Functional proteomics and biochemsitry: working together to unravel mitochondrial phenomena of African trypansomes

Eukaryotic cells are compartmentalized into membrane-bound organelles in order to provide sheltered reaction rooms for various specific processes. Organelles are not randomly distributed in a cell or operate isolated from each other. At the contrary — some organelles are closely linked and their functions are tightly orchestrated. The most well-known example of two such organelles acting in concert are the ER and the mitochondrion that work together in order to coordinate cellular lipid biosynthesis, maintain Ca2+-homeostasis, regulate mitochondrial division and control mitochondrial/ER shape as well as to synchronize the movement of these organelles within a cell. To study the mitochondrion and its interface to the ER requires a simplified mitochondrial system. African trypanosomes represent such a system. The unicellular parasite that causes devastating diseases in humans and animals has only one large mitochondrion that does not undergo fission/fusion events except for the context of cell division. Moreover, mitochondrial functions and morphology are highly regulated throughout the life cycle of the protozoan. Central to the understanding of how mitochondria control their morphology, communicate with their surroundings and manage exchange of metabolites and transport of biopolymers (proteins, RNAs) is the mitochondrial outer membrane (MOM), as the MOM defines the boundary of the organelle. Recently, we have purified the MOM of T. brucei and characterized its proteome using label-free quantitative mass spectrometry for protein abundance profiling in combination with statistical analysis. Our results show that the trypanosomal MOM proteome consists of 82 proteins, two thirds of which have never been associated with mitochondria before. Among these, we identified novel factors required to regulate mitochondrial morphology and the long-elusive protein import machinery of T. brucei. A comparison with the MOM proteome of yeast defines a set of 17 common proteins that are likely present in the mitochondrial outer membrane of all eukaryotes. One of these is the Miro-GTPase Gem1. In yeast, this Ca2+-EF-Hand containing polypeptide is thought to be involved in a protein complex that physically tethers the mitochondrion to the ER. Interestingly, a putative tethering complex in mammalian cells was linked to the mitochondrial fusion/fission machinery. Thus, the concept of a protein complex-mediated connection seems to be a general and conserved feature. We are currently investigating, if such a protein complex exists in T. brucei and if the trypanosomal Gem1 protein is involved. This ER-subdomain associated with mitochondria has been termed mitochondria-associated ER-membranes or MAM. The MAM has recently been implicated to play a key role in Alzheimer’s disease. It is therefore of broad and general interest to establish other eukaryotic model systems in order to investigate the MAM-MOM connection in more detail.

Functional proteomics and biochemsitry: working together to unravel mitochondrial phenomena of African trypansomes

Central to the understanding of how mitochondria control their morphology, communicate with their surroundings and manage exchange of metabolites and transport of biopolymers (proteins, RNAs) is the mitochondrial outer membrane (MOM), as the MOM defines the boundary of the organelle. Recently, we have purified the MOM of the mitochondrial model organism T. brucei and characterized its proteome. Our results show that the trypanosomal MOM proteome consists of 82 proteins. Among these, we identified novel factors required to regulate mitochondrial morphology and the long-elusive protein import machinery of T. brucei. A comparison with the MOM proteome of yeast defines a set of 17 common proteins that are likely present in the mitochondrial outer membrane of all eukaryotes. One of these is the Miro-GTPase Gem1. In yeast, this Ca2+-EF-Hand containing polypeptide is thought to be involved in a protein complex that physically tethers the mitochondrion to the ER. In mammalian cells, a putative tethering complex was linked to the mitochondrial fusion/fission machinery. Thus, the concept of a protein complex-mediated connection seems to be a general and conserved feature. We are currently investigating if such a protein complex exists in T. brucei and if the trypanosomal Gem1 protein is involved.

Sensitive Questions in Online Surveys: An Experimental Evaluation of the Randomized Response Technique and the Crosswise Model

Self-administered online surveys provide a higher level of privacy protection to respondents than surveys administered by an interviewer. Yet, studies indicate that asking sensitive questions is problematic also in self-administered surveys. Because respondents might not be willing to reveal the truth and provide answers that are subject to social desirability bias, the validity of prevalence estimates of sensitive behaviors from online surveys can be challenged. A well-known method to overcome these problems is the Randomized Response Technique (RRT). However, convincing evidence that the RRT provides more valid estimates than direct questioning in online surveys is still lacking. A new variant of the RRT called the Crosswise Model has recently been proposed to overcome some of the deficiencies of existing RRT designs. We therefore conducted an experimental study in which different implementations of the RRT, including two implementations of the crosswise model, were tested and compared to direct questioning. Our study is a large-scale online survey (N = 6,037) on sensitive behaviors by students such as cheating in exams and plagiarism. Results indicate that the crosswise-model RRT---unlike the other variants of RRT we evaluated---yields higher prevalence estimates of sensitive behaviors than direct questioning. Whether higher estimates are a sufficient condition for more valid results, however, remains questionable.

