phosphatase levels. FXR deficiency and high-fat feeding increased serum cholesterol and triglycerides. Although high fat led to macrosteatosis and hepatocyte ballooning in livers of mice regardless of genotype, no inflammatory infiltrate was observed in the livers of LDLr(-/-) mice. In contrast, in the livers of LDLr(-/-)/FXR(-/-) mice, foci of inflammatory cells were observed occasionally when fed the control diet and were greatly increased when fed the high-fat diet. Consistent with enhanced inflammatory cells, hepatic levels of tumor necrosis factor alpha and intercellular adhesion molecule-1 mRNA were increased by the high-fat diet in LDLr(-/-)/FXR(-/-) mice. In agreement with elevated levels of procollagen 1 alpha 1 and TGF-beta mRNA, type 1 collagen protein levels were increased in livers of LDLr(-/-)/FXR(-/-) mice fed a high-fat diet. In conclusion, FXR deficiency induces pathologic manifestations required for NASH diagnosis in a mouse model of hypercholesterolemia, including macrosteatosis, hepatocyte ballooning, and inflammation, which suggest a combination of FXR deficiency and high-fat diet is a risk factor for NASH development, and activation of FXR may be a therapeutic intervention in the treatment of NASH.

NASH is an Inflammatory Disorder: Pathogenic, Prognostic and Therapeutic Implications

PubMed Central

van Rooyen, Derrick; Gan, Lay; Chitturi, Shivrakumar

2012-01-01

While non-alcoholic fatty liver disease (NAFLD) is highly prevalent (15% to 45%) in modern societies, only 10% to 25% of cases develop hepatic fibrosis leading to cirrhosis, end-stage liver disease or hepatocellular carcinoma. Apart from pre-existing fibrosis, the strongest predictor of fibrotic progression in NAFLD is steatohepatitis or non-alcoholic steatohepatitis (NASH). The critical features other than steatosis are hepatocellular degeneration (ballooning, Mallory hyaline) and mixed inflammatory cell infiltration. While much is understood about the relationship of steatosis to metabolic factors (over-nutrition, insulin resistance, hyperglycemia, metabolic syndrome, hypoadiponectinemia), less is known about inflammatory recruitment, despite its importance for the perpetuation of liver injury and fibrogenesis. In this review, we present evidence that liver inflammation has prognostic significance in NAFLD. We then consider the origins and components of liver inflammation in NASH. Hepatocytes injured by toxic lipid molecules (lipotoxicity) play a central role in the recruitment of innate immunity involving Toll-like receptors (TLRs), Kupffer cells (KCs), lymphocytes and neutrophils and possibly inflammasome. The key pro-inflammatory signaling pathways in NASH are nuclear factor-kappa B (NF-κB) and c-Jun N-terminal kinase (JNK). The downstream effectors include adhesion molecules, chemokines, cytokines and the activation of cell death pathways leading to apoptosis. The upstream activators of NF-κB and JNK are more contentious and may depend on the experimental model used. TLRs are strong contenders. It remains possible that inflammation in NASH originates outside the liver and in the gut microbiota that prime KC/TLR responses, inflamed adipose tissue and circulating inflammatory cells. We briefly review these mechanistic considerations and project their implications for the effective treatment of NASH. PMID:22570745

Induction of steatohepatitis (NASH) with insulin resistance in wildtype B6 mice by a western-type diet containing soybean oil and cholesterol.

PubMed

Henkel, Janin; Coleman, Charles Dominic; Schraplau, Anne; Jӧhrens, Korinna; Weber, Daniela; Castro, José Pedro; Hugo, Martin; Schulz, Tim Julius; Krämer, Stephanie; Schürmann, Annette; Püschel, Gerhard Paul

2017-03-21

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are hepatic manifestations of the metabolic syndrome. Many currently used animal models of NAFLD/NASH lack clinical features of either NASH or metabolic syndrome such as hepatic inflammation and fibrosis (e.g. high-fat diets) or overweight and insulin resistance (e.g. methionine-choline-deficient diets) or they are based on monogenetic defects (e.g. ob/ob mice). In the current study, a western-type diet containing soybean oil with high n 6-PUFA and 0.75% cholesterol (SOD+Cho) induced steatosis, inflammation and fibrosis accompanied by hepatic lipid peroxidation and oxidative stress in livers of C57BL/6-mice which in addition showed increased weight gain and insulin resistance, thus displaying a phenotype closely resembling all clinical features of NASH in patients with metabolic syndrome. In striking contrast a soybean oil-containing western-type diet without cholesterol (SOD) induced only mild steatosis but neither hepatic inflammation nor fibrosis, weight gain or insulin resistance. Another high-fat diet mainly consisting of lard and supplemented with fructose in drinking water (LAD+Fru) resulted in more prominent weight gain, insulin resistance and hepatic steatosis than SOD+Cho but livers were devoid of inflammation and fibrosis. Although both LAD+Fru- and SOD+Cho-fed animals had high plasma cholesterol, liver cholesterol was elevated only in SOD+Cho animals. Cholesterol induced expression of chemotactic and inflammatory cytokines in cultured Kupffer cells and rendered hepatocytes more susceptible to apoptosis. Summarizing, dietary cholesterol in SOD+Cho diet may trigger hepatic inflammation and fibrosis. SOD+Cho-fed animals may be a useful disease model displaying many clinical features of patients with the metabolic syndrome and NASH.

The Conference Proceedings of the 1999 Air Transport Research Group (ATRG) of the WCTR Society. Volume 2

NASA Technical Reports Server (NTRS)

Zhang, Anming (Editor); Bowen Brent D. (Editor)

1999-01-01

In this paper, we develop a model with which allows us to measure not only the changes in equilibrium outcomes and welfare consequences of liberalizing a bilateral air transport agreement, but also the distribution of the gains and losses to carriers and consumers of each bilateral country and those of the third foreign countries. Our model also allows to measure the effects of changes in a bilateral agreement on the amount of traffic diversion between the direct bilateral routes and the indirect routes via a third country. We also provide an extension of our model to a case of oligopoly market outcome (Coumot Nash equilibrium). In our model, quality aspects are treated in the framework of hedonic price theory by specifying the quality-adjusted price (quantity) as a multiplication of the observed price (quantity) by the reciprocal quality index function (the quality index function). Numerical simulations were conducted to measure the effects of changing the following major policy levers in a bilateral air transport agreement: 1) Removing price regulation while retaining frequency and entry restrictions; 2) Removing price and entry regulation while retaining frequency restrictions; 3) Removing frequency regulations while retaining price and entry regulations; 4) Removing frequency and entry regulations while retaining price regulation; 5) Removing price and frequency regulations while retaining entry restriction; and 6) Removing all price, frequency and entry regulations (de facto, open skies).

Distributed Power Allocation for Wireless Sensor Network Localization: A Potential Game Approach.

PubMed

Ke, Mingxing; Li, Ding; Tian, Shiwei; Zhang, Yuli; Tong, Kaixiang; Xu, Yuhua

2018-05-08

The problem of distributed power allocation in wireless sensor network (WSN) localization systems is investigated in this paper, using the game theoretic approach. Existing research focuses on the minimization of the localization errors of individual agent nodes over all anchor nodes subject to power budgets. When the service area and the distribution of target nodes are considered, finding the optimal trade-off between localization accuracy and power consumption is a new critical task. To cope with this issue, we propose a power allocation game where each anchor node minimizes the square position error bound (SPEB) of the service area penalized by its individual power. Meanwhile, it is proven that the power allocation game is an exact potential game which has one pure Nash equilibrium (NE) at least. In addition, we also prove the existence of an ϵ -equilibrium point, which is a refinement of NE and the better response dynamic approach can reach the end solution. Analytical and simulation results demonstrate that: (i) when prior distribution information is available, the proposed strategies have better localization accuracy than the uniform strategies; (ii) when prior distribution information is unknown, the performance of the proposed strategies outperforms power management strategies based on the second-order cone program (SOCP) for particular agent nodes after obtaining the estimated distribution of agent nodes. In addition, proposed strategies also provide an instructional trade-off between power consumption and localization accuracy.

Drought in the northern Bahamas from 3300 to 2500 years ago

NASA Astrophysics Data System (ADS)

van Hengstum, Peter J.; Maale, Gerhard; Donnelly, Jeffrey P.; Albury, Nancy A.; Onac, Bogdan P.; Sullivan, Richard M.; Winkler, Tyler S.; Tamalavage, Anne E.; MacDonald, Dana

2018-04-01

Intensification and western displacement of the North Atlantic Subtropical High (NASH) is projected for this century, which can decrease Caribbean and southeastern American rainfall on seasonal and annual timescales. However, additional hydroclimate records are needed from the northern Caribbean to understand the long-term behavior of the NASH, and better forecast its future behavior. Here we present a multi-proxy sinkhole lake reconstruction from a carbonate island that is proximal to the NASH (Abaco Island, The Bahamas). The reconstruction indicates the northern Bahamas experienced a drought from ∼3300 to ∼2500 Cal yrs BP, which coincides with evidence from other hydroclimate and oceanographic records (e.g., Africa, Caribbean, and South America) for a synchronous southern displacement of the Intertropical Convergence Zone and North Atlantic Hadley Cell. The specific cause of the hydroclimate change in the northeastern Caribbean region from ∼3300 to 2500 Cal yrs BP was probably coeval southern or western displacement of the NASH, which would have increased northeastern Caribbean exposure to subsiding air from higher altitudes.

Hepatic manifestations of women with polycystic ovary syndrome.

PubMed

Chen, Mei-Jou; Ho, Hong-Nerng

2016-11-01

Women with polycystic ovary syndrome (PCOS) have a higher prevalence of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) than the general population. The link between NAFLD/NASH and PCOS is not just a coincidence. Indeed, both of these disorders comprise common risk factors, including central obesity, insulin resistance, chronic low-grade inflammation, and hyperandrogenemia. The characteristics of hyperandrogenemia in women with PCOS include elevated total and free testosterone levels and low sex hormone-binding globulin levels and are reported to be associated with NAFLD and elevated liver enzymes; however, not all elevated androgen levels in women with PCOS have the same adverse effects on the liver. With the exception of weight loss and encouraging exercise in obese women, few evidence-based effective treatments target NAFLD/NASH in women with PCOS. Selective antiandrogens and insulin sensitizers might be beneficial in treating NAFLD/NASH in women with PCOS, but further elucidation is needed. Copyright © 2016. Published by Elsevier Ltd.

Misregulation of membrane trafficking processes in human nonalcoholic steatohepatitis.

PubMed

Dzierlenga, Anika L; Cherrington, Nathan J

2018-03-01

Nonalcoholic steatohepatitis (NASH) remodels the expression and function of genes and proteins that are critical for drug disposition. This study sought to determine whether disruption of membrane protein trafficking pathways in human NASH contributes to altered localization of multidrug resistance-associated protein 2 (MRP2). A comprehensive immunoblot analysis assessed the phosphorylation, membrane translocation, and expression of transporter membrane insertion regulators, including several protein kinases (PK), radixin, MARCKS, and Rab11. Radixin exhibited a decreased phosphorylation and total expression, whereas Rab11 had an increased membrane localization. PKCδ, PKCα, and PKA had increased membrane activation, whereas PKCε had a decreased phosphorylation and membrane expression. Radixin dephosphorylation may activate MRP2 membrane retrieval in NASH; however, the activation of Rab11/PKCδ and PKA/PKCα suggest an activation of membrane insertion pathways as well. Overall these data suggest an altered regulation of protein trafficking in human NASH, although other processes may be involved in the regulation of MRP2 localization. © 2018 Wiley Periodicals, Inc.

Nonalcoholic fatty liver disease: diagnosis, pathogenesis, and management.

PubMed

Başaranoğlu, Metin; Örmeci, Necati

2014-04-01

Nonalcoholic fatty liver disease (NAFLD) is an umbrella term that covers both a relatively benign condition, which is simple steatosis, and nonalcoholic steatohepatitis (NASH). NASH is characterized by a chronic and progressive liver pathology that may progress to cirrhosis, end-stage liver disease, hepatocellular carcinoma, and liver transplantation. Despite the growing body of evidence, one of the important and unresolved problems is the pathogenesis of NASH. It might be a metabolic disturbance as a primary abnormality in NAFLD. Insulin resistance is at the center of these metabolic abnormalities. Then, hepatocyte injury might be induced by oxidative stress. This ongoing process progresses to NASH, even to cirrhosis in some patients. In addition to oxidative stress, possibilities for the next hit are lipid peroxidation, reactive metabolites, adipose tissue products, transforming growth factor-β₁, Fas ligand, mitochondrial dysfunction, respiratory chain deficiency, and intestinal microbiota. Currently, there is no well-established and approved therapy. Recommendations are to improve existing co-morbidities, such as obesity, hyperlipidemia, or type 2 diabetes, and lifestyle modification with weight loss and exercise.

Rosiglitazone attenuates liver inflammation in a rat model of nonalcoholic steatohepatitis.

PubMed

Tahan, Veysel; Eren, Fatih; Avsar, Erol; Yavuz, Dilek; Yuksel, Meral; Emekli, Ebru; Imeryuz, Nese; Celikel, Cigdem; Uzun, Hafize; Haklar, Goncagul; Tozun, Nurdan

2007-12-01

Rosiglitazone is an insulin-sensitizing agent. We aimed to assess the effects of rosiglitazone on a methionine- and choline-deficient diet (MCDD) model of nonalcoholic steatohepatitis (NASH) in rats. Wistar rats were fed either MCDD or a control diet in the 4-week induction study; they were given saline or 4 mg/kg/day rosiglitazone. After the induction study period, the rats were divided into four groups and fed MCDD or given a control diet for an additional 8 weeks and received saline or rosiglitazone. Serum and tissue samples were obtained. Rosiglitazone improved inflammation in NASH and improved ALT, alkaline phosphatase, and interleukin-6 levels in the induction study and interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha levels in the treatment study. Our preliminary study is the first to show the anti-inflammatory effects of rosiglitazone in NASH. Rosiglitazone's effect on cytokines may be a key mechanism of its anti-inflammatory effect in NASH.

Connecting Solubility, Equilibrium, and Periodicity in a Green, Inquiry Experiment for the General Chemistry Laboratory

ERIC Educational Resources Information Center

Cacciatore, Kristen L.; Amado, Jose; Evans, Jason J.; Sevian, Hannah

2008-01-01

We present a novel first-year chemistry laboratory experiment that connects solubility, equilibrium, and chemical periodicity concepts. It employs a unique format that asks students to replicate experiments described in different sample lab reports, each lacking some essential information, rather than follow a scripted procedure. This structure is…

Liraglutide efficacy and action in non-alcoholic steatohepatitis (LEAN): study protocol for a phase II multicentre, double-blinded, randomised, controlled trial

PubMed Central

Armstrong, Matthew J; Barton, Darren; Gaunt, Piers; Hull, Diana; Guo, Kathy; Stocken, Deborah; Gough, Stephen C L; Tomlinson, Jeremy W; Brown, Rachel M; Hübscher, Stefan G; Newsome, Philip N

2013-01-01

Introduction Non-alcoholic steatohepatitis (NASH) is now the commonest cause of chronic liver disease. Despite this, there are no universally accepted pharmacological therapies for NASH. Liraglutide (Victoza), a human glucagon-like peptide-1 (GLP-1) analogue, has been shown to improve weight loss, glycaemic control and liver enzymes in type 2 diabetes. There is currently a lack of prospective-controlled studies investigating the efficacy of GLP-1 analogues in patients with NASH. Methods and analysis Liraglutide efficacy and action in NASH (LEAN) is a phase II, multicentre, double-blinded, placebo-controlled, randomised clinical trial designed to investigate whether a 48-week treatment with 1.8 mg liraglutide will result in improvements in liver histology in patients with NASH. Adult, overweight (body mass index ≥25 kg/m2) patients with biopsy-confirmed NASH were assessed for eligibility at five recruitment centres in the UK. Patients who satisfied the eligibility criteria were randomly assigned (1:1) to receive once-daily subcutaneous injections of either 1.8 mg liraglutide or liraglutide-placebo (control). Using A'Hern's single stage phase II methodology (significance level 0.05; power 0.90) and accounting for an estimated 20% withdrawal rate, a minimum of 25 patients were randomised to each treatment group. The primary outcome measure will be centrally assessed using an intention-to-treat analysis of the proportion of evaluable patients achieving an improvement in liver histology between liver biopsies at baseline and after 48 weeks of treatment. Histological improvement will be defined as a combination of the disappearance of active NASH and no worsening in fibrosis. Ethics and dissemination The protocol was approved by the National Research Ethics Service (East Midlands—Northampton committee; 10/H0402/32) and the Medicines and Healthcare products Regulatory Agency. Recruitment into the LEAN started in August 2010 and ended in May 2013, with 52 patients randomised. The treatment follow-up of LEAN participants is currently ongoing and is due to finish in July 2014. The findings of this trial will be disseminated through peer-reviewed publications and international presentations. Trial registration clinicaltrials.gov NCT01237119. PMID:24189085

Expression of genes for microRNA-processing enzymes is altered in advanced non-alcoholic fatty liver disease.

