Testing for Speculative Bubbles in Foreign Exchange Markets

Foreign currency speculation has always been a well publicized topic that has captured the attention of people who have not formally studied economics. It is also a topic that has captured the attention of researchers in International Finance because speculative bubbles have often been considered as a possible explanation for the excess volatility of exchange rates. An examination of past studies reveals that different methods have been used by researchers to test for the existence of speculative bubbles in major currencies over the period from 1970-1984. In this paper, I will apply three methods which have been used in the past to reach conclusions about the existence of speculative bubbles in the U.S Dollar/German Mark and the U.S Dollar/Japanese Yen exchange rate over the period from 1982-1992 and the U.S Dollar/British Pound exchange rate from 1987-1992. One objective of this paper is to update previous studies by expanding their scope into the most recent decade. The other objective is to use several testing methods for each currency in order to gain an insight into both the robustness of the conclusions and the dependency of the conclusions on a particular method of testing

Testing for Speculative Bubbles in Foreign Exchange Markets

Foreign currency speculation has always been a well publicized topic that has captured the attention of people who have not formally studied economics. It is also a topic that has captured the attention of researchers in International Finance because speculative bubbles have often been considered as a possible explanation for the excess volatility of exchange rates. An examination of past studies reveals that different methods have been used by researchers to test for the existence of speculative bubbles in major currencies over the period from 1970-1984. In this paper, I will apply three methods which have been used in the past to reach conclusions about the existence of speculative bubbles in the U.S Dollar/German Mark and the U.S Dollar/Japanese Yen exchange rate over the period from 1982-1992 and the U.S Dollar/British Pound exchange rate from 1987-1992. One objective of this paper is to update previous studies by expanding their scope into the most recent decade. The other objective is to use several testing methods for each currency in order to gain an insight into both the robustness of the conclusions and the dependency of the conclusions on a particular method of testing

Terrorism From Within: An Economic Model of Terrorism

In this paper, we develop and explore the implications of an economic model that links the incidence of terrorism in a country to the economic circumstances facing that country. We briefly sketch out a theory, in the spirit of Tornell (1998), that describes terrorist activities as being initiated by groups that are unhappy with the current economic status quo, yet unable to bring about drastic political and institutional changes that can improve their situation. Such groups with limited access to opportunity may find it rational to engage in terrorist activities. The result is then a pattern of reduced economic activity and increased terrorism. In contrast, an alternative environment can emerge where access to economic resources is more abundant and terrorism is reduced. Our empirical results are consistent with the theory. We find that for democratic, high income countries, economic contractions (i.e. recessions) can provide the spark for increased probabilities of terrorist activities.Growth; Terrorism; Political Economy

Investigating asparagine-linked protein glycosylation in eukaryotic and prokaryotic systems

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2006.Vita.Includes bibliographical references.N-linked protein glycosylation is characterized by the formation of a -glycosylamine linkage to an asparagine residue within the Asn-Xaa-Ser/Thr consensus sequence. This modification is found in organisms from eukaryotic, archaeal and bacterial domains and is implicated in numerous cellular processes. Recently, a system of N-linked glycosylation was characterized in a gram-negative bacterium, Campylobacter jejuni. Glycosylation in this organism involves the transfer of a heptasaccharide from an undecaprenyl-pyrophosphate (Und-PP) carrier onto the asparagine side-chain of a protein. The genes in the 'pgl gene cluster' encode all of the proteins necessary for the biosynthesis of the glycan donor and its ultimate transfer to protein. The heptasaccharide donor has been characterized as GalNAc-al,4- GalNAc-al,4-(Glcpl1,3)-GalNAc-al,4-GalNAc-al,4-GalNAc-al,3-Bac-al ,PP-Und, where Bac is bacillosamine (2,4-diacetamido-2,4,6-trideoxyglucose). A synthetic route was developed to access bacillosamine-phosphate, which was incorporated into UDP-bacillosamine (UDP-Bac) and undecaprenyl-pyrophosphate-bacillosamine (Und-PP-Bac), which are substrates for the Pgl enzymes. Using the synthetic UDP-Bac, the role of the PglC glycophosphoryltransferase was elucidated in vitro.(cont.) The activities of the Pgl glycosyltransferases, PglA, PglJ, PglH and PglI were validated using the synthetic Und-PP-Bac substrate and it was discovered that PglH is a polymerase that catalyzes the transfer of the three terminal GalNAc residues. PglB is the oligosaccharyl transferase of the bacterial system. Using the synthetic glycan donor, PglB was shown to act in vitro on a short peptide substrate. This in vitro system enables detailed mechanistic investigations into the action of this intriguing enzyme. N-linked glycosylation in eukaryotes is catalyzed by oligosaccharyl transferase (OT), a multimeric protein complex localized in the lumen of the endoplasmic reticulum. The Stt3p protein of the eukaryotic OT cluster is homologous to the bacterial PglB enzyme. With the goal of inhibiting OT in a cellular environment, a family of peptidomimetic inhibitors with nanomolar affinity was synthesized. These inhibitors were evaluated for cellular inhibition of OT using a novel, high-throughput assay that monitors the production of a reporter glycoprotein, secreted alkaline phosphatase. The results from the screening yielded a hydrophobic peptidomimetic compound as a potential candidate for further studies into the in vivo inhibition of OT.by Eranthie Weerapana.Ph.D

