Theoretical and empirical aspects of financial market volatility : herding, contagion and intervention

This thesis examines the theoretical and empirical aspects of financial market volatility. Financial markets are essentially volatile. However, excess volatility may impair the smooth functioning of the financial system and economic performance. Volatility that was evident in financial markets during the recent financial crisis, and, even more recently, during the European debt crisis, has attracted renewed interest in studying volatility. The most prominent feature of this crisis was its widespread effects on the financial markets of developed countries, while leaving emerging markets as the success story. The main objectives of this thesis are twofold. The first is to quantify and investigate the nature of the factors behind the transmission of volatility on and among financial markets during the crisis of 2007-2011, with a special focus on developed countries. Both analytical and empirical modeling approaches are used. The analytical approach in Chapter 2 is built up on the herd behavior of international investors, using the role of carry traders' as a conduit. Particular attention is given to modeling the way in which private signals on margin requirements lead some investors to change their decisions, and how their strategic behavior transmits shocks across countries. Chapter 3 adopts an empirical approach using a latent factor methodology, and aims to explore the transmission mechanisms of the crisis through equity and bond markets over different phases of the crisis of 2007-2011. The factor model in particular specifies contagion channels through cross-country and cross-market contagion linkages, after controlling for other forms of fundamentals through the factor structure. The second objective of the thesis is to examine whether and how successfully emerging market central banks attempt to shield their domestic currency market from externally sourced financial market volatility through foreign exchange intervention. Two empirical approaches, the generalized autoregressive heteroskedasticity approach in Chapter 4 and the latent factor approach in Chapter 5, are used to explore the significance and effectiveness of foreign exchange intervention using a unique data set of daily intervention obtained from the Central Bank of Sri Lanka. Overall, this thesis finds strong evidence for the transmission of asset market volatility across developed countries during the crisis of 2007-2011. Through herd behavior and the feedback effects in asset prices and exchange rates, financial markets can be destabilized during crises. Financial market contagion is another significant channel through which the stability in the financial system can be compromised, and several channels of contagion are identified and estimated for different phases of the crisis. However, the relative importance of each contagion channel varies depending on the source asset market and the phase of the crisis. Turning to emerging market responses to periods of global volatility, foreign exchange intervention is found to be an effective policy instrument for shielding against external shocks, as is evident for Sri Lanka. Intervention is aimed to "lean against the wind" to reduce volatility and to accumulate international reserves. The central bank responds to global movements in currency markets when intervening, rather than movements specific to the domestic currency market

Multiseptate Gallbladder in an Asymptomatic Child

A one-year-old child being investigated for urinary tract infection was diagnosed with a multiseptate gallbladder. The patient remains asymptomatic, and investigations demonstrate no associated anomalies. Forty-three cases, including 13 cases in children were identified in the literature. Their presentation and management were reviewed

Gammaretroviruses tether to mitotic chromatin by directly binding nucleosomal histone proteins

The gammaretroviral gag cleavage product, p12, is essential for replication at both early and late stages of the virus life cycle. During the early stage of infection, the viral core is released into the cytoplasm, the viral RNA genome is reversed transcribed to cDNA and this viral DNA is then integrated into the host cell chromatin to form a provirus. The p12 protein has N- and C-terminal domains (NTD and CTD) that are required for steps leading up to integration, but the molecular details of their functions remain poorly characterised. Using the prototypic gammaretrovirus, murine leukemia virus (MLV) as a model, we recently showed that the NTD of p12 directly binds to and stabilises the capsid (CA) lattice of the viral core. Alterations to the CTD of MLV p12 prevented the viral pre-integration complex (PIC) tethering to host chromatin in mitosis, and this could be partially rescued by addition of a heterologous chromatin binding motif. In this study we demonstrated that the CTD of p12 directly binds to nucleosomal histone proteins, targeting not only p12 but also CA to mitotic chromatin. Additionally, cell-cycle-dependent phosphorylation of p12 appeared to increase the affinity of p12 for chromatin in mitosis relative to interphase. Thus, we have revealed how p12 can link the CA-containing PIC to mitotic chromatin, ready for integration. Importantly, we observed that direct binding to nucleosomes is a conserved feature of p12 orthologs across the gammaretrovirus genus and that the nucleosomal docking site is potentially shared with that of spumaretroviral Gag proteins

Human Antibodies that Slow Erythrocyte Invasion Potentiate Malaria-Neutralizing Antibodies.