PubMed

Sharma, Haveesh; Estep, Michael; Birerdinc, Aybike; Afendy, Arian; Moazzez, Amir; Elariny, Hazem; Goodman, Zachary; Chandhoke, Vikas; Baranova, Ancha; Younossi, Zobair M

2013-08-01

Recently, microRNAs (miRNA) have been linked to the pathogenesis of non-alcoholic fatty liver disease (NAFLD) and its progression to non-alcoholic steatohepatitis (NASH). First transcribed as pri-miRNA, these molecules are further processed by a complex of endonuclear and cytosolic RNA binding molecules to form mature miRNAs. The aim of this study is to investigate mechanisms of miRNA regulation in the visceral adipose of obese NAFLD patients via measuring expression of miRNA processing enzymes and pri-miRNA. Total RNAs were extracted from visceral adipose tissue (VAT) samples collected from patients undergoing bariatric surgery. All patients had biopsy-proven NAFLD (NASH patients [n = 12] and non-NASH NAFLD [n = 12]). For each patient, we profiled mRNA levels for three miRNA processing elements (Drosha, DGCR8, and Dicer1) and seven pri-miRNAs (pri-miR-125b-2, pri-miR-16-2, pri-miR-26a-1, pri-miR-26a-2, pri-miR-7-1, pri-miR-7-2, and pri-miR-7-3). Expression of Dicer1, Drosha and DGCR8 was significantly increased within the NASH cohort along with expression of pri-miR-7-1. The presence of focal necrosis on the liver biopsy correlated significantly with levels of Dicer1 and DGRC8. Both NASH and ballooning degeneration of hepatocytes correlated negatively with the expression levels of hsa-miR-125b. Histologic NASH correlated positively with the expression levels of pri-miR-16-2 and pri-miR-7-1. The presence of the hepatocyte's ballooning degeneration in the liver biopsy correlated positively with pri-miR-26a-1 and pri-miR-7-1. The expression profile of pri-miR-125b-2 also correlated positively with body mass index. Our findings support the hypothesis that VAT-derived miRNA may contribute to the pathogenesis of NASH in obese patients. © 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

[Non-alcoholic fatty liver disease--new view].

PubMed

Raszeja-Wyszomirska, Joanna; Lawniczak, Małgorzata; Marlicz, Wojciech; Miezyńska-Kurtycz, Joanna; Milkiewicz, Piotr

2008-06-01

Non-alcoholic fatty liver disease (NAFLD) covers a wide spectrum of liver pathology--from steatosis alone, through the necroinflammatory disorder of non-alcoholic steatohepatitis (NASH) to cirrhosis and liver cancer. NAFLD/NASH is mostly related with visceral adiposity, obesity, type 2 diabetes melitus (DM t.2) and metabolic syndrome. Pathogenetic concepts of NAFLD include overnutrition and underactivity, insulin resistance (IR) and genetic factor. The prevalence of NAFLD has been estimated to be 17-33% in some countries, NASH may be present in about 1/3 of such cases, while 20-25% of NASH cases could progress to cirrhosis. NAFLD is now recognized as one of the most frequent reason of liver tests elevation without clinical symptoms. Insulin resistance is considering as having a central role in NAFLD pathogenesis. In hepatocytes, IR is related to hyperglycaemia and hyperinsulinaemia, formation of advanced glycation end-products, increased free fatty acids and their metabolites, oxidative stress and altered profiles of adipocytokines. Early stages of fatty liver are clinically silent and include elevation of ALT and GGTP, hyperechogenic liver in USG and/or hepatomegaly. Among clinical symptoms, abdominal discomfort is relatively common as well as chronic fatigue. NAFLD/NASH is not a benign disease, progressive liver biopsy have shown histological progression of fibrosis in 32%, the estimated rate of cirrhosis development is 20% and a liver--related death is 12% over 10 years. No treatment has scientifically proved to ameliorate NAFLD or to avoid its progression. The various therapeutic alternatives are aimed at interfering with the risk factors involved in the pathogenesis of the disorder in order to prevent the progression to end-stage liver disease. The most important therapeutic measure is increasing insulin sensitivity by an attempt to change a lifestyle mostly by dieting and physical activity in order to loose weight. The most used agent is metformin, the others are under controlled trials or their effectiveness is low. NASH is not a common indication for liver transplantation because of the older age distribution of patients and high prevalence of comorbidity, related to metabolic syndrome. Recurence of NASH in the grafted liver is also a relatively frequent complication.

TLR9 is up-regulated in human and murine NASH: pivotal role in inflammatory recruitment and cell survival.

PubMed

Mridha, Auvro R; Haczeyni, Fahrettin; Yeh, Matthew M; Haigh, W Geoffrey; Ioannou, George N; Barn, Vanessa; Ajamieh, Hussam; Adams, Leon; Hamdorf, Jeffrey M; Teoh, Narci C; Farrell, Geoffrey C

2017-08-15

Background and aims : TLR9 deletion protects against steatohepatitis due to choline-amino acid depletion and high-fat diet. We measured TLR9 in human non-alcoholic steatohepatitis (NASH) livers, and tested whether TLR9 mediates inflammatory recruitment in three murine models of non-alcoholic fatty liver disease (NAFLD). Methods : We assayed TLR mRNA in liver biopsies from bariatric surgery patients. Wild-type ( Wt ), appetite-dysregulated Alms1 mutant (foz/foz), Tlr9 -/- , and Tlr9 -/- foz/foz C57BL6/J mice and bone marrow (BM) chimeras were fed 0.2% cholesterol, high-fat, high sucrose (atherogenic[Ath]) diet or chow, and NAFLD activity score (NAS)/NASH pathology, macrophage/neutrophil infiltration, cytokines/chemokines, and cell death markers measured in livers. Results : Hepatic TLR9 and TLR4 mRNA were increased in human NASH but not simple steatosis, and in Ath-fed foz/foz mice with metabolic syndrome-related NASH. Ath-fed Tlr9 -/- mice showed simple steatosis and less Th1 cytokines than Wt. Tlr9 -/- foz/foz mice were obese and diabetic, but necroinflammatory changes were less severe than Tlr9 +/+ .foz/foz mice. TLR9-expressing myeloid cells were critical for Th1 cytokine production in BM chimeras. BM macrophages from Tlr9 -/- mice showed M2 polarization, were resistant to M1 activation by necrotic hepatocytes/other pro-inflammatory triggers, and provoked less neutrophil chemotaxis than Wt Livers from Ath-fed Tlr9 -/- mice appeared to exhibit more markers of necroptosis [receptor interacting protein kinase (RIP)-1, RIP-3, and mixed lineage kinase domain-like protein (MLKL)] than Wt , and ∼25% showed portal foci of mononuclear cells unrelated to NASH pathology. Our novel clinical data and studies in overnutrition models, including those with diabetes and metabolic syndrome, clarify TLR9 as a pro-inflammatory trigger in NASH. This response is mediated via M1-macrophages and neutrophil chemotaxis. © 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Short-term therapy with peroxisome proliferation-activator receptor-alpha agonist Wy-14,643 protects murine fatty liver against ischemia-reperfusion injury.

PubMed

Teoh, Narci C; Williams, Jacqueline; Hartley, Jennifer; Yu, Jun; McCuskey, Robert S; Farrell, Geoffrey C

2010-03-01

Steatosis increases operative morbidity/mortality from ischemia-reperfusion injury (IRI); few pharmacological approaches have been protective. Using novel genetic/dietary models of nonalcoholic steatohepatitis (NASH) and simple steatosis (SS) in Alms1 mutant (foz/foz) mice, we characterized severity of IRI in NASH versus SS and lean liver and tested our hypothesis that the lipid-lowering effects of the peroxisome proliferation-activator receptor (PPAR)-alpha agonist Wy-14,643 would be hepatoprotective. Mice were subjected to 60-minute partial hepatic IRI. Microvascular changes were assessed at 15-minute reperfusion by in vivo microscopy, injury at 24 hours by serum alanine aminotransferase (ALT), and hepatic necrosis area. Injury and inflammation mediators were determined by way of immunoblotting for intercellular cellular adhesion molecule, vascular cellular adhesion molecule, p38, c-jun N-terminal kinase, IkappaB-alpha, interleukin (IL)-1a, IL-12, tumor necrosis factor-alpha (TNF-alpha) and IL-6, cell cycle by cyclin D1 and proliferating cell nuclear antigen immunohistochemistry. In foz/foz mice fed a high-fat diet (HFD) to cause NASH or chow (SS), IRI was exacerbated compared with HFD-fed or chow-fed wild-type littermates by ALT release; corresponding necrotic areas were 60 +/- 22% NASH, 29 +/- 9% SS versus 7 +/- 1% lean. Microvasculature of NASH or SS livers was narrowed by enormous lipid-filled hepatocytes, significantly reducing numbers of perfused sinusoids, all exacerbated by IRI. Wy-14,643 reduced steatosis in NASH and SS livers, whereas PPAR-alpha stimulation conferred substantial hepatoprotection against IRI by ALT release, with reductions in vascular cellular adhesion molecule-1, IL-1a, TNF-alpha, IL-12, activated nuclear factor-kappaB (NF-kappaB), p38, IL-6 production and cell cycle entry. NASH and SS livers are both more susceptible to IRI. Mechanisms include possible distortion of the microvasculature by swollen fat-laden hepatocytes, and enhanced production of several cytokines. The beneficial effects of Wy-14,643 may be exerted by dampening adhesion molecule and cytokine responses, and activating NF-kappaB, IL-6 production, and p38 kinase to effect cell cycle entry.

An estrogen receptor β-selective agonist inhibits non-alcoholic steatohepatitis in preclinical models by regulating bile acid and xenobiotic receptors.

PubMed

Ponnusamy, Suriyan; Tran, Quynh T; Thiyagarajan, Thirumagal; Miller, Duane D; Bridges, Dave; Narayanan, Ramesh

2017-03-01

Non-alcoholic steatohepatitis (NASH) affects 8-10 million people in the US and up to 75% of obese individuals. Despite this, there are no approved oral therapeutics to treat NASH and therefore the need for novel approaches exists. The estrogen receptor β (ER-β)-selective agonist, β-LGND2, inhibits body weight and white adipose tissue, and increases metabolism, resulting in higher energy expenditure and thermogenesis. Due to favorable effects of β-LGND2 on obesity, we hypothesized that β-LGND2 will prevent NASH directly by reducing lipid accumulation in the liver or indirectly by favorably changing body composition. Male C57BL/6 mice fed with high fat diet (HFD) for 10 weeks or methionine choline-deficient diet for four weeks and treated with vehicle exhibited altered liver weights by twofold and increased serum transaminases by 2-6-folds. These changes were not observed in β-LGND2-treated animals. Infiltration of inflammatory cells and collagen deposits, an indication of fibrosis, were observed in the liver of mice fed with HFD for 10 weeks, which were effectively blocked by β-LGND2. Gene expression studies in the liver indicate that pregnane X receptor target genes were significantly increased by HFD, and the increase was inhibited by β-LGND2. On the other hand, metabolomics indicate that bile acid metabolites were significantly increased by β-LGND2. These studies demonstrate that an ER-β agonist might provide therapeutic benefits in NASH by directly modulating the function of xenobiotic and bile acid receptors in the liver, which have important functions in the liver, and indirectly, as demonstrated before, by inhibiting adiposity. Impact statement Over 75-90% of those classified as clinically obese suffer from co-morbidities, the most common of which is non-alcoholic steatohepatitis (NASH). While there are currently no effective treatment approaches for NASH, data presented here provide preliminary evidence that an estrogen receptor β-selective ligand could have the potential to reduce lipid accumulation and inflammation, and protect liver from NASH.

p38 MAPK signal pathway involved in anti-inflammatory effect of Chaihu-Shugan-San and Shen-ling-bai-zhu-San on hepatocyte in non-alcoholic steatohepatitis rats.

PubMed

Yang, QinHe; Xu, YongJian; Feng, GaoFei; Hu, ChaoFeng; Zhang, YuPei; Cheng, ShaoBing; Wang, YanPing; Gong, XiangWen

2014-01-01

Traditional Chinese Medicine (TCM), has over thousands-of-years history of use. Chaihu-Shugan-San (CSS), and Shen-ling-bai-zhu-San (SLBZS), are famous traditional Chinese herbal medicine formulas, which have been used in China, for the treatment of many chronic diseases. This study investigated the anti-inflammatory effects of CSS and SLBZS on signaling molecules involved in p38 mitogen-activated protein kinase (p38 MAPK), pathway on hepatocytes of non-alcoholic steatohepatitis (NASH), rats induced by high fat diet. SD male rats were randomly divided into 8 groups: negative control group, model control group, high (9.6g/kg/day)/low (3.2g/kg/day)-dose CSS group, high (30g/kg/day)/low (10g/kg/day)-dose SLBZS group, high (39.6g/kg/day)/low (13.2g/kg/day)-dose integrated group. The rats of NASH model were induced by feeding a high-fat diet. After 16, wks, Hepatocytes were isolated from 6, rats in each group by collagenase perfusion. The liver histopathological changes and serum inflammatory cytokines TNF-α, IL-6 were determined. The proteins of TLR4, phosphor-p38 MAPK and p38 MAPK involved in p38 MAPK signal pathway were assayed. The statistical data indicated the NASH model rats reproduced typical histopathological features of NASH in human. CSS and SLBZS ameliorated lipid metabolic disturbance, attenuated NASH progression, decreased the levels of TNF-α and IL-6 in serum, as well as inhibited TLR4 protein expression, p38 MAPK phosphorylation, and activation of p38 MAPK. In conclusion, CSS and SLBZS might work as a significant anti-inflammatory effect on hepatocyte of NASH by inhibiting the activation of TLR4, p-p38 MAPK and p38 MAPK involved in p38 MAPK signal pathway. To some extent, CSS and SLBZS may be a potential alternative and complementary medicine to protect against liver injury, alleviate the inflammation reaction, moderate NASH progression.

Global stability of a multiple infected compartments model for waterborne diseases

NASA Astrophysics Data System (ADS)

Wang, Yi; Cao, Jinde

2014-10-01

In this paper, mathematical analysis is carried out for a multiple infected compartments model for waterborne diseases, such as cholera, giardia, and rotavirus. The model accounts for both person-to-person and water-to-person transmission routes. Global stability of the equilibria is studied. In terms of the basic reproduction number R0, we prove that, if R0⩽1, then the disease-free equilibrium is globally asymptotically stable and the infection always disappears; whereas if R0>1, there exists a unique endemic equilibrium which is globally asymptotically stable for the corresponding fast-slow system. Numerical simulations verify our theoretical results and present that the decay rate of waterborne pathogens has a significant impact on the epidemic growth rate. Also, we observe numerically that the unique endemic equilibrium is globally asymptotically stable for the whole system. This statement indicates that the present method need to be improved by other techniques.

Bright solitons in non-equilibrium coherent quantum matter

PubMed Central

Pinsker, F.; Flayac, H.

2016-01-01

We theoretically demonstrate a mechanism for bright soliton generation in spinor non-equilibrium Bose–Einstein condensates made of atoms or quasi-particles such as polaritons in semiconductor microcavities. We give analytical expressions for bright (half) solitons as minimizing functions of a generalized non-conservative Lagrangian elucidating the unique features of inter and intra-competition in non-equilibrium systems. The analytical results are supported by a detailed numerical analysis that further shows the rich soliton dynamics inferred by their instability and mutual cross-interactions. PMID:26997892

Remediating Language Deficient/Dyslexic College Students: An Interview with Robert Nash.

ERIC Educational Resources Information Center

Lundquist, Arlene J.; Nash, Robert

1988-01-01

Robert Nash responds to questions concerning his personal and professional background, the Simultaneous Multisensory Instructional Procedure for Teaching the Complete Sound Structure of the Language, problems associated with dyslexia, the social/emotional impact of learning disabilities, and the University of Wisconsin's Project Success for…

United States Navy Oceanic Armed Reconnaissance System

DTIC Science & Technology

2011-12-12

This report was prepared by: Rahul Petrie Daniel Reese Kurtis Hoots Robert Taylor Drew Nash Bunny Cooper Jonathan Trdan-Schmidt Marshall...NPS – Cohort 311-102S, Team OARS: Mr. Marshall Rice, Mr. Rahul Petrie, Mr. Daniel Reese, Mr. Kurtis Hoots, Mr. Robert Taylor, Mr. Drew Nash

Two Different Approaches to Nonzero-Sum Stochastic Differential Games

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rainer, Catherine

2007-06-15

We make the link between two approaches to Nash equilibria for nonzero-sum stochastic differential games: the first one using backward stochastic differential equations and the second one using strategies with delay. We prove that, when both exist, the two notions of Nash equilibria coincide.

