This dissertation comprises three essays. The theme that unifies them is "experiments on corruption and preferences." The first essay (chapter 2) reports theory-testing experiments on the effect of yardstick competition (a form of government competition) on corruption. The second essay (chapter 3) reports theory-testing experiments on the effect of efficiency and transparency on corruption. Furthermore, this essay revisits the yardstick competition question by implementing an alternative experimental design and protocol. Finally, the third essay (chapter 4) reports a theory-testing randomized field experiment that identifies the causes and consequences of corruption. The first essay finds the following. Theoretically, the paper derives a main proposition which suggests that institutions with more noise give rise to an increase in corrupt behavior and a decrease in voter welfare. Empirically, the paper finds a few key results. First, there are an initial nontrivial proportion of good incumbents in the population. This proportion goes down as the experiment session progresses. Secondly, a large proportion of bad incumbents make theoretically inconsistent choices given the assumptions of the model. Third, overall evidence of yardstick competition is mild. Yardstick competition has little effect as a corruption-taming mechanism when the proportion of good incumbents is low. Namely, an institution that is characterized by a small number of good incumbents has little room for yardstick competition, since bad incumbents are likely to be replaced by equally bad incumbents. Thus, incumbents have less of an incentive to build a reputation. This is also the case in which (1) yardstick competition leads to non-increasing voter welfare and (2) voters are more likely to re-elect bad domestic incumbents. Finally, a partitioning of the data by gender suggests that males and females exhibit different degrees of learning depending on the payoffs they face. Furthermore, male voter behavior exhibits mild evidence of yardstick competition when voters face the pooling equilibrium payoff. The second essay finds the following. First, efficiency is an important determinant of corruption. A decrease in efficiency makes it more costly for incumbents to "do the right thing." This drives them to divert maximum rents. While voters retaliate slightly, voters tend to be worse off. Secondly, increased lack of a particular form of transparency (as defined in terms of an increase in risk in the distribution of the unit cost) leaves corrupt incumbent behavior unchanged. In particular, if the draw of the unit cost is unfavorable, incumbents tend to be less corrupt. Third, there is strong evidence of yardstick competition. On the incumbent's side, yardstick competition acts as a corruption-taming mechanism if the incumbent is female. On the voter's side, voters are less likely to re-elect the incumbent in the presence of yardstick competition. Specifically, voters pay attention to the difference between the tax signal in their own jurisdiction and that in another. As this difference increases, voters re-elect less. This gives true meaning to the concept of "benchmarking." Finally, the analysis sheds light on the role of history and beliefs on behavior. Beliefs are an important determinant of incumbents' choices. If an incumbent perceives a tax signal to be associated with a higher likelihood of re-election, he is more likely to choose it. On the voter's side, history tends to be important. In particular, voters are more likely to vote out incumbents as time progresses. This suggests that incumbents care about tax signals because they provide access to re-elections while voters use the history of taxes and re-elections in addition to current taxes to formulate their re-election decisions. Finally, the third essay finds the following. First, 19.08% of mail is lost. Secondly, money mail is more likely to be lost at a rate of 20.90% and this finding is significant at the 10% level. This finding suggests that loss of mail is systematic (non-random), which implies that this type of corruption is due to strategic behavior as opposed to plain shirking on the part of mail handlers. Third, we find that loss of mail is non-random across other observables. In particular, middle-income neighborhoods are more likely to experience lost (money) mail. Also, female heads of household in low-income neighborhoods are more likely to experience lost mail while female heads of household in high-income neighborhoods are much less likely to experience lost (money) mail. Finally, this form of corruption is costly to different stakeholders. The sender of mail bears a direct and an indirect cost. The direct cost is the value of the mail. The indirect cost is the cost of having to switch carriers once mail has been lost. Corruption is also costly to the intended mail recipient as discussed above. Finally, corruption is costly the mail company (SERPOST) in terms of lost revenue and to society in terms of loss of trust. Overall, the findings suggest that public-private partnerships need not increase efficiency by reducing corruption; particularly, when the institution remains a monopoly. Increased efficiency in mail delivery is likely to require (1) privatization and (2) competition; otherwise, the monopolist has no incentive to provide better service and loss of mail is likely to persist.

