Non-alcoholic fatty liver disease (NAFLD) represents the major cause of pediatric chronic liver pathology in the United States. The objective of this study was to investigate the effect of partial substitution of dietary lard by an isocaloric amount of olive or coconut oil on endpoints of NAFLD. Thirty-eight 15-d-old Iberian pigs housed in pens balanced for weight and sex were randomly assigned to receive 1 of 3 hypercaloric high-fructose high-fat (HFF) diets for 10 weeks: 1) lard (LAR; n=5 pens), 2) lard + olive oil (OLI, n=10), and 3) lard + coconut oil (COC; n=10). Additional pigs (BSL, n=4) were fed a eucaloric diet to establish baseline values. Animals were euthanized at 85 d of age after blood sampling. Liver tissue was collected for histology, metabolomics, and transcriptomics. Compared with BSL, OLI decreased high-density lipoproteins, phosphatidylcholines (PC), and total cholesterol in blood, and increased acylcarnitines in liver, whereas COC increased triacylglycerides (TAGs) in liver and blood. All HFF diets increased bile acids in liver, and decreased choline and fibroblast growth factor 19 in liver and blood. OLI and COC increased hepatic steatosis, necrosis, ballooning, and composite lesion score compared with LAR. OLI decreased gene expression of carnitine O-palmitoyltransferase 1, and COC increased expression of fatty acid binding proteins and acyl-CoA synthetase. In conclusion, partial replacement of dietary lard with olive and coconut oil dysregulated acylcarnitine metabolism and lipogenesis in the liver, increasing the severity of NAFLD in juvenile pigs.

<p> In this thesis, we focus on the rationing polices for the hotel room inventory control problems. Our study begins with a brief overview of revenue management in hotel industry, emphasizing the importance of room inventory control in revenue management problems. Mathematical models for controlling the room inventory in the literature are then reviewed along with recently developed game theoretic applications in revenue management. In game theoretic context, we establish three types of models to solve the hotel room inventory control problem in three different situations: 1) two-player two-fare-class static single-period game with complete information; 2) two-player two-fare-class dynamic multiple-period game with complete information; and 3) two-player two-fare-class single-period game with incomplete information.</p> <p> In the first situation, we find the existence of unique Nash equilibrium and Stackelberg equilibrium in the non-cooperative case. We provide the exact forms for these equilibria and corresponding conditions. Next, under the dynamic game settings, we provide the sufficient conditions for the unique Nash equilibrium. In the last situation, we consider the static single-period games with incomplete information and discuss the optimal strategies for the uninformed case, secret information case, private information case and public information case. The unique Bayesian Nash equilibrium in each case is found. We then analyze the values of different types of information and study their relations in different situations. Under each game theoretic setting, we present the managerial implications of our solutions along with the numerical examples. The thesis is concluded by a discussion of how game theory can is useful in hotel industry, and its relationship to other topics in revenue management.</p> / Thesis / Doctor of Philosophy (PhD)