Verification of B-lymphocyte activating factor's involvement in the exacerbation of insulin resistance as well as an autoimmune response in patients with nonalcoholic steatohepatitis and patients with HCV-related chronic liver disease.

PubMed

Himoto, Takashi; Fujita, Koji; Nomura, Takako; Tani, Joji; Morishita, Asahiro; Yoneyama, Hirohito; Haba, Reiji; Masaki, Tsutomu

2017-01-01

Ten to forty percent of nonalcoholic steatohepatitis (NASH) and HCV-related chronic liver disease (CLD-C) patients have antinuclear antibodies (ANAs). However, the relationship between autoimmune response and insulin resistance remains uncertain among those patients. The primary purpose of this study was to investigate whether or not ANA status was associated with the development of insulin resistance and obesity in NASH and CLD-C patients. Degrees of hepatic fibrosis and steatosis were evaluated by the classification proposed by Brunt et al. Obesity and insulin resistance were estimated by calculating body mass index and the value of homeostasis model of for assessment of insulin resistance (HOMA-IR), respectively. A revised scoring system was applied to the diagnosis of autoimmune hepatitis (AIH). Serum B-lymphocyte activating factor (BAFF) levels were determined, using an ELISA technique. Ten of 25 (40%) NASH patients and 9 of 22 (41%) CLD-C patients had ANAs, though the titers were weak in most patients. Only one NASH patient met the category of "definite" AIH among the enrolled patients. Serum IgG levels were significantly higher in NASH and CLD-C patients with ANAs than in those without ANAs, and NASH and CLD-C patients with ANAs had significantly higher HOMA-IR values than those without ANAs (6.81 ± 3.36 vs. 4.00 ± 2.57, p = 0.0305, 3.01 ± 1.31 vs. 1.28 ± 0.50, p = 0.0011). CLD-C patients with ANAs had more advanced hepatic fibrosis and steatosis than those without ANAs, while ANA status was not associated with hepatic fibrosis or steatosis in NASH patients. Obesity was independent of ANA status in both subjects. Serum BAFF levels were significantly higher in CLD-C patients with ANAs than those in CLD-C patients without ANAs (1303 ± 268 vs. 714 ± 143 pg/ml, p = 0.0036). A close correlation between serum BAFF level and the HOMA-IR value was observed in CLD-C patients (r = 0.467, p = 0.0485). Our data suggest that NASH and CLD-C patients with ANAs have more severe insulin resistance than those without ANAs. More advanced insulin resistance deriving from excessive BAFF production may result in severe hepatic fibrosis and steatosis in CLD-C patients with ANAs.

Effects of dark chocolate on endothelial function in patients with non-alcoholic steatohepatitis.

PubMed

Loffredo, L; Baratta, F; Ludovica, P; Battaglia, S; Carnevale, R; Nocella, C; Novo, M; Pannitteri, G; Ceci, F; Angelico, F; Violi, F; Del Ben, M

2018-02-01

Oxidative stress plays a pivotal role in inducing endothelial dysfunction and progression from simple fatty liver steatosis (FLD) to non-alcoholic steatohepatitis (NASH). Polyphenols could reduce oxidative stress and restore endothelial function by inhibiting the nicotinamide-adenine-dinucleotide-phosphate (NADPH) oxidase isoform Nox2. The aim of this study was to assess endothelial function and oxidative stress in a population affected by simple FLD and NASH. Furthermore, we analysed the effect of high vs low content of cocoa polyphenols on endothelial function and oxidative stress in patients with NASH. In a cross-sectional study we analysed endothelial function, as assessed by flow-mediated dilation (FMD), and oxidative stress, as assessed by Nox2 activation, serum isoprostanes and nitric oxide bioavailability (NOx), in patients with NASH (n = 19), FLD (n = 19) and controls (n = 19). Then, we performed a randomized, cross-over study in 19 subjects with NASH comparing the effect of 14-days administration of 40 g of chocolate at high (dark chocolate, cocoa >85%) versus low content (milk chocolate, cocoa <35%) of polyphenols on FMD and oxidative stress. Compared to controls, NASH and FLD patients had higher Nox2 activity and isoprostanes levels and lower FMD and NOx, with a significant gradient between FLD and NASH. The interventional study showed that, compared to baseline, FMD and NOx increased (from 2.9 ± 2.4 to 7.2 ± 3.0% p < 0.001 and from 15.9 ± 3.6 to 20.6 ± 4.9 μM, p < 0.001, respectively) in subjects given dark but not in those given milk chocolate. A simple linear regression analysis showed that Δ (expressed by difference of values between before and after 14 days of chocolate assumption) of FMD was associated with Δ of Nox2 activity (Rs = -0.323; p = 0.04), serum isoprostanes (Rs: -0.553; p < 0.001) and NOx (Rs: 0.557; p < 0.001). Cocoa polyphenols improve endothelial function via Nox2 down-regulation in NASH patients. Copyright © 2017 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.

Role of white adipose lipolysis in the development of NASH induced by methionine-and choline-deficient diet

PubMed Central

Tanaka, Naoki; Takahashi, Shogo; Fang, Zhong-Ze; Matsubara, Tsutomu; Krausz, Kristopher W.; Qu, Aijuan; Gonzalez, Frank J.

2014-01-01

Methionine- and choline-deficient diet (MCD) is a model for nonalcoholic steatohepatitis (NASH) in rodents. However, the mechanism of NASH development by dietary methionine/choline deficiency remains undetermined. To elucidate the early metabolic changes associated with MCD-NASH, serum metabolomic analysis was performed using mice treated with MCD and control diet for three days and one week, revealing significant increases in oleic and linoleic acids after MCD treatment. These increases were correlated with reduced body weight and white adipose tissue (WAT) mass, increased phosphorylation of hormone-sensitive lipase, and up-regulation of genes encoding carboxylesterase 3 and β2-adrenergic receptor in WAT, indicating accelerated lipolysis in adipocytes. The changes in serum fatty acids and WAT by MCD treatment were reversed by methionine supplementation, and similar alterations were detected in mice fed a methionine-deficient diet (MD), thus demonstrating that dietary methionine deficiency enhances lipolysis in WAT. MD treatment decreased glucose and increased fibroblast growth factor 21 in serum, thus exhibiting a similar metabolic phenotype as the fasting response. Comparison between MCD and choline-deficient diet (CD) treatments suggested that the addition of MD-induced metabolic alterations, such as WAT lipolysis, to CD-induced hepatic steatosis promotes liver injury. Collectively, these results demonstrate an important role for dietary methionine deficiency and WAT lipolysis in the development of MCD-NASH. PMID:25178843

A dietary restriction influences the progression but not the initiation of MSG-Induced nonalcoholic steatohepatitis.

PubMed

Fujimoto, Makoto; Tsuneyama, Koichi; Nakanishi, Yuko; Salunga, Thucydides L; Nomoto, Kazuhiro; Sasaki, Yoshiyuki; Iizuka, Seiichi; Nagata, Mitsunobu; Suzuki, Wataru; Shimada, Tsutomu; Aburada, Masaki; Shimada, Yutaka; Gershwin, M Eric; Selmi, Carlo

2014-03-01

The metabolic syndrome is a major worldwide health care issue and a dominant risk factor for cardiovascular disease. The liver manifestations of this syndrome include nonalcoholic fatty liver disease (NAFLD) and its progressive variant nonalcoholic steatohepatitis (NASH). Although significant research has been performed, the basic pathogenesis of NAFLD/NASH remains controversial and effective treatments are still unavailable. We have previously reported on a murine model of NASH induced by the neonatal injection of monosodium glutamate (MSG), which includes the clinical manifestations of central obesity, diabetes, hyperlipidemia, and ultimately liver inflammation, fibrosis, and cancer. Although MSG is considered a safe food additive, its administration to pregnant rats increases the voracity and growth hormone levels in the offspring. To further understand the biology of this model, we have investigated the influence of the calorie intake on these clinical manifestations by feeding animals a restrictive diet. MSG-treated animals fed a restrictive diet continue to manifest obesity and early stage NASH but have improvements in serum lipid profiles. At 12 months of age, mice had manifestations of obesity, whether animals were fed a restricted or control diet, but animals fed a restrictive diet had a reduction in the progression of NASH. In conclusion, MSG appears to be a critical factor in the initiation of obesity, whereas calorie intake may modulate the progression of disease.

Beyond Reasonable Doubt: Who Is the Culprit in Lipotoxicity in NAFLD/NASH?

PubMed Central

Arteel, Gavin E.

2016-01-01

BACKGROUND & AIMS Type 2 diabetes and nonalcoholic steatohepatitis (NASH) are associated with insulin resistance and disordered cholesterol homeostasis. We investigated the basis for hepatic cholesterol accumulation with insulin resistance and its relevance to the pathogenesis of NASH. METHODS Alms1 mutant (foz/foz) and wild-type NOD.B10 mice were fed high-fat diets that contained varying percentages of cholesterol; hepatic lipid pools and pathways of cholesterol turnover were determined. Hepatocytes were exposed to insulin concentrations that circulate in diabetic foz/foz mice. RESULTS Hepatic cholesterol accumulation was attributed to up-regulation of low-density lipoprotein receptor via activation of sterol regulatory element binding protein 2 (SREBP-2), reduced biotransformation to bile acids, and suppression of canalicular pathways for cholesterol and bile acid excretion in bile. Exposing primary hepatocytes to concentrations of insulin that circulate in diabetic Alms1 mice replicated the increases in SREBP-2 and low-density lipoprotein receptor and suppression of bile salt export pump. Removing cholesterol from diet prevented hepatic accumulation of free cholesterol and NASH; increasing dietary cholesterol levels exacerbated hepatic accumulation of free cholesterol, hepatocyte injury or apoptosis, macrophage recruitment, and liver fibrosis. CONCLUSIONS In obese, diabetic mice, hyperinsulinemia alters nuclear transcriptional regulators of cholesterol homeostasis, leading to hepatic accumulation of free cholesterol; the resulting cytotoxicity mediates transition of steatosis to NASH. PMID:22422583

Clinical Model for NASH and Advanced Fibrosis in Adult Patients With Diabetes and NAFLD: Guidelines for Referral in NAFLD.

PubMed

Bazick, Jessica; Donithan, Michele; Neuschwander-Tetri, Brent A; Kleiner, David; Brunt, Elizabeth M; Wilson, Laura; Doo, Ed; Lavine, Joel; Tonascia, James; Loomba, Rohit

2015-07-01

Approximately 18 million people in the U.S. have coexisting type 2 diabetes and nonalcoholic fatty liver disease (NAFLD). It is not known who among these patients has nonalcoholic steatohepatitis (NASH) with advanced fibrosis. Therefore, we aimed to determine factors that are associated with both NASH and advanced fibrosis in patients with diabetes and NAFLD in order to identify who should be prioritized for referral to a hepatologist for further diagnostic evaluation and treatment. This study was derived from the NASH Clinical Research Network studies and included 1,249 patients with biopsy-proven NAFLD (including a model development cohort of 346 patients and an independent validation cohort of 100 patients with type 2 diabetes as defined by the American Diabetes Association criteria). Outcome measures were presence of NASH or advanced fibrosis (stage 3 or 4) using cross-validated, by jackknife method, multivariable-adjusted area under the receiver operating characteristic curve (AUROC) and 95% CI. The mean ± SD age and BMI of patients with diabetes and NAFLD was 52.5 ± 10.3 years and 35.8 ± 6.8 kg/m(2), respectively. The prevalence of NASH and advanced fibrosis was 69.2% and 41.0%, respectively. The model for NASH included white race, BMI, waist, alanine aminotransferase (ALT), Aspartate aminotransferase (AST), albumin, HbA1c, HOMA of insulin resistance, and ferritin with an AUROC of 0.80 (95% CI 0.75-0.84, P = 0.007). The specificity, sensitivity, negative predictive values (NPVs), and positive predictive values (PPVs) were 90.0%, 56.8%, 47.7%, and 93.2%, respectively, and the model correctly classified 67% of patients as having NASH. The model for predicting advanced fibrosis included age, Hispanic ethnicity, BMI, waist-to-hip ratio, hypertension, ALT-to-AST ratio, alkaline phosphatase, isolated abnormal alkaline phosphatase, bilirubin (total and direct), globulin, albumin, serum insulin, hematocrit, international normalized ratio, and platelet count with an AUROC of 0.80 (95% CI 0.76-0.85, P < 0.001). The specificity, sensitivity, NPV, and PPV were 90.0%, 57%, 75.1%, and 80.2%, respectively, and the model correctly classified 76.6% of patients as having advanced fibrosis. Results remained consistent for both models in the validation cohort. The proposed model performed better than the NAFLD fibrosis score in detecting advanced fibrosis. Routinely available clinical variables can be used to quantify the likelihood of NASH or advanced fibrosis in adult diabetic patients with NAFLD. The clinical models presented can be used to guide clinical decision making about referrals of patients with diabetes and NAFLD to hepatologists. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

A Tribute to Gary Nash

ERIC Educational Resources Information Center

Jason-Fives, Alli

2009-01-01

In this article, the author gives tribute to Gary Nash, a brilliant scholar, an award-winning professor, a prolific writer, a true humanitarian, and a revered historian. She honors him for his work with public school teachers. He has provided the educational support, encouragement, and motivation behind the importance of teaching history. Here,…

Inverse design of an isotropic suspended Kirchhoff rod: theoretical and numerical results on the uniqueness of the natural shape.

PubMed

Bertails-Descoubes, Florence; Derouet-Jourdan, Alexandre; Romero, Victor; Lazarus, Arnaud

2018-04-01

Solving the equations for Kirchhoff elastic rods has been widely explored for decades in mathematics, physics and computer science, with significant applications in the modelling of thin flexible structures such as DNA, hair or climbing plants. As demonstrated in previous experimental and theoretical studies, the natural curvature plays an important role in the equilibrium shape of a Kirchhoff rod, even in the simple case where the rod is isotropic and suspended under gravity. In this paper, we investigate the reverse problem: can we characterize the natural curvature of a suspended isotropic rod, given an equilibrium curve? We prove that although there exists an infinite number of natural curvatures that are compatible with the prescribed equilibrium, they are all equivalent in the sense that they correspond to a unique natural shape for the rod. This natural shape can be computed efficiently by solving in sequence three linear initial value problems, starting from any framing of the input curve. We provide several numerical experiments to illustrate this uniqueness result, and finally discuss its potential impact on non-invasive parameter estimation and inverse design of thin elastic rods.

Slope-velocity equilibrium and evolution of surface roughness on a stony hillslope

NASA Astrophysics Data System (ADS)

Nearing, Mark A.; Polyakov, Viktor O.; Nichols, Mary H.; Hernandez, Mariano; Li, Li; Zhao, Ying; Armendariz, Gerardo

2017-06-01

Slope-velocity equilibrium is hypothesized as a state that evolves naturally over time due to the interaction between overland flow and surface morphology, wherein steeper areas develop a relative increase in physical and hydraulic roughness such that flow velocity is a unique function of overland flow rate independent of slope gradient. This study tests this hypothesis under controlled conditions. Artificial rainfall was applied to 2 m by 6 m plots at 5, 12, and 20 % slope gradients. A series of simulations were made with two replications for each treatment with measurements of runoff rate, velocity, rock cover, and surface roughness. Velocities measured at the end of each experiment were a unique function of discharge rates, independent of slope gradient or rainfall intensity. Physical surface roughness was greater at steeper slopes. The data clearly showed that there was no unique hydraulic coefficient for a given slope, surface condition, or rainfall rate, with hydraulic roughness greater at steeper slopes and lower intensities. This study supports the hypothesis of slope-velocity equilibrium, implying that use of hydraulic equations, such as Chezy and Manning, in hillslope-scale runoff models is problematic because the coefficients vary with both slope and rainfall intensity.

Inverse design of an isotropic suspended Kirchhoff rod: theoretical and numerical results on the uniqueness of the natural shape

NASA Astrophysics Data System (ADS)

Bertails-Descoubes, Florence; Derouet-Jourdan, Alexandre; Romero, Victor; Lazarus, Arnaud

2018-04-01

Solving the equations for Kirchhoff elastic rods has been widely explored for decades in mathematics, physics and computer science, with significant applications in the modelling of thin flexible structures such as DNA, hair or climbing plants. As demonstrated in previous experimental and theoretical studies, the natural curvature plays an important role in the equilibrium shape of a Kirchhoff rod, even in the simple case where the rod is isotropic and suspended under gravity. In this paper, we investigate the reverse problem: can we characterize the natural curvature of a suspended isotropic rod, given an equilibrium curve? We prove that although there exists an infinite number of natural curvatures that are compatible with the prescribed equilibrium, they are all equivalent in the sense that they correspond to a unique natural shape for the rod. This natural shape can be computed efficiently by solving in sequence three linear initial value problems, starting from any framing of the input curve. We provide several numerical experiments to illustrate this uniqueness result, and finally discuss its potential impact on non-invasive parameter estimation and inverse design of thin elastic rods.