The Hedgehog (Hh) signaling pathway has received attention regarding its important role in embryonic development, however the mechanism by which pathway regulators, such as Suppressor of fused (Sufu), Kinesin family member 7 (Kif7), and primary cilium, mediate Hh signaling transduction is not entirely understood. The work presented here examines the roles of Sufu and Kif7 in regulating Hh signaling in growth plate chondrocytes, as well as how they mediate parathyroid hormone-like hormone (Pthlh) signaling during chondrocyte development. I show here that Sufu and Kif7 are essential regulators of Indian hedgehog (Ihh) signaling. While Sufu negatively regulates Gli transcription factors, Kif7 functions both positively and negatively in chondrocytes. Kif7 plays a role in Sufu protein degradation and the exclusion of Sufu-Gli complexes from the primary cilium. Importantly, halving the dosage of Sufu restores normal Hh pathway activity and chondrocyte development in Kif7-null mice, demonstrating that the positive role of Kif7 is to restrict the inhibitory function of Sufu. Furthermore, Kif7 exerts inhibitory function on Gli transcriptional activity in chondrocytes when Sufu function is absent. Therefore, Kif7 regulates the activity of Gli transcription factors through both Sufu-dependent and Sufu-independent mechanisms. I show that Sufu is crucial for mediating the negative effect of Pthlh on Gli transcriptional activity and chondrocyte hypertrophic differentiation, whereas Kif7 and primary cilium are dispensable in this process. Although primary cilium is required for Hh ligand-mediated activation of Gli transcription, Pthlh negatively controls Gli transcriptional activity in a cilia-independent manner. The results of this work provide insight into how Hh signaling is regulated by Sufu and Kif7 in the context of primary cilium, but also suggest Sufu serves as an important link between Ihh and Pthlh signaling during growth plate chondrocyte development.

Wnt signaling is important in human development and disease, thus dysregulated beta-catenin constitutes an attractive target for drug intervention. The few functional inhibitors currently available target transcriptional activation, therefore, identifying novel upstream modulators would be of tremendous importance to elucidating the mechanisms involved in regulatingbeta-catenin activity. To achieve this, I developed a high-throughput screen to assess beta-catenin stability in mammalian cells using a luciferase tagged beta-catenin molecule. This assay was used to screen three chemical libraries to identify small molecule modulators of the pathway. Identified inhibitors/activators of the pathway were investigated via secondary assays. The most promising inhibitor, 21H7, significantly attenuated activated beta-catenin signaling in colon cancer cells, decreasing beta-catenin stability. The inhibitory effects of 21H7 and a structurally similar compound were shown to not only inhibit Wnt target gene expression in colon cancer cells, but also prostate cancer lines. Thus, 21H7 represents an attractive lead compound for further study.

Insulin signaling plays a prominent role in regulation of dauer formation and longevity in Caenorhabditis elegans. Here, I show that insulin signaling also is required in benzaldehyde-starvation associative plasticity, where worms pre-exposed to the odor attractant benzaldehyde in the absence of food subsequently demonstrate a conditioned aversion response towards the odorant. Animals with mutations in ins-1, daf-2, and age-1 which encode the homolog of human insulin, insulin/IGF-1 receptor, and PI-3 kinase, respectively, have significant deficits in benzaldehyde-starvation associative plasticity. Using a conditional allele I show that the behavioral roles of DAF-2 signaling in associative plasticity can be dissociated, with DAF-2 signaling playing a more significant role in the memory retrieval than in memory acquisition. I propose DAF-2 signaling acts as a learning specific starvation signal in the memory acquisition phase of benzaldehyde-starvation associative plasticity but functions to switch benzaldehyde-sensing AWC neurons into an avoidance signaling mode during memory retrieval.

