Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver dysfunction in the western world and one of the main contributors to cirrhosis and potentially liver cancer and liver failure. A variety of behaviors and other factors can predispose certain individuals to an increased risk of developing NAFLD and non-alcoholic steatohepatitis (NASH). These factors include, but are not limited to, obesity, insulin resistance, hyperglycemia, and high levels of fat in the blood. The result is the accumulation of fat in hepatocytes that over time leads to inflammation and scarring of the liver and ultimately liver damage. At present, the mainstay of therapy remains weight loss through dietary modification and lifestyle change. Due to the lack of specific targeted pharmacotherapies, there is great interest from the scientific community to find a potential therapy that can provide benefit to the many patients in need. Some existing medications, including pioliglitazones and angiotensin receptor antagonists, may be repurposed to help treat this condition. Vitamin E may improve the histology in NASH, but safety issues limit its use. Other drugs, such as farnesoid X receptor agonist, obeticholic acid, are also in clinical trials with great hope for the future. However, as the cause of NAFLD and thereby NASH is poorly understood, there is a need for further research in the field to better understand the pathophysiology of the disease and the potential for pharmacotherapy for treatment of the disease. There has, however, been evidence that the antidiabetic drug class known as glucagon-like receptor agonists (GLP-1 RAs) has been shown to reduce liver damage in patients with non-alcoholic steatohepatitis. Liraglutide, currently a drug for type 2 diabetes and obesity, has been shown to provide great benefit in type 2 diabetes and obesity and after reviewing multiple studies, seems to provide a potential treatment also for patients with NAFLD and NASH. However, more research needs to be done to confirm this hypothesis. Its more potent version, called semaglutide, is currently in phase 2 clinical trials and provides great hope in potentially further reducing liver damage. This class of drugs provides a huge opportunity to address an unmet clinical need that could benefit millions of patients worldwide. .

Master of Science / Electrical and Computer Engineering / Sanjoy Das / Groundwater is one of the most vital of all common pool resources throughout the world. More than half of groundwater is used to grow crops. This research models groundwater depletion patterns within a multi-agent system framework. Irrigators are modeled as agents in the multi-agent system. The irrigation strategies adopted by the agents are investigated using game theory, under several futuristic scenarios. The consequence of unregulated groundwater extraction in each case is analyzed. A set of five irrigators, growing three crops: corn, sorghum and wheat, have been considered in this study. To allow groundwater flow, these agents are assumed to be located in adjoining farm lands. Irrigators are modeled selfish agents that strategize their irrigation patterns in order to maximize their own utilities, i.e. the difference between the total revenue obtained from crop sales and the costs incurred, including groundwater extraction costs. Due to groundwater flow, irrigators have no incentive to conserve groundwater for later use. This leads to unsustainable depletion of the resource. Using the Nikaido-Isoda relaxation algorithm, their irrigation strategies under Nash equilibrium, when no irrigator can increase its utility by unilaterally changing its strategy, are obtained. All parameters in this research are representative of Kansas. Recorded environmental and economic data of the region, along with the DSSAT software, have been used to obtain these futuristic projections. These scenarios include temperature increase, lowering of the water table, different precipitation levels, and different price increases for the crops. One of the emergent phenomena of the simulations is the adoption of crop rotation patterns by the irrigators to conserve groundwater. The irrigators grow corn, which is a more profitable yet water intensive crop in one year, and in the next, conserve water by growing sorghum instead. Another emergent outcome of this research is the viability of LEMAs. When the irrigators are subject to LEMA-level limits on groundwater use, there is a slight increase in the aggregate utility of the LEMA

Objetivo: Evaluar los factores asociados a NASH severo según algortimos FLIP/Clasificación SAF en pacientes obesos intervenidos en un centro bariátrico de Lima, Perú. Diseño: El diseño del estudio es de tipo transversal analítico, en el cual se analizará una base de datos secundaria.