On the Uniqueness Conditions and Bifurcation Criteria in Coupled Thermo-Elasto-Plasticity

NASA Astrophysics Data System (ADS)

Śloderbach, Z.

2017-02-01

The global and local conditions of uniqueness and the criteria excluding a possibility of bifurcation of the equilibrium state for small strains are derived. The conditions and criteria are derived analyzing the problem of uniqueness of solution of the basic incremental boundary problem of coupled generalized thermo-elasto-plasticity. This paper is a continuation of some previous works by the author, but contains new derivation of the global and local criteria excluding a possibility of bifurcation of the equilibrium state for a comparison body dependent on statically admissible fields of stress velocity. All the thermal elastoplastic coupling effects, non-associated laws of plastic flow and influence of plastic strains on thermoplastic properties of a body were taken into account in this work. Thus, the mathematical problem considered here is not a self-conjugated problem. The paper contains four Appendices A, B, C and D where the local necessery and sufficient conditions of uniqueness have been derived.

Incorporation of the equilibrium temperature approach in a Soil and Water Assessment Tool hydroclimatological stream temperature model

NASA Astrophysics Data System (ADS)

Du, Xinzhong; Shrestha, Narayan Kumar; Ficklin, Darren L.; Wang, Junye

2018-04-01

Stream temperature is an important indicator for biodiversity and sustainability in aquatic ecosystems. The stream temperature model currently in the Soil and Water Assessment Tool (SWAT) only considers the impact of air temperature on stream temperature, while the hydroclimatological stream temperature model developed within the SWAT model considers hydrology and the impact of air temperature in simulating the water-air heat transfer process. In this study, we modified the hydroclimatological model by including the equilibrium temperature approach to model heat transfer processes at the water-air interface, which reflects the influences of air temperature, solar radiation, wind speed and streamflow conditions on the heat transfer process. The thermal capacity of the streamflow is modeled by the variation of the stream water depth. An advantage of this equilibrium temperature model is the simple parameterization, with only two parameters added to model the heat transfer processes. The equilibrium temperature model proposed in this study is applied and tested in the Athabasca River basin (ARB) in Alberta, Canada. The model is calibrated and validated at five stations throughout different parts of the ARB, where close to monthly samplings of stream temperatures are available. The results indicate that the equilibrium temperature model proposed in this study provided better and more consistent performances for the different regions of the ARB with the values of the Nash-Sutcliffe Efficiency coefficient (NSE) greater than those of the original SWAT model and the hydroclimatological model. To test the model performance for different hydrological and environmental conditions, the equilibrium temperature model was also applied to the North Fork Tolt River Watershed in Washington, United States. The results indicate a reasonable simulation of stream temperature using the model proposed in this study, with minimum relative error values compared to the other two models. However, the NSE values were lower than those of the hydroclimatological model, indicating that more model verification needs to be done. The equilibrium temperature model uses existing SWAT meteorological data as input, can be calibrated using fewer parameters and less effort and has an overall better performance in stream temperature simulation. Thus, it can be used as an effective tool for predicting the changes in stream temperature regimes under varying hydrological and meteorological conditions. In addition, the impact of the stream temperature simulations on chemical reaction rates and concentrations was tested. The results indicate that the improved performance of the stream temperature simulation could significantly affect chemical reaction rates and the simulated concentrations, and the equilibrium temperature model could be a potential tool to model stream temperature in water quality simulations.

Financial Symmetry and Moods in the Market

PubMed Central

Savona, Roberto; Soumare, Maxence; Andersen, Jørgen Vitting

2015-01-01

This paper studies how certain speculative transitions in financial markets can be ascribed to a symmetry break that happens in the collective decision making. Investors are assumed to be bounded rational, using a limited set of information including past price history and expectation on future dividends. Investment strategies are dynamically changed based on realized returns within a game theoretical scheme with Nash equilibria. In such a setting, markets behave as complex systems whose payoff reflect an intrinsic financial symmetry that guarantees equilibrium in price dynamics (fundamentalist state) until the symmetry is broken leading to bubble or anti-bubble scenarios (speculative state). We model such two-phase transition in a micro-to-macro scheme through a Ginzburg-Landau-based power expansion leading to a market temperature parameter which modulates the state transitions in the market. Via simulations we prove that transitions in the market price dynamics can be phenomenologically explained by the number of traders, the number of strategies and amount of information used by agents, all included in our market temperature parameter. PMID:25856392

Symmetry associated with symmetry break: Revisiting ants and humans escaping from multiple-exit rooms

NASA Astrophysics Data System (ADS)

Ji, Q.; Xin, C.; Tang, S. X.; Huang, J. P.

2018-02-01

Crowd panic has incurred massive injuries or deaths throughout the world, and thus understanding it is particularly important. It is now a common knowledge that crowd panic induces "symmetry break" in which some exits are jammed while others are underutilized. Amazingly, here we show, by experiment, simulation and theory, that a class of symmetry patterns come to appear for ants and humans escaping from multiple-exit rooms while the symmetry break exists. Our symmetry pattern is described by the fact that the ratio between the ensemble-averaging numbers of ants or humans escaping from different exits is equal to the ratio between the widths of the exits. The mechanism lies in the effect of heterogeneous preferences of agents with limited information for achieving the Nash equilibrium. This work offers new insights into how to improve public safety because large public areas are always equipped with multiple exits, and it also brings an ensemble-averaging method for seeking symmetry associated with symmetry breaking.

When does "economic man" dominate social behavior?

PubMed

Camerer, Colin F; Fehr, Ernst

2006-01-06

The canonical model in economics considers people to be rational and self-regarding. However, much evidence challenges this view, raising the question of when "Economic Man" dominates the outcome of social interactions, and when bounded rationality or other-regarding preferences dominate. Here we show that strategic incentives are the key to answering this question. A minority of self-regarding individuals can trigger a "noncooperative" aggregate outcome if their behavior generates incentives for the majority of other-regarding individuals to mimic the minority's behavior. Likewise, a minority of other-regarding individuals can generate a "cooperative" aggregate outcome if their behavior generates incentives for a majority of self-regarding people to behave cooperatively. Similarly, in strategic games, aggregate outcomes can be either far from or close to Nash equilibrium if players with high degrees of strategic thinking mimic or erase the effects of others who do very little strategic thinking. Recently developed theories of other-regarding preferences and bounded rationality explain these findings and provide better predictions of actual aggregate behavior than does traditional economic theory.

Game theoretic power allocation and waveform selection for satellite communications

NASA Astrophysics Data System (ADS)

Shu, Zhihui; Wang, Gang; Tian, Xin; Shen, Dan; Pham, Khanh; Blasch, Erik; Chen, Genshe

2015-05-01

Game theory is a useful method to model interactions between agents with conflicting interests. In this paper, we set up a Game Theoretic Model for Satellite Communications (SATCOM) to solve the interaction between the transmission pair (blue side) and the jammer (red side) to reach a Nash Equilibrium (NE). First, the IFT Game Application Model (iGAM) for SATCOM is formulated to improve the utility of the transmission pair while considering the interference from a jammer. Specifically, in our framework, the frame error rate performance of different modulation and coding schemes is used in the game theoretic solution. Next, the game theoretic analysis shows that the transmission pair can choose the optimal waveform and power given the received power from the jammer. We also describe how the jammer chooses the optimal power given the waveform and power allocation from the transmission pair. Finally, simulations are implemented for the iGAM and the simulation results show the effectiveness of the SATCOM power allocation, waveform selection scheme, and jamming mitigation.

On defense strategies for system of systems using aggregated correlations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rao, Nageswara S.; Imam, Neena; Ma, Chris Y. T.

2017-04-01

We consider a System of Systems (SoS) wherein each system Si, i = 1; 2; ... ;N, is composed of discrete cyber and physical components which can be attacked and reinforced. We characterize the disruptions using aggregate failure correlation functions given by the conditional failure probability of SoS given the failure of an individual system. We formulate the problem of ensuring the survival of SoS as a game between an attacker and a provider, each with a utility function composed of asurvival probability term and a cost term, both expressed in terms of the number of components attacked and reinforced.more » The survival probabilities of systems satisfy simple product-form, first-order differential conditions, which simplify the Nash Equilibrium (NE) conditions. We derive the sensitivity functions that highlight the dependence of SoS survival probability at NE on cost terms, correlation functions, and individual system survival probabilities.We apply these results to a simplified model of distributed cloud computing infrastructure.« less

Financial symmetry and moods in the market.

PubMed

Savona, Roberto; Soumare, Maxence; Andersen, Jørgen Vitting

2015-01-01

This paper studies how certain speculative transitions in financial markets can be ascribed to a symmetry break that happens in the collective decision making. Investors are assumed to be bounded rational, using a limited set of information including past price history and expectation on future dividends. Investment strategies are dynamically changed based on realized returns within a game theoretical scheme with Nash equilibria. In such a setting, markets behave as complex systems whose payoff reflect an intrinsic financial symmetry that guarantees equilibrium in price dynamics (fundamentalist state) until the symmetry is broken leading to bubble or anti-bubble scenarios (speculative state). We model such two-phase transition in a micro-to-macro scheme through a Ginzburg-Landau-based power expansion leading to a market temperature parameter which modulates the state transitions in the market. Via simulations we prove that transitions in the market price dynamics can be phenomenologically explained by the number of traders, the number of strategies and amount of information used by agents, all included in our market temperature parameter.

Public goods games on adaptive coevolutionary networks

NASA Astrophysics Data System (ADS)

Pichler, Elgar; Shapiro, Avi M.

2017-07-01

Productive societies feature high levels of cooperation and strong connections between individuals. Public Goods Games (PGGs) are frequently used to study the development of social connections and cooperative behavior in model societies. In such games, contributions to the public good are made only by cooperators, while all players, including defectors, reap public goods benefits, which are shares of the contributions amplified by a synergy factor. Classic results of game theory show that mutual defection, as opposed to cooperation, is the Nash Equilibrium of PGGs in well-mixed populations, where each player interacts with all others. In this paper, we explore the coevolutionary dynamics of a low information public goods game on a complex network in which players adapt to their environment in order to increase individual payoffs relative to past payoffs parameterized by greediness. Players adapt by changing their strategies, either to cooperate or to defect, and by altering their social connections. We find that even if players do not know other players' strategies and connectivity, cooperation can arise and persist despite large short-term fluctuations.

Public goods games on adaptive coevolutionary networks.

PubMed

Pichler, Elgar; Shapiro, Avi M

2017-07-01

Productive societies feature high levels of cooperation and strong connections between individuals. Public Goods Games (PGGs) are frequently used to study the development of social connections and cooperative behavior in model societies. In such games, contributions to the public good are made only by cooperators, while all players, including defectors, reap public goods benefits, which are shares of the contributions amplified by a synergy factor. Classic results of game theory show that mutual defection, as opposed to cooperation, is the Nash Equilibrium of PGGs in well-mixed populations, where each player interacts with all others. In this paper, we explore the coevolutionary dynamics of a low information public goods game on a complex network in which players adapt to their environment in order to increase individual payoffs relative to past payoffs parameterized by greediness. Players adapt by changing their strategies, either to cooperate or to defect, and by altering their social connections. We find that even if players do not know other players' strategies and connectivity, cooperation can arise and persist despite large short-term fluctuations.

Chaos in learning a simple two-person game

PubMed Central

Sato, Yuzuru; Akiyama, Eizo; Farmer, J. Doyne

2002-01-01

We investigate the problem of learning to play the game of rock–paper–scissors. Each player attempts to improve her/his average score by adjusting the frequency of the three possible responses, using reinforcement learning. For the zero sum game the learning process displays Hamiltonian chaos. Thus, the learning trajectory can be simple or complex, depending on initial conditions. We also investigate the non-zero sum case and show that it can give rise to chaotic transients. This is, to our knowledge, the first demonstration of Hamiltonian chaos in learning a basic two-person game, extending earlier findings of chaotic attractors in dissipative systems. As we argue here, chaos provides an important self-consistency condition for determining when players will learn to behave as though they were fully rational. That chaos can occur in learning a simple game indicates one should use caution in assuming real people will learn to play a game according to a Nash equilibrium strategy. PMID:11930020

Geo-information processing service composition for concurrent tasks: A QoS-aware game theory approach

NASA Astrophysics Data System (ADS)

Li, Haifeng; Zhu, Qing; Yang, Xiaoxia; Xu, Linrong

2012-10-01

Typical characteristics of remote sensing applications are concurrent tasks, such as those found in disaster rapid response. The existing composition approach to geographical information processing service chain, searches for an optimisation solution and is what can be deemed a "selfish" way. This way leads to problems of conflict amongst concurrent tasks and decreases the performance of all service chains. In this study, a non-cooperative game-based mathematical model to analyse the competitive relationships between tasks, is proposed. A best response function is used, to assure each task maintains utility optimisation by considering composition strategies of other tasks and quantifying conflicts between tasks. Based on this, an iterative algorithm that converges to Nash equilibrium is presented, the aim being to provide good convergence and maximise the utilisation of all tasks under concurrent task conditions. Theoretical analyses and experiments showed that the newly proposed method, when compared to existing service composition methods, has better practical utility in all tasks.

A distributed predictive control approach for periodic flow-based networks: application to drinking water systems

NASA Astrophysics Data System (ADS)

Grosso, Juan M.; Ocampo-Martinez, Carlos; Puig, Vicenç

2017-10-01

This paper proposes a distributed model predictive control approach designed to work in a cooperative manner for controlling flow-based networks showing periodic behaviours. Under this distributed approach, local controllers cooperate in order to enhance the performance of the whole flow network avoiding the use of a coordination layer. Alternatively, controllers use both the monolithic model of the network and the given global cost function to optimise the control inputs of the local controllers but taking into account the effect of their decisions over the remainder subsystems conforming the entire network. In this sense, a global (all-to-all) communication strategy is considered. Although the Pareto optimality cannot be reached due to the existence of non-sparse coupling constraints, the asymptotic convergence to a Nash equilibrium is guaranteed. The resultant strategy is tested and its effectiveness is shown when applied to a large-scale complex flow-based network: the Barcelona drinking water supply system.

Game theory competition analysis of reservoir water supply and hydropower generation

NASA Astrophysics Data System (ADS)

Lee, T.

2013-12-01

The total installed capacity of the power generation systems in Taiwan is about 41,000 MW. Hydropower is one of the most important renewable energy sources, with hydropower generation capacity of about 4,540 MW. The aim of this research is to analyze competition between water supply and hydropower generation in water-energy systems. The major relationships between water and energy systems include hydropower generation by water, energy consumption for water system operation, and water consumption for energy system. In this research, a game-theoretic Cournot model is formulated to simulate oligopolistic competition between water supply, hydropower generation, and co-fired power generation in water-energy systems. A Nash equilibrium of the competitive market is derived and solved by GAMS with PATH solver. In addition, a case study analyzing the competition among water supply and hydropower generation of De-ji and Ku-Kuan reservoirs, Taipower, Star Energy, and Star-Yuan power companies in central Taiwan is conducted.

Defense strategies for asymmetric networked systems under composite utilities

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rao, Nageswara S.; Ma, Chris Y. T.; Hausken, Kjell

We consider an infrastructure of networked systems with discrete components that can be reinforced at certain costs to guard against attacks. The communications network plays a critical, asymmetric role of providing the vital connectivity between the systems. We characterize the correlations within this infrastructure at two levels using (a) aggregate failure correlation function that specifies the infrastructure failure probability giventhe failure of an individual system or network, and (b) first order differential conditions on system survival probabilities that characterize component-level correlations. We formulate an infrastructure survival game between an attacker and a provider, who attacks and reinforces individual components, respectively.more » They use the composite utility functions composed of a survival probability term and a cost term, and the previously studiedsum-form and product-form utility functions are their special cases. At Nash Equilibrium, we derive expressions for individual system survival probabilities and the expected total number of operational components. We apply and discuss these estimates for a simplified model of distributed cloud computing infrastructure« less

Detection of content adaptive LSB matching: a game theory approach

NASA Astrophysics Data System (ADS)

Denemark, Tomáš; Fridrich, Jessica

2014-02-01

This paper is an attempt to analyze the interaction between Alice and Warden in Steganography using the Game Theory. We focus on the modern steganographic embedding paradigm based on minimizing an additive distortion function. The strategies of both players comprise of the probabilistic selection channel. The Warden is granted the knowledge of the payload and the embedding costs, and detects embedding using the likelihood ratio. In particular, the Warden is ignorant about the embedding probabilities chosen by Alice. When adopting a simple multivariate Gaussian model for the cover, the payoff function in the form of the Warden's detection error can be numerically evaluated for a mutually independent embedding operation. We demonstrate on the example of a two-pixel cover that the Nash equilibrium is different from the traditional Alice's strategy that minimizes the KL divergence between cover and stego objects under an omnipotent Warden. Practical implications of this case study include computing the loss per pixel of Warden's ability to detect embedding due to her ignorance about the selection channel.