The 5-hydroxytryptamine (5-HT) system modulates numerous physiological and behavioural processes, and dysfunction within this system underlies many behavioural disorders, such as major depression. The 5-HT1A receptor is the primary somatodendritic autoreceptor that controls the firing rate of 5-HT neurons, but is also coupled to numerous signalling pathways. An understanding of 5-HT1A receptor signalling may lead to the development of antidepressant drugs that selectively target therapeutic pathways in treating depression. The 5-HT1A receptor is coupled to inhibitory G-proteins via its intracellular loops 2 and 3. Point mutations within these loops selectively uncouple receptor signalling pathways. In this thesis, I addressed whether mutant receptors’ uncoupling from signalling pathways is associated with alteration in G-protein interaction and coupling. Using bioluminescence resonance energy transfer (BRET) to monitor receptor-G-protein interactions, we show that both wild-type and mutant receptors demonstrate a saturable interaction with Gαi protein in unstimulated conditions. Addition of 5-HT increased the BRET signal for the wild-type 5-HT1A receptor, and this increase was blocked by a 5-HT1A receptor antagonist and G-protein blocker (pertussis toxin). Mutant receptors that were deficient in Gαi signalling, but not those that still signalled to Gαi, failed to respond to receptor activation with increased receptor-Gαi interaction. Pull down studies verified the basal and agonist-induced interaction of 5-HT1A receptors with Gαi proteins. In conclusion, we have shown that the 5-HT1A receptor interacts with Gαi consistent with a pre-coupled model and that 5-HT-induced activation enhances this interaction and requires specific residues in the intracellular loops.

The eukaryotic elongation factor 1 alpha 2 (eEF1A2) is a protein normally expressed only in the brain, heart and skeletal muscle. eEF1A2 is likely to be a breast and ovarian cancer oncogene based on its high expression in these malignancies and its in vitro transforming capacity . The goal of my thesis is to understand eEF1A2’s role in oncogenesis. In order to determine if eEF1A2 was a prognostic marker for ovarian cancer, we examined eEF1A2 expression in 500 primary human ovarian tumours. We show that eEF1A2 is highly expressed in approximately 30% of ovarian tumours. In serous cancer, high expression of eEF1A2 was associated with an increased 20-year survival probability. Expression of eEF1A2, in a clear cell carcinoma cell line, SK-OV-3, increased the cells ability to form spheroids in hanging drop culture, enhanced in vitro proliferative capacity, increased stress fiber formations, and reduced cell-cell junction spacing. Expression of eEF1A2 did not alter sensitivity to anoikis, cisplatin, or taxol. In order to examine the role of eEF1A2 in breast cancer, we used a three-dimensional culture system. The ability to disrupt the in vitro morphogenesis of breast cells cultured on reconstituted basement membranes is a common property of breast oncogenes. I found that phosphatidylinositol 4-kinase (PI4KIIIβ), a lipid kinase that phosphorylates phosphatidylinositol (PI) to PI(4)P, disrupts in vitro mammary acinar formation. The PI4KIIIβ protein localizes to the basal surface of acini created by the human MCF10A cells and ectopic expression of PI4KIIIβ induces multi-acinar formation. Expression of the PI4KIIIβ activator, eEF1A2, also causes a multi-acinar phenotype. Ectopic expression of PI4KIIIβ or eEF1A2 alters PI(4)P and PI(4,5)P2 localization, indicating a role for these lipids in acinar development. Therefore, eEF1A2 is highly expressed in ovarian carcinomas and its expression enhances cell growth in vitro. eEF1A2 expression is likely to be a useful ovarian cancer prognostic factor in ovarian patients with serous tumours. Furthermore, PI4KIIIβ and eEF1A2 both have an important role in the disruption of three-dimensional morphogenesis of MCF10A cells. Additionally, PI4KIIIβ and eEF1A2 likely have an important role in mammary neoplasia and development and could be anti-cancer targets.

Little is known about how the size of a tissue is established during development and maintained subsequently. Proliferation-inhibiting signals secreted by cells within a tissue that act specifically on cells within that tissue can provide negative feedback on cell number, thus regulating tissue size. A better understanding of tissue-specific inhibitors of proliferation could be useful for designing therapies for cancer and other diseases. However, few signals of this sort have been identified, and little is known about how these signals function. Two examples of such signals are the proteins AprA and CfaD, which are secreted by the social amoeba Dictyostelium discoideum and inhibit cell proliferation in a concentration-dependent manner. Cells lacking either AprA or CfaD proliferate rapidly, and adding recombinant AprA or CfaD to cells reduces proliferation. However, little is known about the signal transduction pathways downstream of AprA and CfaD. I identified three proteins that are required for the normal function of AprA and CfaD: the kinase QkgA, the putative transcription factor BzpN, and the putative kinase PakD. Cells lacking any one of these proteins proliferate rapidly, and adding AprA or CfaD to cells lacking these proteins does not cause reduced proliferation, indicating that these proteins are involved in AprA/CfaD signal transduction. I also found that, in addition to its proliferation-inhibiting activity, AprA also functions as an autocrine chemorepellant. Colonies of cells lacking AprA expand less rapidly than wild-type colonies, despite the fact that individual cells lacking AprA show a random motility like that of wild-type cells. Further, two independent assays demonstrate that cells show a biased movement away from a source of AprA. The chemorepellant activity of AprA requires CfaD, QkgA, and PakD, but not BzpN, indicating that AprA affects proliferation and chemorepulsion through distinct but overlapping pathways. These results suggest that AprA functions as a readout of local cell density, to which cells respond by slowing proliferation and chemotaxing to regions of lower cell density, where nutrients are more likely to be present. The study of human AprA, CfaD, QkgA, BzpN, and PakD orthologs may serve to guide therapeutic approaches that modulate chemorepulsive or antiproliferative processes.