Introduktion: Icke-alkoholorsakad fettleversjukdom (NAFLD) kännetecknas av hepatisk fettinlagring i frånvaro av alkoholmissbruk. För en andel av patienterna leder sjukdomen till leverinflammation och fibros och benämns då icke-alkoholorsakad steatohepatit (NASH). Denna variant av sjukdomen kan utvecklas till levercirros eller levercancer. Farmakoterapi vid NAFLD är ett forskningsområde som utvecklas snabbt och som domineras av agonister på farnesoid X receptorer (FXR) och peroxisomproliferatoraktiverade receptorer (PPAR). Dessa receptorer är inblandade i lipid- och glukosmetabolism och modulerar även inflammatorisk signalering. Syfte: Detta arbete syftar till att undersöka om FXR-agonister och PPAR-agonister har terapeutisk potential vid NAFLD/NASH. Metod: Litteratursökningen utfördes på databasen PubMed. Totalt granskades tre studier på FXR-agonisten obetikolsyra och tre studier på PPAR-agonisterna saroglitazar, elafibranor och lanifibranor. Resultat: Behandling med 25 mg obetikolsyra ledde till minskad sjukdomsaktivitet hos en större andel patienter jämfört med placebo (45 % vs 21%; p &lt; 0,0002 i FLINT och 36% vs 24%; p = 0,0012 i REGENERATE) och även till minskad leverfibros hos en större andel patienter jämfört med placebo (35% vs 19%; p = 0,004 i FLINT och 23% vs 12% p = 0,0012 i REGENERATE). Behandling med obetikolsyra ledde till ökat LDL-C och minskat HDL-C. Behandling med PPAR-α/γ agonisten saroglitazar gav en signifikant sänkning av leverenzymvärden (p &lt; 0,001) jämfört med placebo. PPAR-α/δ agonisten elafibranor orsakade tillbakagång av NASH för en större andel patienter jämfört med placebo enligt en post-hoc analys (19% vs 12%; p = 0,045). Pan-PPAR agonisten lanifibranor minskade sjukdomsaktiviteten i högre utsträckning än placebo (55% vs 33%; p = 0,007) och uppfyllde även sekundära effektmått på tillbakagång av NASH och minskning av leverfibros. Samtliga PPAR-agonister hade positiva effekter på patienternas lipidprofil och insulinkänslighet. Slutsats: Båda klasser av läkemedel ger en kliniskt meningsfull förbättring av leverhistologin vid NASH. PPAR-agonister har dessutom gynnsamma metabola effekter. Följaktligen har både FXR-agonister och PPAR-agonister terapeutisk potential vid NAFLD/NASH.

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This dissertation builds a model of information exchange, where the information is skills. A two-sided matching market for skills is employed that includes two distinct sides, skilled and unskilled agents, and the matches that connect these agents. The unskilled agents wish to purchase skills from the skilled agents, who each possess one valuable and unique skill. Skilled agents may match with many unskilled agents, while each unskilled agent may match with only one skilled agent. Direct interaction is necessary between the agents to teach and learn the skill. Thus, there must be mutual consent for a match to occur and the skill to be exchanged. In this market for skills, a discrete, simultaneous move game is employed where all agents announce their strategies at once, every skilled agent announcing a price and every unskilled agent announcing the skill she wishes to purchase. First, both Nash equilibria and a correlated equilibrium are determined for an example of this skills market game. Next, comparative statics are employed on this discrete, simultaneous move game through computer simulations. Finally, a continuous, simultaneous move game is studied where all agents announce their strategies at once, every skilled agent announcing a price and every unskilled agent announcing a skill and price pair. For this game, an algorithm is developed that if used by all agents to determine their strategies leads to a strong Nash equilibrium for the game. / Economics

A large part of the empirical work on differentiated products markets has focused on demand estimation and the pricing behavior of firms. These two themes are key inputs in important applications such as the merging of two firms or the introduction of new products. The validity of inferences, therefore, depends on accurate demand estimates and sound assumptions about the pricing behavior of firms. This dissertation makes a contribution to this literature in two ways. First, it adds to previous techniques of estimating demand for differentiated products. Second, it extends previous analyses of pricing behavior to models of price leadership that, while important, have received limited attention. The investigation focuses on the U.S. brewing industry, where price leadership appears to be an important type of firm behavior. The analysis is conducted in two stages. In the first stage, the recent Distance Metric (DM) method devised by Pinkse, Slade and Brett is used to estimate the demand for 64 brands of beer in 58 major metropolitan areas of the United States. This study adds to previous applications of the DM method (Pinkse and Slade; Slade 2004) by employing a demand specification that is more flexible and also by estimating advertising substitution coefficients for numerous beer brands. In the second stage, different pricing models are compared and ranked by exploiting the exogenous change in the federal excise tax of 1991. Demand estimates of the first stage are used to compute the implied marginal costs for the different models of pricing behavior prior to the tax increase. Then, the tax increase is added to the these pre-tax increase marginal costs, and equilibrium prices for all brands are simulated for each model of pricing behavior. These "predicted" prices are then compared to actual prices for model assessment. Results indicate that Bertrand-Nash predicts the pricing behavior of firms more closely than other models, although Stackelberg leadership yields results that are not substanitally different from the Bertrand-Nash model. Nevertheless, Bertrand-Nash tends to under-predict prices of more price-elastic brands and to over-predict prices of less price- elastic brands. An implication of this result is that Anheuser-Busch could exert more market power by increasing the price of its highly inelastic brands, especially Budweiser. Overall, actual price movements as a result of the tax increase tend to be more similar across brands than predicted by any of the models considered. While this pattern is not inconsistent with leadership behavior, leadership models considered in this dissertation do not conform with this pattern. / Ph. D.