No Regret Learning in Oligopolies: Cournot vs. Bertrand

NASA Astrophysics Data System (ADS)

Nadav, Uri; Piliouras, Georgios

Cournot and Bertrand oligopolies constitute the two most prevalent models of firm competition. The analysis of Nash equilibria in each model reveals a unique prediction about the stable state of the system. Quite alarmingly, despite the similarities of the two models, their projections expose a stark dichotomy. Under the Cournot model, where firms compete by strategically managing their output quantity, firms enjoy positive profits as the resulting market prices exceed that of the marginal costs. On the contrary, the Bertrand model, in which firms compete on price, predicts that a duopoly is enough to push prices down to the marginal cost level. This suggestion that duopoly will result in perfect competition, is commonly referred to in the economics literature as the "Bertrand paradox".

Approximation of Nash equilibria and the network community structure detection problem

PubMed Central

2017-01-01

Game theory based methods designed to solve the problem of community structure detection in complex networks have emerged in recent years as an alternative to classical and optimization based approaches. The Mixed Nash Extremal Optimization uses a generative relation for the characterization of Nash equilibria to identify the community structure of a network by converting the problem into a non-cooperative game. This paper proposes a method to enhance this algorithm by reducing the number of payoff function evaluations. Numerical experiments performed on synthetic and real-world networks show that this approach is efficient, with results better or just as good as other state-of-the-art methods. PMID:28467496

Advocacy, prejudice, and role modeling in the deaf community.

PubMed

Cumming, C E; Rodda, M

1989-02-01

Prejudiced attitudes toward deaf people are a well-established phenomenon (Higgins & Nash, 1982; Moores, 1982; Quigley & Kretschmer, 1982). In recent years, however, a new phenomenon has appeared, and some members of the deaf population now openly express prejudice against the hearing (Boros & Stuckless, 1982; Nash & Nash, 1981). The phenomenon may be an interesting example of Allport's (1954) classical analysis: The victims of the prejudice may tend to reciprocate and/or internalize the prejudice to which they have been exposed. The purpose of our analysis is to examine this phenomenon in more detail, particularly from the perspective of social learning theory as described by Bandura and Walters (1963), Walters (1966), and Bandura (1977).

Nonalcoholic Steatohepatitis Induced by a High-Fat Diet Promotes Diethylnitrosamine Initiated Early Hepatocarcinogenesis in Rats

USDA-ARS?s Scientific Manuscript database

It has been suggested that patients with nonalcoholic steatohepatitis (NASH) have a high risk for liver cancer. However, it is unknown whether high-fat diet induced NASH promotes chemical carcinogen-initiated hepatocarcinogenesis. In the present study, Sprague-Dawley rats were injected with a low d...

Gary Nash: Repairing a Necessary Connection

ERIC Educational Resources Information Center

Bender, Thomas

2009-01-01

In this essay, the author comments on the life and the contributions of author Gary Nash. Everyone is thanking him for his remarkable engagement with the schools, as a writer of outstanding textbooks and materials for teachers developed through his work as director of the Center for Teaching History in the Schools, and, of course, the National…

Grace Nash: Nine Decades of Graceful Teaching.

ERIC Educational Resources Information Center

Cole, Judith

2000-01-01

Provides information on the life of Grace Nash, an influential educator and pioneer of Orff Schulwerk in the United States, focusing on issues such as her young life, experience as a prisoner-of-war, development of her interest in the Orff, Kodaly, and Laban methods, and her own work. Offers selected resources. (CMK)

Nonalcoholic steatohepatitis induced by a high-fat diet promotes diethylnitrosamine initiated early hepatocarcinogenesis in rats

USDA-ARS?s Scientific Manuscript database

It has been suggested that patients with nonalcoholic steatohepatitis (NASH) are at a high risk for liver cancer. However, it is unknown whether high-fat diet induced NASH promotes hepatocarcinogenesis. In the present study, Sprague-Dawley rats were injected with a low dose of hepatic carcinogen die...

Nifedipine prevents hepatic fibrosis in a non-alcoholic steatohepatitis model induced by an L-methionine-and choline-deficient diet.

PubMed

Nakagami, Hironori; Shimamura, Munehisa; Miyake, Takashi; Shimosato, Takashi; Minobe, Noriko; Moritani, Toshinori; Kiomy Osako, Mariana; Nakagami, Futoshi; Koriyama, Hiroshi; Kyutoku, Mariko; Shimizu, Hideo; Katsuya, Tomohiro; Morishita, Ryuichi

2012-01-01

Recent reports have shown that nifedipine, a calcium channel blocker, increases peroxisome proliferator-activated receptor-γ (PPARγ) activity. Since PPARγ agonists, such as pioglitazone and rosiglitazone, are effective in reducing non-alcoholic steatohepatitis (NASH) and cirrhosis in animal models, we examined the protective effects of nifedipine, as compared with bezafibrate, a PPARα agonist, in a NASH model induced by an L-methionine- and choline-deficient (MCD) diet. An MCD diet for 20 weeks changed the color of the rat liver to yellow with an irregular surface, whereas the color of the liver in both the bezafibrate and nifedipine treatment groups was markedly changed to yellow-brown with a smooth surface. Furthermore, nifedipine, as well as bezafibrate, significantly prevented liver fibrosis induced by an MCD diet, as assessed by Masson's trichrome staining, accompanied by a significant decrease in serum AST. Overall, nifedipine treatment resulted in an improvement in NASH, similar to bezafibrate, in a rat model. In hypertensive patients with metabolic syndrome, nifedipine may provide additional benefits, beyond its blood pressure-lowering effects, to prevent NASH and fatty liver disease.

Bile acid metabolism regulated by the gut microbiota promotes non-alcoholic steatohepatitis-associated hepatocellular carcinoma in mice

PubMed Central

Yamada, Shoji; Takashina, Yoko; Watanabe, Mitsuhiro; Nagamine, Ryogo; Saito, Yoshimasa; Kamada, Nobuhiko; Saito, Hidetsugu

2018-01-01

Gut microbiota plays a significant role in the development of hepatocellular carcinoma (HCC) in non-alcoholic steatohepatitis (NASH). However, understanding of the precise mechanism of this process remains incomplete. A new class steatohepatitis-inducing high-fat diet (HFD), namely STHD-01, can promote the development of HCC without the administration of chemical carcinogens. Using this diet, we comprehensively analyzed changes in the gut microbiota and its metabolic functions during the development of HCC in NASH. Mice fed the STHD-01 developed NASH within 9 weeks. NASH further progressed into HCC by 41 weeks. Treatment with antibiotics significantly attenuated liver pathology and suppressed tumor development, indicating the critical role of the gut microbiota in tumor development in this model. Accumulation of cholesterol and bile acids in the liver and feces increased after feeding the mice with STHD-01. Treatment with antibiotics did not reverse these phenotypes. In contrast, accumulation of secondary bile acids was dramatically reduced after the treatment with antibiotics, suggesting the critical role of the gut microbiota in the conversion of primary bile acids to secondary bile acids. Secondary bile acids such as deoxycholic acid activated the mTOR, pathway in hepatocytes. Activation of mTOR was observed in the liver of mice fed STHD-01, and the activation was reduced when mice were treated with antibiotics. Collectively, bile acid metabolism by the gut microbiota promotes HCC development in STHD-01-induced NASH. PMID:29515780

Vitamin E has a beneficial effect on nonalcoholic fatty liver disease: a meta-analysis of randomized controlled trials.

PubMed

Sato, Ken; Gosho, Masahiko; Yamamoto, Takaya; Kobayashi, Yuji; Ishii, Norimitsu; Ohashi, Tomohiko; Nakade, Yukiomi; Ito, Kiyoaki; Fukuzawa, Yoshitaka; Yoneda, Masashi

2015-01-01

Vitamin E is often used in the treatment of nonalcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis (NASH); however, the magnitude of treatment response associated with vitamin E in improving liver function and histology in NAFLD/NASH has not, to our knowledge, been quantified systematically. Thus, we conducted a meta-analysis of randomized controlled trials (RCTs) using vitamin E in the treatment of NAFLD/NASH. PubMed, Medline, and Cochrane Library Full Text Database, and Japan Medical-Literature Database (Igaku Chuo Zasshi) were searched until March 2014, and five RCTs were identified for meta-analysis. According to a random effect model analysis of the five studies, vitamin E significantly reduced aspartate transaminase (AST) by -19.43 U/L, alanine aminotransferase (ALT) by -28.91 U/L, alkaline phosphatase (ALP) by -10.39 U/L, steatosis by -0.54 U/L, inflammation by -0.20 U/L, and hepatocellular ballooning by -0.34 U/L compared with the control group. Vitamin E treatment with NASH adult patients showed obvious reductions in not only AST of -13.91 U/L, ALT by -22.44 U/L, steatosis of -0.67 U/L, inflammation of -0.20 U/L, but also fibrosis of -0.30 U/L compared to the control treatment. Vitamin E significantly improved liver function and histologic changes in patients with NAFLD/NASH. Copyright © 2015 Elsevier Inc. All rights reserved.

Fibromyalgia Symptoms and Cirrhosis

PubMed Central

Bielefeldt, Klaus; Wasan, Ajay D.; Szigethy, Eva; Lotrich, Francis; DiMartini, Andrea F.

2015-01-01

Background An association between fibromyalgia and hepatitis C virus (HCV) has been previously described. However, the relationship between nonalcoholic steatohepatitis (NASH) and fibromyalgia symptoms has not been assessed, though they share several risk factors. Aim We aimed to assess the factors associated with fibromyalgia symptoms across etiologies of liver disease. Methods Patients with cirrhosis due to HCV, NASH, or alcohol were recruited from an outpatient hepatology clinic and administered the Hospital Anxiety and Depression Score, Pittsburgh Sleep Quality Index, and the modified 2010 American College of Rheumatology Diagnostic Criteria for Fibromyalgia. Serum inflammatory markers were measured with standard luminex assays. Results Of 193 participants, 53 (27 %) met criteria for fibromyalgia. Fibromyalgia symptoms were significantly associated with etiology of liver disease (HCV: 35 %, NASH: 30 %, alcohol-related liver disease: 12 %, p < 0.01). Using logistic regression, mood symptoms (OR 1.14, 95 % CI 1.06, 1.22), sleep disturbance (OR 1.32, 95 % CI 1.16, 1.52), and etiology of liver disease (NASH vs. HCV not different, alcohol vs. HCV OR 0.19, 95 % CI 0.05, 0.63) were associated with fibromyalgia symptoms. If abdominal pain was included in the model, etiology became nonsignificant, indicating that it may be central sensitization due to abdominal pain in patients with chronic liver disease that explains fibromyalgia symptoms rather than the etiology of liver disease or inflammation. Conclusions Fibromyalgia symptoms were significantly associated with HCV and NASH cirrhosis and with psychiatric symptoms. Future work should focus on the underlying pathophysiology and management of widespread pain in patients with cirrhosis. PMID:25433921

Efficacy of docosahexaenoic acid-choline-vitamin E in paediatric NASH: a randomized controlled clinical trial.

PubMed

Zöhrer, Evelyn; Alisi, Anna; Jahnel, Jörg; Mosca, Antonella; Della Corte, Claudia; Crudele, Annalisa; Fauler, Günter; Nobili, Valerio

2017-09-01

Nonalcoholic steatohepatitis (NASH), a progressive form of nonalcoholic fatty liver disease, is one of the most common hepatic diseases in children. We conducted a randomized controlled clinical trial on children with biopsy-proven NASH based on a combinatorial nutritional approach compared with placebo. Participants were assigned to lifestyle modification plus placebo or lifestyle modification plus a mix containing docosahexaenoic acid, choline, and vitamin E (DHA-CHO-VE). Forty children and adolescents participated in the entire trial. The primary outcome was the improvement of liver hyperechogenicity. Secondary outcomes included alterations of alanine aminotransferase (ALT) and other metabolic parameters. Furthermore, changes of serum bile acids (BA) and plasma fibroblast growth factor 19 (FGF19) levels were evaluated as inverse biomarkers of disease severity. At the end of the study, we observed a significant decrease in severe steatosis in the treatment group (50% to 5%, p = 0.001). Furthermore, although the anthropometric and biochemical measurements in the placebo and DHA-CHO-VE groups were comparable at baseline, at the end of the study ALT and fasting glucose levels improved only in the treatment group. Finally, we found that BA levels were not influenced whereas FGF19 levels were significantly increased by DHA-CHO-VE. The results suggest that a combination of DHA, VE, and CHO could improve steatosis and reduce ALT and glucose levels in children with NASH. However, further studies are needed to assess the impact of a DHA and VE combination on repair of liver damage in paediatric NASH.

Multicentric occurrence of hepatocellular carcinoma with nonalcoholic steatohepatitis

PubMed Central

Kawai, Hirokazu; Nomoto, Minoru; Suda, Takeshi; Kamimura, Kenya; Tsuchiya, Atsunori; Tamura, Yasushi; Yano, Masahiko; Takamura, Masaaki; Igarashi, Masato; Wakai, Toshifumi; Yamagiwa, Satoshi; Matsuda, Yasunobu; Ohkoshi, Shogo; Kurosaki, Isao; Shirai, Yoshio; Okada, Masahiko; Aoyagi, Yutaka

2011-01-01

AIM: To reveal the manner of hepatocellular carcinoma (HCC) development in patients with nonalcoholic steatohepatitis (NASH) focusing on multicentric occurrence (MO) of HCC. METHODS: We compared clinicopathological characteristics between patients with and without MO of HCC arising from NASH background. The clinical features were implicated with reference to the literature available. RESULTS: MO of HCC was identified with histological proof in 4 out of 12 patients with NASH-related HCC (2 males and 2 females). One patient had synchronous MO; an advanced HCC, two well-differentiated HCCs and a dysplastic nodule, followed by the development of metachronous MO of HCC. The other three patients had multiple advanced HCCs accompanied by a well-differentiated HCC or a dysplastic nodule. Of these three patients, one had synchronous MO, one had metachronous MO and the other had both synchronous and metachronous MO. There were no obvious differences between the patients with or without MO in terms of liver function tests, tumor markers and anatomical extent of HCC. On the other hand, all four patients with MO of HCC were older than 70 years old and had the comorbidities of obesity, type 2 diabetes mellitus (T2DM), hypertension and cirrhosis. Although these conditions were not limited to MO of HCC, all the conditions were met in only one of eight patients without MO of HCC. Thus, concurrence of these conditions may be a predisposing situation to synchronous MO of HCC. In particular, old age, T2DM and cirrhosis were suggested to be prerequisite for MO because these factors were depicted in common among two other cases with MO of HCC under NASH in the literature. CONCLUSION: The putative predisposing factors and necessary preconditions for synchronous MO of HCC in NASH were suggested in this study. Further investigations are required to clarify the accurate prevalence and predictors of MO to establish better strategies for treatment and prevention leading to the prognostic improvement in NASH. PMID:21307983

Ultra-high-field magnetic resonance spectroscopy in non-alcoholic fatty liver disease: Novel mechanistic and diagnostic insights of energy metabolism in non-alcoholic steatohepatitis and advanced fibrosis.