Functional proteomics and biochemistry: working together to unravel mitochondrial phenomena of African trypanosomes

Eukaryotic cells are compartmentalized into membrane-bound organelles in order to provide sheltered reaction rooms for various specific processes. Organelles are not randomly distributed in a cell or operate isolated from each other. At the contrary — some organelles are closely linked and their functions are tightly orchestrated. The most well-known example of two such organelles acting in concert are the ER and the mitochondrion that work together in order to coordinate cellular lipid biosynthesis, maintain Ca2+-homeostasis, regulate mitochondrial division and control mitochondrial/ER shape as well as to synchronize the movement of these organelles within a cell. To study the mitochondrion and its interface to the ER requires a simplified mitochondrial system. African trypanosomes represent such a system. The unicellular parasite that causes devastating diseases in humans and animals has only one large mitochondrion that does not undergo fission/fusion events except for the context of cell division. Moreover, mitochondrial functions and morphology are highly regulated throughout the life cycle of the protozoan. Central to the understanding of how mitochondria control their morphology, communicate with their surroundings and manage exchange of metabolites and transport of biopolymers (proteins, RNAs) is the mitochondrial outer membrane (MOM), as the MOM defines the boundary of the organelle. Recently, we have purified the MOM of T. brucei and characterized its proteome using label-free quantitative mass spectrometry for protein abundance profiling in combination with statistical analysis. Our results show that the trypanosomal MOM proteome consists of 82 proteins, two thirds of which have never been associated with mitochondria before. Among these, we identified novel factors required to regulate mitochondrial morphology and the long-elusive protein import machinery of T. brucei. A comparison with the MOM proteome of yeast defines a set of 17 common proteins that are likely present in the mitochondrial outer membrane of all eukaryotes. One of these is the Miro-GTPase Gem1. In yeast, this Ca2+-EF-Hand containing polypeptide is thought to be involved in a protein complex that physically tethers the mitochondrion to the ER. Interestingly, a putative tethering complex in mammalian cells was linked to the mitochondrial fusion/fission machinery. Thus, the concept of a protein complex-mediated connection seems to be a general and conserved feature. We are currently investigating, if such a protein complex exists in T. brucei and if the trypanosomal Gem1 protein is involved. This ER-subdomain associated with mitochondria has been termed mitochondria-associated ER-membranes or MAM. The MAM has recently been implicated to play a key role in Alzheimer’s disease. It is therefore of broad and general interest to establish other eukaryotic model systems in order to investigate the MAM-MOM connection in more detail.

A model of factors determining levels of public support for health care policy in the United States

Public preferences for policy are formed in a little-understood process that is not adequately described by traditional economic theory of choice. In this paper I suggest that U.S. aggregate support for health reform can be modeled as tradeoffs among a small number of behavioral values and the stage of policy development. The theory underlying the model is based on Samuelson, et al.'s (1986) work and Wilke's (1991) elaboration of it as the Greed/Efficiency/Fairness (GEF) hypothesis of motivation in the management of resource dilemmas, and behavioral economics informed by Kahneman and Thaler's prospect theory. ^ The model developed in this paper employs ordered probit econometric techniques applied to data derived from U.S. polls taken from 1990 to mid-2003 that measured support for health reform proposals. Outcome data are four-tiered Likert counts; independent variables are dummies representing the presence or absence of operationalizations of each behavioral variable, along with an integer representing policy process stage. Marginal effects of each independent variable predict how support levels change on triggering that variable. Model estimation results indicate a vanishingly small likelihood that all coefficients are zero and all variables have signs expected from model theory. ^ Three hypotheses were tested: support will drain from health reform policy as it becomes increasingly well-articulated and approaches enactment; reforms appealing to fairness through universal health coverage will enjoy a higher degree of support than those targeted more narrowly; health reforms calling for government operation of the health finance system will achieve lower support than those that do not. Model results support the first and last hypotheses. Contrary to expectations, universal health care proposals did not provide incremental support beyond those targeted to “deserving” populations—children, elderly, working families. In addition, loss of autonomy (e.g. restrictions on choice of care giver) is found to be the “third rail” of health reform with significantly-reduced support. When applied to a hypothetical health reform in which an employer-mandated Medical Savings Account policy is the centerpiece, the model predicts support that may be insufficient to enactment. These results indicate that the method developed in the paper may prove valuable to health policy designers. ^

Consumption asymmetry and the stock market: New evidence through a threshold adjustment model

This paper investigates whether stock market wealth affects real consumption asymmetrically through a threshold adjustment model. The empirical findings for the US show that wealth produces an asymmetric effect on real consumption, with negative 'news' affecting consumption less than positive 'news.' Thus, policy makers may want to focus more attention on preventing asset 'bubbles' than on responding to negative asset shocks.