Obesity and its comorbidities have emerged as serious healthcare concerns in the western world due to increased prevalence of nutritional overabundance and decreased physical activity. Due to the significant population affected and economic burden placed on national healthcare systems, there is a demonstrated need for effective weight management therapeutics. Obesity presents clinically diverse phenotypes that increase a person's susceptibility to comorbidities that commonly result in deteriorated health (cardiovascular disease, diabetes mellitus, hypertension, etc). A comorbidity of specific relevance is non-alcoholic fatty liver disease (NAFLD) and its advanced disease state known as non-alcoholic steatohepatitis (NASH), as it has had a documented rise in prevalence parallel to that observed with obesity. Currently there are no FDA approved therapeutics for NAFLD or NASH, with the majority in clinical development aiming to mitigate the effects caused by accumulation of adipose tissue in the liver known as steatosis. An alternative therapeutic approach is to use small molecules to uncouple oxidative phosphorylation in the mitochondria by passively shuttling protons from the mitochondrial inner membrane space into the mitochondrial matrix. Mitochondrial uncoupling results in the disruption of the proton motive force leading to an upregulation of metabolism (i.e., decrease in steatosis). Small molecule mitochondrial uncouplers have recently garnered great interest for their potential in treating the advanced disease state of NASH. In this study, we report the structure-activity relationship (SAR) profiling of a 6-amino-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol core, which utilizes the hydroxy moiety as the proton transporter across the mitochondrial inner membrane. We demonstrated that a wide array of substituents are tolerated with this novel scaffold that increased cellular metabolic rates in vitro using changes in oxygen consumption rate as a read-out. In particular, compound SHS4121705 (2.12i) displayed an EC50 of 4.3 M in L6 myoblast cells and excellent oral bioavailability and liver exposure in mice. In the preclinical stelic animal model (STAM) mouse model of NASH, administration of 2.12i at 25 mg kg-1day-1 resulted in decreased liver triglyceride levels and improved liver enzymes, NAFLD activity score, and fibrosis without affecting body temperature or food intake. Overall, our initial studies showcased the promise of mitochondrial uncouplers toward the treatment of NASH. While initial results were promising, the lead compound 2.12i had reduced potency compared to the alkyl derivatives reported in the SAR, unfortunately alkyl derivatives suffered from poor physiochemical properties, possibly due to metabolism of the alkyl chain. We hypothesized that addressing metabolic liabilities of these compounds could lead to increased potency with maintained efficacy in the STAM mouse model of NASH. Herein, we detail the SAR profiling of a 6-amino-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol core derivatized with 1,1'-biphenyl anilines capable of eliciting mild mitochondrial uncoupling. A wide array of substituents are tolerated, and demonstrated sustained and stable increases in ¬cellular oxygen consumption rates over a broad concentration range. In particular, compound SHS4091862 (3.9b) displayed an EC50 of 2.0 μM in L6 myoblast cells with a pharmacokinetic profile of Cmax = 46 μM and t1/2 = 4.7 h indicating excellent oral bioavailability. Administration of 3.9b at 60 mg kg-1 day-1 in the STAM mouse model of NASH decreased fibrosis, steatosis, and hepatocellular ballooning to result in a 1.9-point decrease in NAFLD activity score (NAS) compared to vehicle. No changes in food intake, body weight, alanine transaminase (ALT) or aspartate transaminase (AST) levels were observed with 3.9b. Positive control Resmetirom afforded a 1.2-point decrease in NAS score, but increased ALT levels. Cumulatively, our work demonstrates the therapeutic potential of small molecule mitochondrial uncouplers to address metabolic diseases, namely NAFLD. / Doctor of Philosophy / There has been a significant increase in the population suffering from metabolic diseases in the western world. Among the most concerning metabolic diseases are obesity and nonalcoholic fatty liver disease, which have been shown to arise from excessive consumption of calorie dense food and limited physical activity. A novel approach to combat these diseases is to use mitochondrial uncouplers that disrupt the body's natural process for ATP production, causing an increase in metabolism. This increase in the metabolic rate results in the reduction of fat mass including in organs such as the liver. This work describes the design, development, and biological study of mitochondrial uncouplers capable of producing an increase in metabolism; specifically, SHS4121705 (2.12i) and SHS4091862 (3.9b) were shown to be potent uncouplers in vitro and were active in mouse models of fatty liver disease.