PubMed

Traussnigg, Stefan; Kienbacher, Christian; Gajdošík, Martin; Valkovič, Ladislav; Halilbasic, Emina; Stift, Judith; Rechling, Christian; Hofer, Harald; Steindl-Munda, Petra; Ferenci, Peter; Wrba, Fritz; Trattnig, Siegfried; Krššák, Martin; Trauner, Michael

2017-10-01

With the rising prevalence of non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) non-invasive tools obtaining pathomechanistic insights to improve risk stratification are urgently needed. We therefore explored high- and ultra-high-field magnetic resonance spectroscopy (MRS) to obtain novel mechanistic and diagnostic insights into alterations of hepatic lipid, cell membrane and energy metabolism across the spectrum of NAFLD. MRS and liver biopsy were performed in 30 NAFLD patients with NAFL (n=8) or NASH (n=22). Hepatic lipid content and composition were measured using 3-Tesla proton ( 1 H)-MRS. 7-Tesla phosphorus ( 31 P)-MRS was applied to determine phosphomonoester (PME) including phosphoethanolamine (PE), phosphodiester (PDE) including glycerophosphocholine (GPC), phosphocreatine (PCr), nicotinamide adenine dinucleotide phosphate (NADPH), inorganic phosphate (Pi), γ-ATP and total phosphorus (TP). Saturation transfer technique was used to quantify hepatic ATP flux. Hepatic steatosis in 1 H-MRS highly correlated with histology (P<.001) showing higher values in NASH than NAFL (P<.001) without differences in saturated or unsaturated fatty acid indices. PE/TP ratio increased with advanced fibrosis (F3/4) (P=.002) whereas GPC/PME+PDE decreased (P=.05) compared to no/mild fibrosis (F0-2). γ-ATP/TP was lower in advanced fibrosis (P=.049), while PCr/TP increased (P=.01). NADPH/TP increased with higher grades of ballooning (P=.02). Pi-to-ATP exchange rate constant (P=.003) and ATP flux (P=.001) were lower in NASH than NAFL. Ultra-high-field MRS, especially saturation transfer technique uncovers changes in energy metabolism including dynamic ATP flux in inflammation and fibrosis in NASH. Non-invasive profiling by MRS appears feasible and may assist further mechanistic and therapeutic studies in NAFLD/NASH. © 2017 The Authors Liver International Published by John Wiley & Sons Ltd.

Interactions of allelic variance of PNPLA3 with nongenetic factors in predicting nonalcoholic steatohepatitis and nonhepatic complications of severe obesity.

PubMed

Guichelaar, M M J; Gawrieh, S; Olivier, M; Viker, K; Krishnan, A; Sanderson, S; Malinchoc, M; Watt, K D; Swain, J M; Sarr, M; Charlton, M R

2013-09-01

Allelic variation (rs738409C→G) in adiponutrin (patatin-like phospholipase domain-containing protein 3, PNPLA3) has been associated with hepatic steatosis and liver fibrosis. The physiologic impact of the PNPLA3 G allele may be exacerbated in patients with severe obesity. In this study, we investigated the interactions of PNPLA3 rs738409 with a broad panel of metabolic and histologic characteristics of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis (NASH) in patients with medically complicated obesity. Consecutive patients undergoing bariatric surgery were selected for a prospective study. They underwent extensive laboratory and histologic (liver biopsy) assessment, as well as evaluation of rs738409 polymorphism by TaqMan assay. Only 12 (8.3%) of the 144 patients had normal liver histology, with 72 (50%) NASH, of whom 15 (10.4% of total patients) had fibrosis stage 2-3. PNPLA3 GG genotype correlated positively (P < 0.05) with serum levels of alanine aminotransferase (ALT), asparate aminotransferase (AST), glucose, fibrinogen, and insulin-dependent diabetes mellitus, homeostasis model assessment-insulin resistance, and presence of NASH. Multivariate analysis indicated that PNPLA3 rs738409 G versus C allele remained an (independent) risk factor for NASH, in addition to CK-18 >145 IU/l, glucose >100 mg/dl, and C-reactive protein (CRP) >0.8 mg/dl. The probability of NASH increased from 9% (no risk factor) to 82% if all four risk factors were present. In this cohort of patients with medically complicated obesity, PNPLA3 rs738409 G allelic expression is associated with hepatic (NASH) and nonhepatic complications of obesity, such as insulin resistance. These novel findings may be related to a greater impact of PNPLA3 variant in magnitude and scope in patients with severe obesity than in less obese populations. Further studies are needed to characterize the nature of these associations. Copyright © 2013 The Obesity Society.

Nonalcoholic steatohepatitis and nonalcoholic Fatty liver disease in young women with polycystic ovary syndrome.

PubMed

Setji, Tracy L; Holland, Nicole D; Sanders, Linda L; Pereira, Kathy C; Diehl, Anna Mae; Brown, Ann J

2006-05-01

Nonalcoholic fatty liver disease and polycystic ovary syndrome (PCOS) are both associated with insulin resistance. Thus, women with PCOS may have an increased prevalence of nonalcoholic fatty liver disease, including nonalcoholic steatohepatitis (NASH). The objective of the study was to determine the prevalence and characteristics of NASH and abnormal aminotransferase activity in women with PCOS. The study is a retrospective chart review. The setting is an academic endocrinology clinic. Patients were 200 women with PCOS, defined as irregular menses and hyperandrogenism. Biopsy-documented NASH and aminotransferase levels were the main outcome measures. Fifteen percent (29 of 200) had aspartate aminotransferase and/or alanine aminotransferase more than 60 U/liter. Women with aminotransferase elevations had lower high-density lipoprotein (HDL) (41 vs. 50 mg/dl, P = 0.006), higher triglycerides (174 vs. 129 mg/dl, P = 0.024), and higher fasting insulin (21 vs. 12 microIU/ml, P = 0.036) compared with women with normal aminotransferases. Six women (mean age 29 yr) with persistent aminotransferase elevations underwent liver biopsy. All six had NASH with fibrosis. Compared with the 194 of 200 PCOS women who did not undergo biopsy, women with biopsy-documented NASH had lower HDL (median 34 vs. 50 mg/dl, P < 0.001), and higher triglycerides (245 vs. 132 mg/dl, P = 0.025), fasting insulin (26 vs. 13 microIU/ml, P = 0.038), aspartate aminotransferase (144 vs. 22 U/liter, P < 0.001), and alanine aminotransferase (143 vs. 28 U/liter, P < 0.001). Abnormal aminotransferase activity is common in women with PCOS. Low HDL, high triglycerides, and high fasting insulin were associated with abnormal aminotransferase activity. Some women already had evidence of NASH with fibrosis. Further studies are needed to evaluate whether to screen PCOS women for liver disease at an earlier age than is currently recommended for the general population.

A genetic risk score is associated with hepatic triglyceride content and non-alcoholic steatohepatitis in Mexicans with morbid obesity.

PubMed

León-Mimila, Paola; Vega-Badillo, Joel; Gutiérrez-Vidal, Roxana; Villamil-Ramírez, Hugo; Villareal-Molina, Teresa; Larrieta-Carrasco, Elena; López-Contreras, Blanca E; Kauffer, Luis R Macías; Maldonado-Pintado, Diana G; Méndez-Sánchez, Nahúm; Tovar, Armando R; Hernández-Pando, Rogelio; Velázquez-Cruz, Rafael; Campos-Pérez, Francisco; Aguilar-Salinas, Carlos A; Canizales-Quinteros, Samuel

2015-04-01

Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) near/in PNPLA3, NCAN, LYPLAL1, PPP1R3B, and GCKR genes associated with non-alcoholic fatty liver disease (NAFLD) mainly in individuals of European ancestry. The aim of the study was to test whether these genetic variants and a genetic risk score (GRS) are associated with elevated liver fat content and non-alcoholic steatohepatitis (NASH) in Mexicans with morbid obesity. 130 morbidly obese Mexican individuals were genotyped for six SNPs in/near PNPLA3, NCAN, LYPLAL1, PPP1R3B, and GCKR genes. Hepatic fat content [triglyceride (HTG) and total cholesterol (HTC)] was quantified directly in liver biopsies and NASH was diagnosed by histology. A GRS was tested for association with liver fat content and NASH using logistic regression models. In addition, 95 ancestry-informative markers were genotyped to estimate population admixture proportions. After adjusting for age, sex and admixture, PNPLA3, LYPLAL1, GCKR and PPP1R3B polymorphisms were associated with higher HTG content (P < 0.05 for PNPLA3, LYPLAL1, GCKR polymorphisms and P = 0.086 for PPP1R3B). The GRS was significantly associated with higher HTG and HTC content (P = 1.0 × 10(-4) and 0.048, respectively), steatosis stage (P = 0.029), and higher ALT levels (P = 0.002). Subjects with GRS ≥ 6 showed a significantly increased risk of NASH (OR = 2.55, P = 0.045) compared to those with GRS ≤ 5. However, the GRS did not predict NASH status, as AUC of ROC curves was 0.56 (P = 0.219). NAFLD associated loci in Europeans and a GRS based on these loci contribute to the accumulation of hepatic lipids and NASH in morbidly obese Mexican individuals. Copyright © 2015 Elsevier Inc. All rights reserved.

Inhibition of NLRP3 inflammasome by thioredoxin-interacting protein in mouse Kupffer cells as a regulatory mechanism for non-alcoholic fatty liver disease development

PubMed Central

He, Kun; Zhu, Xiwen; Liu, Yan; Miao, Chunmu; Wang, Tao; Li, Peizhi; Zhao, Lei; Chen, Yaxi; Gong, Junhua; Cai, Can; Li, Jinzheng; Li, Shengwei; Ruan, Xiong Z.; Gong, Jianping

2017-01-01

NOD-like receptor (NLR) NLRP3 inflammasome activation has been implicated in the progression of non-alcoholic fatty liver disease (NAFLD) from non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH). It has been also shown that palmitic acid (PA) activates NLRP3 inflammasome and promotes interleukin-1β (IL-1β) secretion in Kupffer cells (KCs). However, the specific mechanism of the NLRP3 inflammasome activation is unclear. We studies the molecular mechanisms by investigating the roles of Thioredoxin-interacting protein (TXNIP) and NLRP3 on NAFLD development in patients, high-fat diet (HFD)-induced NAFL and methionine choline deficient (MCD) diet-induced NASH in wild type (WT), TXNIP−/− (thioredoxin-interacting protein) and NLRP3−/− mice, and isolated KCs. We found that the expressions of NLRP3 and TXNIP in human liver tissues were higher in NASH group than in NAFL group. Furthermore, co-immunoprecipitation analyses show that activation of the TXNIP-NLRP3 inflammasome protein complex occurred in KCs of NASH WT mice rather than NAFL WT mice, thus suggesting that the formation and activation of this protein complex is mainly involved in the development of NASH. NLRP3−/− mice exhibited less severe NASH than WT mice in MCD diet model, whereas TXNIP deficiency enhanced NLRP3 inflammasome activation and exacerbated liver injury. PA triggered the activation and co-localization of the NLRP3 inflammasome protein complex in KCs isolated from WT and TXNIP−/− but not NLRP3−/− mice, and most of the complex co-localized with mitochondria of KCs following PA stimulation. Taken together, our novel findings indicate that TXNIP plays a protective and anti-inflammatory role in the development of NAFLD through binding and suppressing NLRP3. PMID:28499273

Role of aramchol in steatohepatitis and fibrosis in mice

PubMed Central

Iruarrizaga‐Lejarreta, Marta; Varela‐Rey, Marta; Fernández‐Ramos, David; Martínez‐Arranz, Ibon; Delgado, Teresa C; Simon, Jorge; Gutiérrez‐de Juan, Virginia; delaCruz‐Villar, Laura; Azkargorta, Mikel; Lavin, José L.; Mayo, Rebeca; Van Liempd, Sebastiaan M.; Aurrekoetxea, Igor; Buqué, Xabier; Delle Cave, Donatella; Peña, Arantza; Rodríguez‐Cuesta, Juan; Aransay, Ana M.; Elortza, Felix; Falcón‐Pérez, Juan M.; Aspichueta, Patricia; Hayardeny, Liat; Noureddin, Mazen; Sanyal, Arun J.; Alonso, Cristina; Anguita, Juan; Martínez‐Chantar, María Luz; Lu, Shelly C.

2017-01-01

Nonalcoholic steatohepatitis (NASH) is the advanced form of nonalcoholic fatty liver disease (NAFLD) that sets the stage for further liver damage. The mechanism for the progression of NASH involves multiple parallel hits, including oxidative stress, mitochondrial dysfunction, inflammation, and others. Manipulation of any of these pathways may be an approach to prevent NASH development and progression. Arachidyl‐amido cholanoic acid (Aramchol) is presently in a phase IIb NASH study. The aim of the present study was to investigate Aramchol's mechanism of action and its effect on fibrosis using the methionine‐ and choline‐deficient (MCD) diet model of NASH. We collected liver and serum from mice fed an MCD diet containing 0.1% methionine (0.1MCD) for 4 weeks; these mice developed steatohepatitis and fibrosis. We also collected liver and serum from mice receiving a control diet, and metabolomes and proteomes were determined for both groups. The 0.1MCD‐fed mice were given Aramchol (5 mg/kg/day for the last 2 weeks), and liver samples were analyzed histologically. Aramchol administration reduced features of steatohepatitis and fibrosis in 0.1MCD‐fed mice. Aramchol down‐regulated stearoyl‐coenyzme A desaturase 1, a key enzyme involved in triglyceride biosynthesis and the loss of which enhances fatty acid β‐oxidation. Aramchol increased the flux through the transsulfuration pathway, leading to a rise in glutathione (GSH) and the GSH/oxidized GSH ratio, the main cellular antioxidant that maintains intracellular redox status. Comparison of the serum metabolomic pattern between 0.1MCD‐fed mice and patients with NAFLD showed a substantial overlap. Conclusion: Aramchol treatment improved steatohepatitis and fibrosis by 1) decreasing stearoyl‐coenyzme A desaturase 1 and 2) increasing the flux through the transsulfuration pathway maintaining cellular redox homeostasis. We also demonstrated that the 0.1MCD model resembles the metabolic phenotype observed in about 50% of patients with NAFLD, which supports the potential use of Aramchol in NASH treatment. (Hepatology Communications 2017;1:911–927) PMID:29159325

Superior reductions in hepatic steatosis and fibrosis with co-administration of a glucagon-like peptide-1 receptor agonist and obeticholic acid in mice.

PubMed

Jouihan, Hani; Will, Sarah; Guionaud, Silvia; Boland, Michelle L; Oldham, Stephanie; Ravn, Peter; Celeste, Anthony; Trevaskis, James L

2017-11-01

Nonalcoholic steatohepatitis (NASH) is an unmet need associated with metabolic syndrome. There are no approved therapies for NASH; however, glucagon-like peptide-1 receptor (GLP-1R) and farnesoid-X receptor (FXR) agonists are promising drug targets. We investigated the therapeutic effects of co-administration of a GLP-1R agonist, IP118, with FXR agonist obeticholic acid (OCA) in mice. OCA and IP118 alone and in combination were sub-chronically administered to Lep ob /Lep ob mice with diet-induced NASH or diet-induced obese (DIO) mice. Metabolic (body weight and glucose) and liver (biochemical and histological) endpoints were assessed. NASH severity in Lep ob /Lep ob mice was graded using a customized integrated scoring system. OCA reduced liver weight and lipid in NASH mice (both by -17%) but had no effect on plasma ALT or AST levels. In contrast, IP118 significantly reduced liver weight (-21%), liver lipid (-15%), ALT (-29%), and AST (-27%). The combination of OCA + IP118 further reduced liver weight (-29%), liver lipid (-22%), ALT (-39%), and AST (-36%). Combination therapy was superior to monotherapies in reducing hepatic steatosis, inflammation, and fibrosis. Hepatic improvements with IP118 and OCA + IP118 were associated with reduced body weight (-4.3% and -3.5% respectively) and improved glycemic control in OCA + IP118-treated mice. In DIO mice, OCA + IP118 co-administration reduced body weight (-25.3%) to a greater degree than IP118 alone (-12.5%) and further improved glucose tolerance and reduced hepatic lipid. Our data suggest a complementary or synergistic therapeutic effect of GLP-1R and FXR agonism in mouse models of metabolic disease and NASH. Copyright © 2017 The Authors. Published by Elsevier GmbH.. All rights reserved.

Peroxisome proliferator-activated receptor-α agonist, Wy 14,643, improves metabolic indices, steatosis and ballooning in diabetic mice with non-alcoholic steatohepatitis.

PubMed

Larter, Claire Z; Yeh, Matthew M; Van Rooyen, Derrick M; Brooling, John; Ghatora, Kamaljit; Farrell, Geoffrey C

2012-02-01

Lipid accumulation precedes hepatocellular injury and liver inflammation in non-alcoholic steatohepatitis (NASH). The peroxisome proliferator-activated receptor (PPAR)α regulates hepatic lipid disposal. We studied whether pharmacological stimulation of PPARα reverses NASH associated with metabolic syndrome in high-fat (HF)-fed foz/foz obese/diabetic mice. Female foz/foz mice and wildtype (WT) littermates were fed HF diet for 16 weeks to initiate NASH then treated with Wy 14,643 (Wy) for 10 days or 20 days. Liver disease was assessed by histology, serum alanine aminotransferase, genes (real-time polymerase chain reaction) and proteins (Western blot, enzyme-linked immunosorbent assay) of interest and pro-inflammatory signaling pathways were determined. In diabetic foz/foz mice, NASH was associated with elevated serum MCP1 and hepatic activation of nuclear factor (NF)-κB and c-Jun N-terminal kinase, but not oxidative or endoplasmic reticulum stress. Wy treatment decreased steatosis and injury, although induction of PPARα-responsive fatty acid oxidation genes was proportionally less than in WT. The PPARα agonist lowered serum insulin, corrected hyperglycemia, and suppressed the carbohydrate-dependent lipogenic transcription factor, carbohydrate response element binding protein. Steatosis resolution was associated with suppression of NF-κB and JNK activation and decreased hepatic macrophages and neutrophils. Despite this, histology inflammation score remained high, associated with serum monocyte chemoattractant protein (MCP)1 elevation, a pro-inflammatory chemokine related to higher adipose, not liver MCP1 mRNA expression. Pharmacological activation of PPARα improves metabolic milieu, steatosis, ballooning, and combats NF-κB and JNK activation, neutrophil and F4/80 macrophage recruitment in diabetes-related NASH. However, persistent liver inflammation with high serum MCP1 due to unsuppressed adipose inflammation may limit PPARα agonists' efficacy as therapy for NASH. © 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.