PURPOSE: The Nrf2/Keap1/ARE pathway is a major regulator of cytoprotective responses to oxidants. Gluatredoxin-1 (Glrx-1), a small thiol transferase removes glutathione (GSH) adducts from proteins and participates in redox signaling. Glrx-/- mice exhibit increased protein GSH adducts (PSSG) and non-alcoholic fatty liver disease (NAFLD). Unexpectedly, our Glrx-/- mice showed increased hepatic glutathione (GSH) levels. The Nrf2/Keap1/ARE pathway, as an important regulator of glutathione synthesis, could be regulated by Glrx-1 activity. METHODS: To determine the role of Nrf2 in vivo, we treated Glrx-/- mice with high fat high sucrose (HFHS) diet to induce metabolic and oxidative stress. Livers were harvested at 10 months of age after 8 months on HFHS diet. Gene expression of Nrf2 and its down-signaling targets were determined using RT-qPCR and protein expression was accessed via WB. To determine the role of Nrf2 in Glrx-deficiency in vitro, Glrx siRNA was transfected in HEK293A and HepG2 cells and exposed to high palmitate high glucose (HPHG) to mimic metabolic stress and hydrogen peroxide to mimic oxidative stress. RESULTS: Glrx-/- deficiency increased Nrf2 activity and gene expression, and decreased Keap1 activity and gene expression. Glrx silencing in liver promoted Nrf2 activity and translocation to the nucleus, and downstream targets of Nrf2 were upregulated. CONCLUSION: Our findings indicate that the Nrf2/Keap1/ARE pathway is regulated by Glrx in vitro and in vivo.

Indiana University-Purdue University Indianapolis (IUPUI) / A burgeoning area of focus within liver disease research is centered on the concomitant muscle atrophy present in end stage liver disease patients which shows a correlation to severity of hepatic fibrosis and transplant survival outcomes. Of particular interest, nonalcoholic steatohepatitis (NASH) is a form of liver disease that is characterized as the hepatic manifestation of metabolic syndrome. If left untreated, the disease can progress to the state of cirrhosis and hepatocellular carcinoma requiring transplant. Concordant with increasing global prevalence of obesity, NASH is projected to become the leading cause for liver transplants by 2020. Due to a lack of therapeutic options, these patients represent a large unmet medical need in the western world. A major hurdle to therapeutic research is the lack of a quick, reproducible, and cost effective in vivo model that recapitulates the plethora of pathologies and their molecular underpinnings manifested by this disorder. Our studies attempted to validate and expand upon a two-hit model of NASH, which incorporated both the integral comorbidities associated with metabolic challenges of obesity along with liver injury. The two-hit model manifests not only the hepatic morphohistological characteristics of the disease, but also incorporates the obligatory muscle atrophy. To further elaborate on the potential direct link between liver and skeletal muscle and remove any confounding issues associated with the model, in vitro administration of hepatotoxins representing various pathologies associated with liver disease, were used to recapitulate the liver-muscle endocrine signaling that exists in vivo. Our data shows that a variety of hepatoxins can elicit hepatocellular damage which releases factors that inhibits myotube size in vitro. The two hit model also preserves many of conserved molecular underpinnings observed in clinical hepatic fibrosis. Of particular interest, the TGFβ superfamily has been demonstrated to play an important regulatory role in the progression of fibrosis in NASH patients. TGFβ, Activin A, and Follistatin are members of the highly conserved family that are increased in NASH patients. Furthermore, these proteins have a well-studied role in muscle health, regeneration, and mass that has been hypothesized to be conserved between liver and muscle tissues. Surprisingly, novel expression of the myokine and negative regulator of muscle mass Gdf8 (myostatin) was increased in our in vivo model as well. Our studies focused on the molecular interactions of these TGFβ superfamily members and their role on liver disease progression. Through specific inhibition of these proteins (Activin A and Gdf8), we demonstrated that they appear to play key individual roles in the progression of the concomitant muscle atrophy observed in NASH patients. Interestingly, superior efficacy was gained with the treatment of a pan inhibitor of these proteins (Activin A, B, Gdf8 etc.) via a soluble decoy receptor (ActRIIB-Fc), suggesting an additional unaccounted for ligand. Activin B, was found to be increased in two separate in vivo models of liver fibrosis (two-hit model and BDL), has been implicated in regulating muscle mass. Our data suggest a pivotal role for several members of the TGFβ superfamily in NASH associated muscle atrophy. Therapies designed to treat liver fibrosis and the resultant decrements in muscle mass and force must account for these agents which will require pan inhibition of TGFβ superfamily ligands that signal through the ActRIIB receptor.