A Generic Model of Financial Repression

The paper develops a growth model in an overlapping generations framework of a financially repressed small open economy, and analyzes the effects of financial liberalization. The following observations are made: An increase (decrease) of interest rate (reserve requirements) reduces (increases) the steady-state stock of capital and the trade balance, but improves (deteriorates) the level of foreign exchange reserves. However, financial liberalization, in any form, is always welfare-improving. The paper, thus, advocates financial liberalization policies to be oriented towards reduction of reserve requirements rather than interest rate deregulation, if foreign reserve holding is not in a critical position.

An Equilibrium Model of Lawmaking

This paper embeds a model of lawmaking in an equilibrium framework in which the demand for trials is rationed by court delay. The lawmaking process depends on a combination of selective litigation, judicial bias, and precedent. The steady state equilibrium of the model determines both the length of delay and the distribution of legal rules. Comparative statics show that an increase in the supply of trials reduces delay but may or may not increase the proportion of efficient rules. An increase in the fraction of judges biased in favor of the efficient rule, however, will likely improve efficiency on both counts.

A Model of Rights

In this paper, we develop a simple model of the rights a government provides its citizenry. Rights are treated as public goods and taken as primitives in agents utility functions; each agent has preferences over the entire policy vector. We model the interaction among citi-zens and the government as a game in which an exogenous lobbying set makes contributions to the government to in uence policy formu-lation in the matter of rights. When examining contribution schedules comprising truthful Nash strategies, we find that members of the lob-bying set obtain rights closer to their most-preferred bundle, while the rights of non-lobbyers further diverge from their most-preferred bun-dle. Further, if the lobbying set comprises the entire population, the government s allocation of rights does not differ from the allocation achieved in the absence of contributions.

An Economic Model of Fair Use

The doctrine of fair use allows unauthorized copying of original works of art, music, and literature for limited purposes like criticism, research, and education, based on the rationale that copyright holders would consent to such uses if bargaining were possible. This paper develops the first formal analysis of fair use in an effort to derive the efficient legal standard for applying the doctrine. The model interprets copies and originals as differentiated products and defines fair use as a threshold separating permissible copying from infringement. Application of the analysis to several key cases (including the recent Napster case) shows that this interpretation is consistent with actual legal reasoning. The analysis also underscores the role of technology in shaping the efficient scope of fair use.

A Bargaining Model of Holdouts and Takings

The holdout problem is commonly cited as the justification for eminent domain, but the nature of the problem is not well understood. This paper models the holdout problem in a bargaining framework, where a developer seeks to acquire several parcels of land for a large-scale development. We show that in the absence of eminent domain, holdouts are inevitable, threatening costly delay. However, if the developer has the power to use eminent domain to acquire the land from holdouts, all sellers will bargain, thus avoiding delay. An offsetting cost is that owners may negotiate prices below their true value, possibly resulting in excessive transfer of land to the developer.

A Principal-Agent Model of Contracting in Major League Baseball

Traditional economic analyses of the reserve clause in major league baseball view it as having arisen from the superior bargaining of owners compared to players. This article interprets it instead as promoting efficient investment by teams in player development, given the transferability of player skills to other teams. Using a principal-agent framework, the article shows that limited player mobility emerges as part of the optimal contract between players (principals) and teams (agents).

Macroeconomic Rationality and Lucas' Misperceptions Model: Further Evidence from Forty-One Countries

Several researchers have examined Lucas's misperceptions model as well as various propositions derived from it within a cross-section empirical framework. The cross-section approach imposes a single monetary policy regime for the entire period. Our paper innovates on existing tests of those rational expectations propositions by allowing the simultaneous effect of monetary and short run aggregate supply (oil price) shocks on output behavior and the employment of advanced panel econometric techniques. Our empirical findings, for a sample of 41 countries over 1949 to 1999, provide evidence in favor of the majority of rational expectations propositions.

Expectations, and Credibility in a Model of Monetary Policy

Recent monetary history has been characterized by monetary authorities which have been, alternatively hard and soft on inflation. In a vintage capital framework, investment decisions are not easily reversed. Therefore, expectations of policy as well as current policy are important to the investment decision. Here, a vintage capital model is used to assess the value of central bank credibility for a policy change. Policy in this model is assumed to be private information of the central banker. Agents learn about that policy which to study the ensuing transitional dynamics following a change in monetary policy regime.

A Dynamic Stochastic Frontier Production Model with Time-Varying Efficiency

In this paper we introduce technical efficiency via the intercept that evolve over time as a AR(1) process in a stochastic frontier (SF) framework in a panel data framework. Following are the distinguishing features of the model. First, the model is dynamic in nature. Second, it can separate technical inefficiency from fixed firm-specific effects which are not part of inefficiency. Third, the model allows one to estimate technical change separate from change in technical efficiency. We propose the ML method to estimate the parameters of the model. Finally, we derive expressions to calculate/predict technical inefficiency (efficiency).