Serum Levels of Oxidative Stress Markers in Patients with Type 2 Diabetes Mellitus and Non-alcoholic Steatohepatitis.

PubMed

Casoinic, F; Sampelean, D; Buzoianu, Anca D; Hancu, N; Baston, Dorina

2016-12-01

Oxidative stress is one of the key mechanisms responsible for disease progression in non-alcoholic fatty liver disease. The aim of this study was to evaluate the serum levels of oxidative stress markers in patients with type 2 diabetes mellitus (DMT2) and non-alcoholic steatohepatitis (NASH) and test their relationships with clinical and biochemical patient characteristics, compared to patients with DMT2 without non-alcoholic fatty liver disease (NAFLD), and controls. In all, 60 consecutive patients with DMT2 and NASH, 55 with DMT2 without NAFLD, and 50 age-and-gender-matched healthy subjects participated in the study. The serum levels of protein carbonyls and 8-isoprostane were determined by ELISA methods, while the serum levels of malondialdehyde (MDA) were detected by means of the spectrophotometric method. Clinical, demographic, and laboratory parameters were examined for all the subjects included in the study. Multivariate logistic regression was used to test the independent predictive factors in the relationships investigated here. Patients with DMT2 and NASH displayed significantly higher serum levels of protein carbonyls (1.112 ± 0.42 nmol/dL), MDA (6.181 ± 1.81 ng/mL), and 8-isoprostane (338.6 ± 98.5 pg/mL) compared to patients with DMT2 without NAFLD, and controls. Results of multivariate logistic regression analyses indicate that in patients with DMT2 and NASH, the serum levels of oxidative stress markers were independently and positively associated with: HbA1c, duration of diabetes, the UKPDS cardiovascular risk score (for protein carbonyls); age, LDL-cholesterol (for 8-isoprostane); and triglycerides serum levels (for MDA). Our findings indicate that the process of oxidative stress tends to increase in patients with DMT2 and NASH, compared to patients with DMT2 without NAFLD, and controls. This evidence suggests that an antioxidant therapy might prove useful in the treatment of patients with DMT2 and NASH.

Mechanisms of the prevention and inhibition of the progression and development of non-alcoholic steatohepatitis by genetic and pharmacological decoy receptor 3 supplementation.

PubMed

Lee, Pei-Chang; Yang, Ling-Yu; Wang, Ying-Wen; Huang, Shiang-Fen; Lee, Kuei-Chuan; Hsieh, Yun-Cheng; Yang, Ying-Ying; Hsieh, Shie-Liang; Hou, Ming-Chih; Lin, Han-Chieh; Lee, Fa-Yuah; Lee, Shou-Dong

2017-11-01

Treatment of non-alcoholic steatohepatitis (NASH) is difficult due to the absence of a proven treatment and its comprehensive mechanisms. In the NASH animal model, upregulated hepatic inflammation and oxidative stress, with the resultant M1 polarization of macrophages as well as imbalanced adipocytokines, all accelerate NASH progression. As a member of the tumor necrosis factor receptor superfamily, decoy receptor 3 (DcR3) not only neutralizes the death ligands, but also performs immune modulations. In this study, we aimed to investigate the possible non-decoy effects of DcR3 on diet-induced NASH mice. Methionine- and choline-deficient (MCD) diet feeding for 9 weeks was applied to induce NASH in BALB/c mice. Decoy receptor 3 heterozygous transgenesis or pharmacological pretreatment with DcR3a for 1 month were designed as interventions. Intrahepatic inflammatory status as well as macrophage polarization, oxidative stress, and steatosis as well as lipogenic gene expression and fibrotic status were analyzed. Additionally, acute effects of DcR3a on HepG2 cells, Hep3B cells, and primary mouse hepatocytes in various MCD medium-stimulated changes were also evaluated. Both DcR3 genetic and pharmacologic supplement significantly reduced MCD diet-induced hepatic M1 polarization. In addition, DcR3 supplement attenuated MCD diet-increased hepatic inflammation, oxidative stress, adipocytokine imbalance, steatosis, and fibrogenesis. Moreover, acute DcR3a incubation in HepG2 cells, Hep3B cells, and mouse hepatocytes could normalize the expression of genes related to lipid oxidation along with inflammation and oxidative stress. The ability of DcR3 to attenuate hepatic steatosis and inflammation through its non-decoy effects of immune modulation and oxidative stress attenuation makes it a potential treatment for NASH. © 2017 The Japan Society of Hepatology.

Biomechanical stability analysis of the lambda-model controlling one joint.

PubMed

Lan, L; Zhu, K Y

2007-06-01

Computer modeling and control of the human motor system might be helpful for understanding the mechanism of human motor system and for the diagnosis and treatment of neuromuscular disorders. In this paper, a brief view of the equilibrium point hypothesis for human motor system modeling is given, and the lambda-model derived from this hypothesis is studied. The stability of the lambda-model based on equilibrium and Jacobian matrix is investigated. The results obtained in this paper suggest that the lambda-model is stable and has a unique equilibrium point under certain conditions.

Interpreting equilibrium-conductivity and conductivity-relaxation measurements to establish thermodynamic and transport properties for multiple charged defect conducting ceramics.

PubMed

Zhu, Huayang; Ricote, Sandrine; Coors, W Grover; Kee, Robert J

2015-01-01

A model-based interpretation of measured equilibrium conductivity and conductivity relaxation is developed to establish thermodynamic, transport, and kinetics parameters for multiple charged defect conducting (MCDC) ceramic materials. The present study focuses on 10% yttrium-doped barium zirconate (BZY10). In principle, using the Nernst-Einstein relationship, equilibrium conductivity measurements are sufficient to establish thermodynamic and transport properties. However, in practice it is difficult to establish unique sets of properties using equilibrium conductivity alone. Combining equilibrium and conductivity-relaxation measurements serves to significantly improve the quantitative fidelity of the derived material properties. The models are developed using a Nernst-Planck-Poisson (NPP) formulation, which enables the quantitative representation of conductivity relaxations caused by very large changes in oxygen partial pressure.

Resolution of non-alcoholic steatohepatitis by rosuvastatin monotherapy in patients with metabolic syndrome.

PubMed

Kargiotis, Konstantinos; Athyros, Vasilios G; Giouleme, Olga; Katsiki, Niki; Katsiki, Evangelia; Anagnostis, Panagiotis; Boutari, Chrysoula; Doumas, Michael; Karagiannis, Asterios; Mikhailidis, Dimitri P

2015-07-07

To investigate the effect of rosuvastatin monotherapy on non-alcoholic steatohepatitis (NASH). At present there is no effective treatment for non-alcoholic fatty liver disease or its advanced form NASH. This prospective study included 20 biopsy proven patients with NASH, metabolic syndrome (MetS) and dyslipidaemia. Biochemical parameters of the blood of the patients and an ultrasonography of the liver were performed at baseline. Then patients received lifestyle advice and were treated for a 12 mo period with rosuvastatin (10 mg/d) monotherapy. Patients were re-evaluated during the study at 3 mo intervals, during which biochemical parameters of the blood were measured including liver enzymes. A repeat biopsy and ultrasonography of the liver were performed at the end of the study in all 20 patients. Changes in liver enzymes, fasting plasma glucose, serum creatinine, serum uric acid (SUA), high sensitivity C reactive protein (hsCRP) and lipid profile were assessed every 3 mo. The primary endpoint was the resolution of NASH and the secondary endpoints were the changes in liver enzyme and lipid values. The repeat liver biopsy and ultrasonography showed complete resolution of NASH in 19 patients, while the 20(th), which had no improvement but no deterioration either, developed arterial hypertension and substantial rise in triglyceride levels during the study, probably due to changes in lifestyle including alcohol abuse. Serum alanine transaminase, aspartate transaminase, and γ-glutamyl transpeptidase were normalised by the 3(rd) treatment month (ANOVA P < 0.001), while alkaline phosphatase activities by the 6(th) treatment month (ANOVA, P = 0.01). Fasting plasma glucose and glycated haemoglobin were significantly reduced (P < 0.001). Lipid values were normalised by the 3(rd) treatment month. No patient had MetS by the 9(th) treatment month. Body mass index and waist circumference remained unchanged during the study. Thus, changes in liver pathology and function should be attributed solely to rosuvastatin treatment. A limitation of the study is the absence of a control group. These findings suggest that rosuvastatin monotherapy could ameliorate biopsy proven NASH and resolve MetS within 12 mo. These effects and the reduction of fasting plasma glucose and SUA levels may reduce the risk of vascular and liver morbidity and mortality in NASH patients. These findings need confirmation in larger studies.

Simultaneous MR quantification of hepatic fat content, fatty acid composition, transverse relaxation time and magnetic susceptibility for the diagnosis of non-alcoholic steatohepatitis.

PubMed

Leporq, B; Lambert, S A; Ronot, M; Vilgrain, V; Van Beers, B E

2017-10-01

Non-alcoholic steatohepatitis (NASH) is characterized at histology by steatosis, hepatocyte ballooning and inflammatory infiltrates, with or without fibrosis. Although diamagnetic material in fibrosis and inflammation can be detected with quantitative susceptibility imaging, fatty acid composition changes in NASH relative to simple steatosis have also been reported. Therefore, our aim was to develop a single magnetic resonance (MR) acquisition and post-processing scheme for the diagnosis of steatohepatitis by the simultaneous quantification of hepatic fat content, fatty acid composition, T 2 * transverse relaxation time and magnetic susceptibility in patients with non-alcoholic fatty liver disease. MR acquisition was performed at 3.0 T using a three-dimensional, multi-echo, spoiled gradient echo sequence. Phase images were unwrapped to compute the B 0 field inhomogeneity (ΔB 0 ) map. The ΔB 0 -demodulated real part images were used for fat-water separation, T 2 * and fatty acid composition quantification. The external and internal fields were separated with the projection onto dipole field method. Susceptibility maps were obtained after dipole inversion from the internal field map with single-orientation Bayesian regularization including spatial priors. Method validation was performed in 32 patients with biopsy-proven, non-alcoholic fatty liver disease from which 12 had simple steatosis and 20 NASH. Liver fat fraction and T 2 * did not change significantly between patients with simple steatosis and NASH. In contrast, the saturated fatty acid fraction increased in patients with NASH relative to patients with simple steatosis (48 ± 2% versus 44 ± 4%; p < 0.05) and the magnetic susceptibility decreased (-0.30 ± 0.27 ppm versus 0.10 ± 0.14 ppm; p < 0.001). The area under the receiver operating characteristic curve for magnetic susceptibility as NASH marker was 0.91 (95% CI: 0.79-1.0). Simultaneous MR quantification of fat content, fatty acid composition, T 2 * and magnetic susceptibility is feasible in the liver. Our preliminary results suggest that quantitative susceptibility imaging has a high diagnostic performance for the diagnosis of NASH. Copyright © 2017 John Wiley & Sons, Ltd.

Nucleus Accumbens Shell and mPFC but Not Insula Orexin-1 Receptors Promote Excessive Alcohol Drinking

PubMed Central

Lei, Kelly; Wegner, Scott A.; Yu, Ji Hwan; Mototake, Arisa; Hu, Bing; Hopf, Frederic W.

2016-01-01

Addiction to alcohol remains a major social and economic problem, in part because of the high motivation for alcohol that humans exhibit and the hazardous binge intake this promotes. Orexin-1-type receptors (OX1Rs) promote reward intake under conditions of strong drives for reward, including excessive alcohol intake. While systemic modulation of OX1Rs can alter alcohol drinking, the brain regions that mediate this OX1R enhancement of excessive drinking remain unknown. Given the importance of the nucleus accumbens (NAc) and anterior insular cortex (aINS) in driving many addictive behaviors, including OX1Rs within these regions, we examined the importance of OX1Rs in these regions on excessive alcohol drinking in C57BL/6 mice during limited-access alcohol drinking in the dark cycle. Inhibition of OX1Rs with the widely used SB-334867 within the medial NAc Shell (mNAsh) significantly reduced drinking of alcohol, with no effect on saccharin intake, and no effect on alcohol consumption when infused above the mNAsh. In contrast, intra-mNAsh infusion of the orexin-2 receptor TCS-OX2-29 had no impact on alcohol drinking. In addition, OX1R inhibition within the aINS had no effect on excessive drinking, which was surprising given the importance of aINS-NAc circuits in promoting alcohol consumption and the role for aINS OX1Rs in driving nicotine intake. However, OX1R inhibition within the mPFC did reduce alcohol drinking, indicating cortical OXR involvement in promoting intake. Also, in support of the critical role for mNAsh OX1Rs, SB within the mNAsh also significantly reduced operant alcohol self-administration in rats. Finally, orexin ex vivo enhanced firing in mNAsh neurons from alcohol-drinking mice, with no effect on evoked EPSCs or input resistance; a similar orexin increase in firing without a change in input resistance was observed in alcohol-naïve mice. Taken together, our results suggest that OX1Rs within the mNAsh and mPFC, but not the aINS, play a central role in driving excessive alcohol drinking. PMID:27625592

Gd-EOB-DTPA-enhanced T1ρ imaging vs diffusion metrics for assessment liver inflammation and early stage fibrosis of nonalcoholic steatohepatitis in rabbits.

PubMed

Xie, Yuanliang; Zhang, Hongfeng; Jin, Chaoling; Wang, Xiang; Wang, Xiaoqi; Chen, Jingting; Xu, Yikai

2018-05-01

To assess the value of T1ρ,T1ρ on hepatobiliary phase (HBP) and diffusion metrics in staging of Non-alcoholic fatty liver disease (NAFLD) activity scores, inflammation, fibrosis in NASH rabbits model. Non-alcoholic steatohepatitis (NASH) rabbits model was induced by feeding a varied duration of high-fat, high-cholesterol diet. T1ρ,T1ρ (HBP) 20min after administration of Gd-EOB-DTPA, and Intravoxel incoherent motion imaging (IVIM) diffusion-weighted imaging were performed on a 3.0T magnetic resonance (MR) imaging unit. The diagnostic value of each parameter for NAS, inflammation and fibrosis severity were determined. T1ρ (r=0.658) and T1ρ (HBP) (r=0.750) have strong association with NASH overall activity, T1ρ (HBP) is strongly relevant to inflammation stage (r=0.812). There was negative association between f and inflammation (r=-0.480), whilst no significant relation between other three parameters (apparent diffusion coefficient (ADC), pseudo-diffusion coefficient (D*) and true diffusion coefficient (D)) and inflammation or overall activity. The areas under the receiver operating characteristic curves (AUCs) of f, ADC, T1ρ and T1ρ-HBP were 0.871, 0.728, 0.849 and 0.949 for differentiating NASH; 0.731, 0.552, 0.925 and 0.922 for G2-3 inflammation; and 0.767, 0.625, 0.816, and 0.882 for S1-2 fibrosis. Comparison of ROC curve showed T1ρ (HBP) had an optimal diagnostic performance for NASH [T1ρ (HBP) vs ADC, AUC:0.949 vs 0.728, P=0.043], inflammation [T1ρ (HBP) vs ADC, AUC:0.922 vs 0.552, P=0.003], fibrosis [T1ρ (HBP) vs ADC, AUC:0.882 vs 0.625, P=0.046]. The combination of T1ρ (HBP)+perfusion fraction (f) showed highest diagnostic value for NASH (AUC:0.971), inflammation (AUC:0.935). Among T1ρ imaging and IVIM diffusion metrics, combination of T1rho (HBP)+f was found to be superior noninvasive imaging biomarker for NASH activity assessment. Copyright © 2017 Elsevier Inc. All rights reserved.

Levels of metacaspase1 and chaperones related to protein quality control in alcoholic and nonalcoholic steatohepatitis.