Nonalcoholic fatty liver disease (NAFLD) is currently the most common cause of abnormal liver function in countries with western-style high fat, high cholesterol diets. Liver damage associated with NAFLD may lead to liver cirrhosis, end-stage liver disease and hepatocellular carcinoma (HCC). Additionally, recent data suggest that nonalcoholic steatohepatitis (NASH), the inflammatory phase of NAFLD, is linked to increased cardiovascular risk independent of the broad spectrum of risk factors of metabolic syndrome. Therefore, novel therapies are needed to inhibit the inflammatory liver damage that drives NAFLD. Hepatic macrophages (HMΦ’s), which include resident Kupffer cells and monocyte-derived macrophages, are the primary drivers of liver inflammation in both human and mouse models. In macrophages, chronic lipid exposure promotes pro-inflammatory polarization and the activation of pyroptosis via the NLRP3 inflammasome. While the role of the canonical pyroptosis pathway has been studied in NAFLD, the role of the newly discovered noncanonical (caspase-11/-Gasdermin-Ddependent) pathway has not been defined. Diet-induced NAFLD promoted hepatic steatosis and lobular inflammation in male WT mice. Caspase-11 deficiency decreases macrovesicular steatosis and total NAFLD Activity Score (NAS). High fat feeding promoted recruitment and activation of HMΦ in both Caspase-11 deficient (Casp11KO) and WT male mice, however, noncanonical pyroptosis (caspase-11 activity, surface Gasdermin-D, expression, liver IL-1β secretion) was ablated in HMΦs from Casp11KO mice. Bone marrow transplantation restored capacity for noncanonical pyroptosis in Casp11KO mice. RNAseq and microarray analysis revealed that lipid peroxidation and trained immunity mediate noncanonical pyroptosis in diet induced NALFD. / Biomedical Sciences / Accompanied by 1 PDF file: DrummerIV_temple_0225E_171/CED

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So Long Sucker is a strategy board game requiring 4 players, each with c chips of their designated color, and a board made of k empty piles. With a clear set-up come intricate rules, such as: players taking turns but not in a fixed order, agreements between some players being made and broken at any time, and a player winning the game even without any chips in hand. One of the main points of interest in studying this game, is finding when a player has a winning strategy. The game begins with four players that get eliminated successively until the winner is left. To study winning strategies, it is of interest to look at endgame situations. We present the following game set-up: there are two players left in the game, Blue and Red, and only their respective chip colors. In this thesis, we characterize Blue's winning situations and strategies through inductive reasoning.

The Internet has a loosely hierarchical structure. At the top of the hierarchy are the backbones, also called Internet Access Providers (hereafter IAPs). The second layer of the hierarchy is comprised of Internet Service Providers (hereafter ISPs). At the bottom of the hierarchy are the end users, consumers, who browse the web, and websites. To provide access to the whole Internet, the providers must interconnect with each other and share their network infrastructure. Two main forms of interconnection have emerged — peering under which the providers carry each other's traffic without any payments and transit under which the downstream provider pays the upstream provider a certain settlement payment for carrying its traffic. This dissertation develops three game theoretical models to describe the interconnection agreements among the providers, and analysis of those models from two alternative modeling perspectives: a purely non-cooperative game and a network perspective. There are two original contributions of the dissertation. First, we model the formation of peering/transit contracts explicitly as a decision variable in a non-cooperative game, while the current literature does not employ such modeling techniques. Second, we apply network analysis to examine interconnection decisions of the providers, which yields much realistic results. Chapter 1 provides a brief description of the Internet history, architecture and infrastructure as well as the economic literature. In Chapter 2 we develop a model, in which IAPs decide on private peering agreements, comparing the benefits of private peering relative to being connected only through National Access Points (hereafter NAPs). The model is formulated as a multistage game. Private peering agreements reduce congestion in the Internet, and so improve the quality of IAPs. The results show that even though the profits are lower with private peerings, due to large investments, the network where all the providers privately peer is the stable network. Chapter 3 discusses the interconnection arrangements among ISPs. Intra-backbone peering refers to peering between ISPs connected to the same backbone, whereas inter-backbone peering refers to peering between ISPs connected to different backbones. We formulate the model as a two-stage game. Peering affects profits through two channels - reduction of backbone congestion and ability to send traffic circumventing congested backbones. The relative magnitude of these factors helps or hinders peering. In Chapter 4 we develop a game theoretic model to examine how providers decide who they want to peer with and who has to pay transit. There is no regulation with regard to interconnection policies of providers, though there is a general convention that the providers peer if they perceive equal benefits from peering, and have transit arrangements otherwise. The model discusses a set of conditions, which determine the formation of peering and transit agreements. We argue that market forces determine the terms of interconnection, and there is no need for regulation to encourage peering. Moreover, Pareto optimum is achieved under the transit arrangements. / Ph. D.