Syftet med studien var att undersöka vad känslor spelar för roll för beslutet att donera pengar till välgörande ändamål. Dessutom undersöktes om motivet ”social signaling” (publikt/anonymt) har någon påverkan på beslutet att ge pengar till en välgörenhetsorganisation. I ett experiment fick försökspersoner fatta ekonomiska beslut om donation till Rädda Barnen. Resultaten visade att generellt är människor generösare när de fattade besluten publikt än anonymt. Positiva/negativa känslor styrde hur personer fattar donationsbeslut. Känslor påverkades dock inte av att de fattade beslutet publikt eller anonymt. Överlag kände de sig positivare när de förlorade mindre pengar och välgörenhetsorganisationen fick mer pengar, dock inte när de både förlorade mer och välgörenhetsorganisationen fick mer. Sammantaget visar studien att både känslor och sociala motiv påverkar donationsbeteende.

Interactive multimedia sessions combine requirements of traditional telephony services and Internet applications. This requires call setup, call signaling, negotiation, routing, security, and network resources. Seeking to facilitate the use of quality of service (QoS) mechanisms to users of such applications, this thesis presented new signaling architectures that addressed the interaction of the Session Initiation Protocol (SIP) as the session control signaling protocol and current resource management frameworks. The Differentiated Services (DiffServ) architecture is used as the primary example. The new architectures addressed the roles of SIP agents and proxy servers in subjects such as resource negotiation, call authorization, and end-to-end QoS in heterogeneous networks. First, an architecture based on the use of QoS-enhanced SIP proxies and a SIP-based interface between the application and network layers was developed, implemented in a testbed, and performance enhancements demonstrated. Further studying of the Internet Engineering Task Force (IETF) proposal for the integration of SIP and resource management led to the development of a new signaling scheme, Resource management Overlapped with Answering Delay (ROAD). It explores the SIP user agent interaction with the network in a way that takes advantage of parallel user answering delays and reservation delays. An experimental evaluation of the ROAD scheme showed its call setup delay savings and reduced signaling load. Then, on the interaction of SIP and call admission control, an inter-domain call authorization model that implements the concepts of proxies as gate controllers (QoS-enhanced SIP proxies-GC), and that provides call authorization status and adds more granularity to the authorization process is proposed. This model showed to be scalable in terms of the need to add more resources to compensate for the increasing service load on the servers. Finally, an example framework that applies the new signaling architectures to achieve end-to-end QoS in heterogeneous networks is presented.

Developmental signaling pathways have many diverse roles throughout the life of an organism. The proper regulation of these pathways is essential for normal development, and misregulation can lead to diseases such as cancer. Heparan sulfate proteoglycans function to modulate growth factor signaling in many biological processes by acting as co-receptors, or by influencing ligand distribution. The heparan sulfate proteoglycan Trol, the Drosophila Perlecan homolog, is known to modulate signaling in a population of neuroblasts in the developing Drosophila central nervous system. My studies aim to determine the function Trol has in regulating signaling pathways during development. trol mutants are examined to determine how various mutant alleles impact signaling in several different developmental contexts. The role growth factor pathways play during induction of a Drosophila prostate cancer model is also examined. Gene expression profiles are determined for two types of prostate model overproliferation. Trol is shown to be able to differentially regulate multiple signaling pathways during several developmental processes. The Drosophila prostate cancer model is also shown to have many characteristics similar to those of human prostate cancer, and that signaling and proteoglycan expression are impacted by aberrant overgrowth in the model. My results indicate that Trol is able to specifically modulate different signaling pathways depending on the tissue and developmental context.