PubMed

Mendoza, Alejandro S; Dorce, Jacques; Peng, Yue; French, Barbara A; Tillman, Brittany; Li, Jun; French, Samuel W

2015-02-01

Efficient management of misfolded or aggregated proteins in ASH and NASH is crucial for continued hepatic viability. Cellular protein quality control systems play an important role in the pathogenesis and progression of ASH and NASH. In a recent study, elevated Mca1 expression counteracted aggregation and accumulation of misfolded proteins and extended the life span of the yeast Saccharomyces cerevisiae (Hill et al, 2014). Mca1 may also associate with Ssa1 and Hsp104 in disaggregation and fragmentation of aggregated proteins and their subsequent degradation through the ER-associated degradation (ERAD) pathway. If degradation is not available, protection of the cellular environment from a misfolded protein is accomplished by its sequestration into two distinct inclusion bodies (Kaganovich et al., 2008) called the JUNQ (JUxta Nuclear Quality control compartment) and the IPOD (Insoluble Protein Deposit). Mca1, Hsp104, Hsp40, Ydj1, Ssa1, VCP/p97, and p62 all play important roles in protein quality control systems. This study aims to measure the expression of Mca1 and related chaperones involved in protein quality control in alcoholic steatohepatitis (ASH), and nonalcoholic steatohepatitis (NASH) compared with normal control liver biopsies. Mca1, Hsp104, Hsp40, Ydj1, Ssa1, VCP/p97, and p62 expressions were measured in three to six formalin-fixed paraffin embedded ASH and NASH liver biopsies and control normal liver specimens by immunofluorescence staining and quantified by immunofluorescence intensity. Mca1, Hsp104, Ydj1 and p62 were significantly upregulated compared to control (p<0.05) in ASH specimens. Hsp40 and VCP/p97 were also uptrending in ASH. In NASH, the only significant difference was the increased expression of Hsp104 compared to control (p<0.05). Ssa1 levels were uptrending in both ASH and NASH specimens. The upregulation of Mca1, Hsp104, Ydj1 and p62 in ASH may be elicited as a response to the chronic exposure of the hepatocytes to the toxicity of alcohol. Recruitment of Mca1, Hsp104, Ydj1 and p62 may indicate that autophagy, the ERAD, JUNQ, and IPOD systems are active in ASH. Whereas in NASH, elevated Hsp104 and uptrending Ssa1 levels may indicate that autophagy and IPOD may be the only active protein quality control systems involved. Published by Elsevier Inc.

Dietary intervention, but not losartan, completely reverses non-alcoholic steatohepatitis in obese and insulin resistant mice.

PubMed

Verbeek, Jef; Spincemaille, Pieter; Vanhorebeek, Ilse; Van den Berghe, Greet; Vander Elst, Ingrid; Windmolders, Petra; van Pelt, Jos; van der Merwe, Schalk; Bedossa, Pierre; Nevens, Frederik; Cammue, Bruno; Thevissen, Karin; Cassiman, David

2017-02-23

Dietary intervention is the cornerstone of non-alcoholic steatohepatitis (NASH) treatment. However, histological evidence of its efficacy is limited and its impact on hepatic pathways involved in NASH is underreported. The efficacy of the angiotensin receptor type 1 blocker losartan is controversial because of varying results in a few animal and human studies. We evaluated the effect of dietary intervention versus losartan on NASH and associated systemic metabolic features in a representative mouse model. Male C57BL/6 J mice with high fat-high sucrose diet (HF-HSD) induced NASH, obesity, insulin resistance and hypercholesterolemia were subjected to dietary intervention (switch from HF-HSD to normal chow diet (NCD)) (n = 9), continuation HF-HSD together with losartan (30 mg/kg/day) (n = 9) or continuation HF-HSD only (n = 9) for 8 weeks. 9 mice received NCD during the entire experiment (20 weeks). We assessed the systemic metabolic effects and performed a detailed hepatic histological and molecular profiling. A P-value of < 0.05, using the group with continuation of HF-HSD only as control, was considered as statistically significant. Dietary intervention normalized obesity, insulin resistance, and hypercholesterolemia (for all P < 0.001), and remarkably, completely reversed all histological features of pre-existent NASH (for all P < 0.001), including fibrosis measured by quantification of collagen proportional area (P < 0.01). At the hepatic molecular level, dietary intervention targeted fibrogenesis with a normalization of collagen type I alpha 1, transforming growth factor β1, tissue inhibitor of metalloproteinase 1 mRNA levels (for all P < 0.01), lipid metabolism with a normalization of fatty acid translocase/CD36, fatty acid transport protein 5, fatty acid synthase mRNA levels (P < 0.05) and markers related to mitochondrial function with a normalization of hepatic ATP content (P < 0.05) together with sirtuin1 and uncoupling protein 2 mRNA levels (for both P < 0.001). Dietary intervention abolished p62 accumulation (P < 0.01), suggesting a restoration of autophagic flux. Losartan did not significantly affect obesity, insulin resistance, hypercholesterolemia or any histological NASH feature. Dietary intervention, and not losartan, completely restores the metabolic phenotype in a representative mouse model with pre-existent NASH, obesity, insulin resistance and hypercholesterolemia.

Gasdermin D plays a key role as a pyroptosis executor of non-alcoholic steatohepatitis in humans and mice.

PubMed

Xu, Bing; Jiang, Mingzuo; Chu, Yi; Wang, Weijie; Chen, Di; Li, Xiaowei; Zhang, Zhao; Zhang, Di; Fan, Daiming; Nie, Yongzhan; Shao, Feng; Wu, Kaichun; Liang, Jie

2017-12-20

Gasdermin D (GSDMD)-executed programmed necrosis is involved in inflammation and controls interleukin (IL)-1β release. However, the role of GSDMD in non-alcoholic steatohepatitis (NASH) remains unclear. We investigated the role of GSDMD in the pathogenesis of steatohepatitis. Human liver tissues from patients with non-alcoholic fatty liver disease (NAFLD) and control individuals were obtained to evaluate GSDMD expression. Gsdmd knockout (Gsdmd -/- ) mice, obese db/db mice and their wild-type (WT) littermates were fed with methionine-choline deficient (MCD) or control diet to induce steatohepatitis. The Gsdmd -/- and WT mice were also used in a high-fat diet (HFD)-induced NAFLD model. In addition, Alb-Cre mice were administered an adeno-associated virus (AAV) vector that expressed the gasdermin-N domain (AAV9-FLEX-GSDMD-N) and were fed with either MCD or control diet for 10 days. GSDMD and its pyroptosis-inducing fragment GSDMD-N were upregulated in liver tissues of human NAFLD/NASH. Importantly, hepatic GSDMD-N protein levels were significantly higher in human NASH and correlated with the NAFLD activity score and fibrosis. GSDMD-N remained a potential biomarker for the diagnosis of NASH. MCD-fed Gsdmd -/- mice exhibit decreased severity of steatosis and inflammation compared with WT littermates. GSDMD was associated with the secretion of pro-inflammatory cytokines (IL-1β, TNF-α, and MCP-1 [CCL2]) and persistent activation of the NF-ĸB signaling pathway. Gsdmd -/- mice showed lower steatosis, mainly because of reduced expression of the lipogenic gene Srebp1c (Srebf1) and upregulated expression of lipolytic genes, including Pparα, Aco [Klk15], Lcad [Acadl], Cyp4a10 and Cyp4a14. Alb-Cre mice administered with AAV9-FLEX-GSDMD-N showed significantly aggravated steatohepatitis when fed with MCD diet. As an executor of pyroptosis, GSDMD plays a key role in the pathogenesis of steatohepatitis, by controlling cytokine secretion, NF-ĸB activation, and lipogenesis. Non-alcoholic fatty liver disease has become one of the most feared chronic liver diseases, because it is the most rapidly growing indication for adult liver transplantation and a major cause of hepatocellular carcinoma. However, the mechanisms involved in the transformation of simple steatosis to steatohepatitis remain unclear. Herein, we show that gasdermin D driven pyroptosis is prominent in patients with non-alcoholic steatohepatitis (NASH), and gasdermin-N domain remains a potential biomarker for the diagnosis of NASH. Gasdermin D plays a key role in the pathogenesis of NASH by regulating lipogenesis, the inflammatory response, and the NF-ĸB signaling pathway, revealing potential treatment targets for NASH in humans. Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Equilibrium Strategy and Population-Size Effects in Lowest Unique Bid Auctions

NASA Astrophysics Data System (ADS)

Pigolotti, Simone; Bernhardsson, Sebastian; Juul, Jeppe; Galster, Gorm; Vivo, Pierpaolo

2012-02-01

In lowest unique bid auctions, N players bid for an item. The winner is whoever places the lowest bid, provided that it is also unique. We use a grand canonical approach to derive an analytical expression for the equilibrium distribution of strategies. We then study the properties of the solution as a function of the mean number of players, and compare them with a large data set of internet auctions. The theory agrees with the data with striking accuracy for small population-size N, while for larger N a qualitatively different distribution is observed. We interpret this result as the emergence of two different regimes, one in which adaptation is feasible and one in which it is not. Our results question the actual possibility of a large population to adapt and find the optimal strategy when participating in a collective game.

Auxiliary principle technique and iterative algorithm for a perturbed system of generalized multi-valued mixed quasi-equilibrium-like problems.

PubMed

Rahaman, Mijanur; Pang, Chin-Tzong; Ishtyak, Mohd; Ahmad, Rais

2017-01-01

In this article, we introduce a perturbed system of generalized mixed quasi-equilibrium-like problems involving multi-valued mappings in Hilbert spaces. To calculate the approximate solutions of the perturbed system of generalized multi-valued mixed quasi-equilibrium-like problems, firstly we develop a perturbed system of auxiliary generalized multi-valued mixed quasi-equilibrium-like problems, and then by using the celebrated Fan-KKM technique, we establish the existence and uniqueness of solutions of the perturbed system of auxiliary generalized multi-valued mixed quasi-equilibrium-like problems. By deploying an auxiliary principle technique and an existence result, we formulate an iterative algorithm for solving the perturbed system of generalized multi-valued mixed quasi-equilibrium-like problems. Lastly, we study the strong convergence analysis of the proposed iterative sequences under monotonicity and some mild conditions. These results are new and generalize some known results in this field.

Are there really no evolutionarily stable strategies in the iterated prisoner's dilemma?

PubMed

Lorberbaum, Jeffrey P; Bohning, Daryl E; Shastri, Ananda; Sine, Lauren E

2002-01-21

The evolutionary form of the iterated prisoner's dilemma (IPD) is a repeated game where players strategically choose whether to cooperate with or exploit opponents and reproduce in proportion to game success. It has been widely used to study the evolution of cooperation among selfish agents. In the past 15 years, researchers proved over a series of papers that there is no evolutionarily stable strategy (ESS) in the IPD when players maintain long-term relationships. This makes it difficult to make predictions about what strategies can actually persist as prevalent in a population over time. Here, we show that this no ESS finding may be a mathematical technicality, relying on implausible players who are "too perfect" in that their probability of cooperating on any move is arbitrarily close to either 0 or 1. Specifically, in the no ESS proof, all strategies were allowed, meaning that after a strategy X experiences any history H, X cooperates with an unrestricted probability p (X, H) where 0< or =p (X, H)< or =1. Here, we restrict strategies to the set S in which X is a member of S [corrected] if after any H, X cooperates with a restricted probability p (X, H) where e< or =p (X, H)< or =1-e and 0

75 FR 41518 - Match-E-Be-Nash-She-Wish (Gun Lake) Tribe Liquor Control Ordinance

Federal Register 2010, 2011, 2012, 2013, 2014

2010-07-16

... ethyl alcohol, hydrated oxide of ethyl, or spirit of wine, commonly produced by the fermentation or... benefit of the Tribe. (j) ``Tribe'' means the Match-E-Be-Nash-She-Wish Band of Pottawatomi Indians of... and wine shall be purchased from distributors licensed by the Michigan Liquor Control Commission. (f...

Memories of Gary Nash over Five Decades

ERIC Educational Resources Information Center

Mellor, Ronald

2009-01-01

It is as a longtime client, softball teammate, colleague, traveling companion, and friend that the author writes this article to honor Gary Nash. He has known him in varied guises in five different decades, and on five continents, with Africa coming in 2009. In this article, the author recalls some of his memories of Gary over five decades.

The Art of Math

ERIC Educational Resources Information Center

Kim, Una; Stabley, Angela

2010-01-01

In the movie "A Beautiful Mind" there is a scene where future Nobel prize winner John Nash is captivated by a fellow student's tie. When asked about his behavior Nash quips, "There has to be a mathematical explanation for how bad that tie is." (Grazer & Howard, 2000) In this light moment, director Ron Howard attempts to show us that the mind of a…

High-fat, high-fructose, high-cholesterol feeding causes severe NASH and cecal microbiota dysbiosis in juvenile Ossabaw swine

USDA-ARS?s Scientific Manuscript database

Pediatric obesity and nonalcoholic steatohepatitis (NASH) are on the rise in industrialized countries, yet our ability to mechanistically examine this relationship is limited by the lack of a suitable higher animal models. Here, we examined the effects of high-fat, high-fructose corn syrup, high-cho...

Critical Realism and Statistical Methods--A Response to Nash

ERIC Educational Resources Information Center

Scott, David

2007-01-01

This article offers a defence of critical realism in the face of objections Nash (2005) makes to it in a recent edition of this journal. It is argued that critical and scientific realisms are closely related and that both are opposed to statistical positivism. However, the suggestion is made that scientific realism retains (from statistical…

Towards Automated Bargaining in Electronic Markets: A Partially Two-Sided Competition Model

NASA Astrophysics Data System (ADS)

Gatti, Nicola; Lazaric, Alessandro; Restelli, Marcello

This paper focuses on the prominent issue of automating bargaining agents within electronic markets. Models of bargaining in literature deal with settings wherein there are only two agents and no model satisfactorily captures settings in which there is competition among buyers, being they more than one, and analogously among sellers. In this paper, we extend the principal bargaining protocol, i.e. the alternating-offers protocol, to capture bargaining in markets. The model we propose is such that, in presence of a unique buyer and a unique seller, agents' equilibrium strategies are those in the original protocol. Moreover, we game theoretically study the considered game providing the following results: in presence of one-sided competition (more buyers and one seller or vice versa) we provide agents' equilibrium strategies for all the values of the parameters, in presence of two-sided competition (more buyers and more sellers) we provide an algorithm that produce agents' equilibrium strategies for a large set of the parameters and we experimentally evaluate its effectiveness.

Game-Theoretic Models of Information Overload in Social Networks

NASA Astrophysics Data System (ADS)

Borgs, Christian; Chayes, Jennifer; Karrer, Brian; Meeder, Brendan; Ravi, R.; Reagans, Ray; Sayedi, Amin

We study the effect of information overload on user engagement in an asymmetric social network like Twitter. We introduce simple game-theoretic models that capture rate competition between celebrities producing updates in such networks where users non-strategically choose a subset of celebrities to follow based on the utility derived from high quality updates as well as disutility derived from having to wade through too many updates. Our two variants model the two behaviors of users dropping some potential connections (followership model) or leaving the network altogether (engagement model). We show that under a simple formulation of celebrity rate competition, there is no pure strategy Nash equilibrium under the first model. We then identify special cases in both models when pure rate equilibria exist for the celebrities: For the followership model, we show existence of a pure rate equilibrium when there is a global ranking of the celebrities in terms of the quality of their updates to users. This result also generalizes to the case when there is a partial order consistent with all the linear orders of the celebrities based on their qualities to the users. Furthermore, these equilibria can be computed in polynomial time. For the engagement model, pure rate equilibria exist when all users are interested in the same number of celebrities, or when they are interested in at most two. Finally, we also give a finite though inefficient procedure to determine if pure equilibria exist in the general case of the followership model.

Asymmetric public goods game cooperation through pest control.

PubMed

Reeves, T; Ohtsuki, H; Fukui, S

2017-12-21

Cooperation in a public goods game has been studied extensively to find the conditions for sustaining the commons, yet the effect of asymmetry between agents has been explored very little. Here we study a game theoretic model of cooperation for pest control among farmers. In our simple model, each farmer has a paddy of the same size arranged adjacently on a line. A pest outbreak occurs at an abandoned paddy at one end of the line, directly threatening the frontier farmer adjacent to it. Each farmer pays a cost of his or her choice to an agricultural collective, and the total sum held by the collective is used for pest control, with success probability increasing with the sum. Because the farmers' incentives depend on their distance from the pest outbreak, our model is an asymmetric public goods game. We derive each farmer's cost strategy at the Nash equilibrium. We find that asymmetry among farmers leads to a few unexpected outcomes. The individual costs at the equilibrium do not necessarily increase with how much the future is valued but rather show threshold behavior. Moreover, an increase in the number of farmers can sometimes paradoxically undermine pest prevention. A comparison with a symmetric public goods game model reveals that the farmer at the greatest risk pays a disproportionate amount of cost in the asymmetric game, making the use of agricultural lands less sustainable. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.