Development of a Suicide Inhibition-Based Protein Labeling Strategy for Nicotinamide N-Methyltransferase

Nicotinamide N-methyltransferase (NNMT) catalyzes the S-adenosyl-l-methionine-dependent methylation of nicotinamide to form N-methylnicotinamide. This enzyme detoxifies xenobiotics and regulates NAD+ biosynthesis. Additionally, NNMT is overexpressed in various cancers. Herein, we describe the first NNMT-targeted suicide substrates. These compounds, which include 4-chloropyridine and 4-chloronicotinamide, exploit the broad substrate scope of NNMT; methylation of the pyridine nitrogen enhances the electrophilicity of the C4 position, thereby promoting an aromatic nucleophilic substitution by C159, a noncatalytic cysteine. On the basis of this activity, we developed a suicide inhibition-based protein labeling strategy using an alkyne-substituted 4-chloropyridine that selectively labels NNMT in vitro and in cells. In total, this study describes the first NNMT-directed activity-based probes

Citrullination Inactivates Nicotinamide-N-methyltransferase

Nicotinamide-N-methyl transferase (NNMT) catalyzes the irreversible methylation of nicotinamide (NAM) to form N-methyl nicotinamide (MeNAM) using SAM as a methyl donor. NNMT is implicated in several chronic disease conditions, including cancers, kidney disease, cardiovascular disease, and Parkinson\u27s disease. Although phosphorylation of NNMT in gastric tumors is reported, the functional effects of this post-translational modification has not been investigated. We previously reported that citrullination of NNMT by Protein Arginine Deiminases (PADs) abolished its methyltransferase activity. Herein, we investigate the mechanism of inactivation. Using tandem MS, we identified three sites of citrullination in NNMT. With this information in hand, we used a combination of site-directed mutagenesis, kinetics, and CD experiments to demonstrate that citrullination of R132 leads to a structural perturbation that ultimately promotes NNMT inactivation

Halogen Bonding Increases the Potency and Isozyme-selectivity of Protein Arginine Deiminase 1 Inhibitors

Protein Arginine Deiminases (PADs) hydrolyze the side chain of arginine to form citrulline. Aberrant PAD activity is associated with rheumatoid arthritis, multiple sclerosis, lupus, and certain cancers. These pathologies established the PADs as therapeutic targets and multiple PAD inhibitors are known. Herein, we describe the first highly potent PAD1-selective inhibitors (1 and 19). Detailed structure-activity relationships indicate that their potency and selectivity is due to the formation of a halogen bond with PAD1. Importantly, these inhibitors inhibit histone H3 citrullination in HEK293TPAD1 cells and mouse zygotes with excellent potency. Based on this scaffold, we also developed a PAD1-selective activity-based probe that shows remarkable cellular efficacy and proteome selectivity. Based on their potency and selectivity we expect that 1 and 19 will be widely used chemical tools to understand PAD1 biology

Calcium Regulates the Nuclear Localization of Protein Arginine Deiminase 2

Protein arginine deiminases (PADs) are calcium-dependent enzymes that mediate the post-translational conversion of arginine into citrulline. Dysregulated PAD activity is associated with numerous autoimmune disorders and cancers. In breast cancer, PAD2 citrullinates histone H3R26 and activates the transcription of estrogen receptor target genes. However, PAD2 lacks a canonical nuclear localization sequence, and it is unclear how this enzyme is transported into the nucleus. Here, we show for the first time that PAD2 translocates into the nucleus in response to calcium signaling. Using BioID2, a proximity-dependent biotinylation method for identifying interacting proteins, we found that PAD2 preferentially associates with ANXA5 in the cytoplasm. Binding of calcium to PAD2 weakens this cytoplasmic interaction, which generates a pool of calcium-bound PAD2 that can interact with Ran. We hypothesize that this latter interaction promotes the translocation of PAD2 into the nucleus. These findings highlight a critical role for ANXA5 in regulating PAD2 and identify an unusual mechanism whereby proteins translocate between the cytosol and nucleus

The Development of Benzimidazole-Based Clickable Probes for the Efficient Labeling of Cellular Protein Arginine Deiminases (PADs)

Citrullination is the post-translational hydrolysis of peptidyl-arginines to form peptidyl-citrulline, a reaction that is catalyzed by the protein arginine deiminases (PADs), a family of calcium-regulated enzymes. Aberrantly increased protein citrullination is associated with a slew of autoimmune diseases (e.g., rheumatoid arthritis (RA), multiple sclerosis, lupus, and ulcerative colitis) and certain cancers. Given the clear link between increased PAD activity and human disease, the PADs are therapeutically relevant targets. Herein, we report the development of next generation cell permeable and clickable probes (BB-Cl-Yne and BB-F-Yne) for covalent labeling of the PADs both in vitro and in cell-based systems. Using advanced chemoproteomic technologies, we also report the off targets of both BB-Cl-Yne and BB-F-Yne. The probes are highly specific for the PADs, with relatively few off targets, especially BB-F-Yne, suggesting the preferential use of the fluoroacetamidine warhead in next generation irreversible PAD inhibitors. Notably, these compounds can be used in a variety of modalities, including the identification of off targets of the parent compounds and as activity-based protein profiling probes in target engagement assays to demonstrate the efficacy of PAD inhibitors