La th´eorie de la complexit´e permet de classifier les probl`emes en fonction de leur difficult´e. Le cadre classique dans lequel elle s’applique est celui d’un algorithme centralis´e qui dispose de toutes les informations. Avec l’essor des r´eseaux et des architectures d´ecentralis´ees, l’algo- rithmique distribu´ee a ´et´e ´etudi´ee. Dans un grand nombre de probl`emes, en optimisation et en ´economie, les d´ecisions et les calculs sont effectu´es par des agents ind´ependants qui suivent des objectifs diff´erents dont la r´ealisation d´epend des d´ecisions des autres agents. La th´eorie des jeux est un cadre naturel pour analyser les solutions de tels probl`emes. Elle propose des concepts de stabilit´e, le plus classique ´etant l’´equilibre de Nash.Une mani`ere naturelle de calculer de telles solutions est de “ faire r´eagir “ les agents ; si un agent voit quelles sont les d´ecisions des autres joueurs ou plus g´en´eralement un “ ´etat du jeu “, il peut d´ecider de changer sa d´ecision pour atteindre son objectif faisant ainsi ´evoluer l’´etat du jeu. On dit que ces algorithmes sont des “ dynamiques “.On sait que certaines dynamiques convergent vers un concept de solution. On s’int´eresse `a la vitesse de convergence des dynamiques. Certains concepts de solutions sont mˆeme complets pour certaines classes de complexit´e ce qui rend peu vraisemblable l’existence de dynamiques simples qui convergent rapidement vers ces solutions. On a utilis´e alors trois approches pour obtenir une convergence rapide : am´eliorer la dynamique (en utilisant par exemple des bits al´eatoires), restreindre la structure du probl`eme, et rechercher une solution approch´ee.Sur les jeux de congestion, on a ´etendu les r´esultats de convergence rapide vers un ´equilibre de Nash approch´e aux jeux n´egatifs. Cependant, on a montr´e que sur les jeux sans contrainte de signe, calculer un ´equilibre de Nash approch´e est PLS-complet. Sur les jeux d ’appariement, on a ´etudi´e la vitesse de dynamiques concurrentes lorsque les joueurs ont une information partielle param´etr´ee par un r´eseau social. En particulier, on a am´elior´e des dynamiques naturelles afin qu’elles atteignent un ´equilibre enO(log(n)) tours (avec n le nombre de joueurs). / Complexity theory allows to classify problems by their algorithmic hardness. The classical framework in which it applies is the one of a centralized algorithm that knows every informa- tion. With the development of networks and decentralized architectures, distributed dynamics was studied. In many problems, in optimization or economy, actions and computations are made by independant agents that don’t share the same objective whose realization depends on the actions of other agents. Game theory is a natural framework to study solutions of this kind of problem. It provides solution concepts such as the Nash equilibrium.A natural way to compute these solutions is to make the agents “react” ; if an agent sees the actions of the other player, or more generally the state of the game, he can decide to change his decision to reach his objective and updates the state of the game. We call �dynamics� this kind of algorithms.We know some dynamics converges to a stable solution. We are interested by the speed of convergence of these dynamics. Some solution concepts are even complete for some complexity classes which make unrealistic the existence of fast converging dynamics. We used three ways to obtain a fast convergence : improving dynamics (using random bits), finding simple subcases, and finding an approximate solution.We extent fast convergence results to an approximate Nash equilibria in negative congestion games. However, we proved that finding an approximate Nash equilibrium in a congestion games without sign restriction is PLS-complete. On matching game, we studied the speed of concurrent dynamics when players have partial information that depends on a social network. Especially, we improved natural dynamics for them to reach an equilibrium inO(log(n)) rounds (with n is the number of players).