Networks, generically, refer to any application of graph theory in economics. Consider an undirected graph where nodes represent players and links represent relationships between them. Players can both form and delete links by which we mean that they can both form new relationships and terminate existing ones. A stable network is one in which no incentives exist to change the network structure. There can be various forms of stability depending on how many links players are allowed to form or delete at a time. Under strong pairwise stability, each player is allowed to delete any number of links at a time while any pair of players can form one link at a time. We introduce a network-value function, which assigns to each possible network a certain value. The value is allocated according to the component-wise egalitarian allocation rule, which divides the value generated by a component equally among members of the component (where a component refers to a maximally connected subgraph). An efficient network is one that maximizes the network value function. We show that there is an underlying conflict between strong pairwise stability and efficiency. Efficient networks are not necessarily strongly pairwise stable. This conflict can be resolved only if value functions satisfy a certain property called "middlemen-security". We further find that there is a broad class of networks called "middlemen-free networks" for which the above condition is automatically satisfied under all possible value functions. We also look at three network applications. A peering contract is an arrangement between Internet Service Providers under which they exchange traffic with one another free of cost. We analyze incentives for peering contracts among Internet service providers using the notion of pairwise stability. A hierarchy is a directed graph with an explicit top-down structure where each pair of linked agents have a superior-subordinate relationship with each other. We apply the notion of conjunctive permission value to demonstrate the formation of hierarchical firms in a competitive labor market. Comparative or targeted advertising is defined as any form of advertising where a firm directly or indirectly names a competitor. We also examine a model of targeted advertising between oligopolistic firms using non-cooperative game theoretic tools. / Ph. D.

In recent years, game theory has emerged as a promising approach to solving the power control problem in wireless networks. This thesis extends the reach of game-theoretic analysis to embrace link adaptation, thereby constituting a generalization of the power control problem. A realistic and natural problem formulation is attempted, wherein transmitter power and a discrete-valued Adaptable Link Parameter (ALP), e.g. code rate, constitute the action set of a player in this game. The dual goals of maximizing throughput and minimizing power consumption are reflected in the utility function selection, which uses the accurate sigmoid model for approximating throughput. The discrete action space makes it difficult to verify the existence of a Nash Equilibrium (NE) in this game using standard techniques. To circumvent this limitation, a heuristic algorithm is proposed. This algorithm is analytically shown to always converge to a NE. The subsequent results probe its validity and sensitivity. Favorable comparisons are drawn between these game-theoretic results and those arising from parallel systems techniques. A linear programming system optimization that exploits properties of the dominant eigenvalue of the system gain matrix is also presented in a comparative context. / Master of Science

The automobile dealership is one of the more important types of small business. The operation of such a business is an integral part of the economy of the country, and conditions existing in the automobile field are usually fairly representative of those in other types of small business; therefore, the general personnel policies of an automobile dealership are basically similar to personnel policies of other small businesses in the distributive field. A study of personnel policies in this field will be of some use to anyone interested in the problems of small business.