The Plasmodium falciparum reticulocyte-binding protein homolog 5 (PfRH5) is the leading target for next-generation vaccines against the disease-causing blood-stage of malaria. However, little is known about how human antibodies confer functional immunity against this antigen. We isolated a panel of human monoclonal antibodies (mAbs) against PfRH5 from peripheral blood B cells from vaccinees in the first clinical trial of a PfRH5-based vaccine. We identified a subset of mAbs with neutralizing activity that bind to three distinct sites and another subset of mAbs that are non-functional, or even antagonistic to neutralizing antibodies. We also identify the epitope of a novel group of non-neutralizing antibodies that significantly reduce the speed of red blood cell invasion by the merozoite, thereby potentiating the effect of all neutralizing PfRH5 antibodies as well as synergizing with antibodies targeting other malaria invasion proteins. Our results provide a roadmap for structure-guided vaccine development to maximize antibody efficacy against blood-stage malaria. Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved

Basigin is a druggable target for host-oriented antimalarial interventions

Plasmodium falciparum is the parasite responsible for the most lethal form of malaria, an infectious disease that causes a large proportion of childhood deaths and poses a significant barrier to socioeconomic development in many countries. Although antimalarial drugs exist, the repeated emergence and spread of drug-resistant parasites limit their useful lifespan. An alternative strategy that could limit the evolution of drug-resistant parasites is to target host factors that are essential and universally required for parasite growth. Host-targeted therapeutics have been successfully applied in other infectious diseases but have never been attempted for malaria. Here, we report the development of a recombinant chimeric antibody (Ab-1) against basigin, an erythrocyte receptor necessary for parasite invasion as a putative antimalarial therapeutic. Ab-1 inhibited the PfRH5-basigin interaction and potently blocked erythrocyte invasion by all parasite strains tested. Importantly, Ab-1 rapidly cleared an established P. falciparum blood-stage infection with no overt toxicity in an in vivo infection model. Collectively, our data demonstrate that antibodies or other therapeutics targeting host basigin could be an effective treatment for patients infected with multi-drug resistant P. falciparum.Wellcome Trust (London, England) (Grant 098051)Singapore. National Research Foundation (Singapore-MIT Alliance for Research and Technology

Investigating the function of Fc-specific binding of IgM to Plasmodium falciparum erythrocyte membrane protein 1 mediating erythrocyte rosetting

Acquired protection from Plasmodium falciparum malaria takes years to develop, probably reflecting the ability of the parasites to evade immunity. A recent example of this is the binding of the Fc region of IgM to VAR2CSA-type PfEMP1. This interferes with specific IgG recognition and phagocytosis of opsonized infected erythrocytes (IEs) without compromising the placental IE adhesion mediated by this PfEMP1 type. IgM also binds via Fc to several other PfEMP1 proteins, where it has been proposed to facilitate rosetting (binding of uninfected erythrocytes to a central IE). To further dissect the functional role of Fc -mediated IgM binding to PfEMP1, we studied the PfEMP1 protein HB3VAR06, which mediates rosetting and binds IgM. Binding of IgM to this PfEMP1 involved the Fc domains Cμ3-Cμ4 in IgM and the penultimate DBL domain (DBLζ2) at the C-terminus of HB3VAR06. However, IgM binding did not inhibit specific IgG labelling of HB3VAR06 or shield IgG-opsonized IEs from phagocytosis. Instead, IgM was required for rosetting, and each pentameric IgM molecule could bind two HB3VAR06 molecules. Together, our data indicate that the primary function of Fc -mediated IgM binding in rosetting is not to shield IE from specific IgG recognition and phagocytosis as in VAR2CSA-type PfEMP1. Rather, the function appears to be strengthening of IE-erythrocyte interactions. In conclusion, our study provides new evidence on the molecular details and functional significance of rosetting, a long-recognized marker of parasites that cause severe P. falciparum malaria

Wild bonobos host geographically restricted malaria parasites including a putative new <i>Laverania</i> species

Malaria parasites, though widespread among wild chimpanzees and gorillas, have not been detected in bonobos. Here, we show that wild-living bonobos are endemically Plasmodium infected in the eastern-most part of their range. Testing 1556 faecal samples from 11 field sites, we identify high prevalence Laverania infections in the Tshuapa-Lomami-Lualaba (TL2) area, but not at other locations across the Congo. TL2 bonobos harbour P. gaboni, formerly only found in chimpanzees, as well as a potential new species, Plasmodium lomamiensis sp. nov. Rare co-infections with non-Laverania parasites were also observed. Phylogenetic relationships among Laverania species are consistent with co-divergence with their gorilla, chimpanzee and bonobo hosts, suggesting a timescale for their evolution. The absence of Plasmodium from most field sites could not be explained by parasite seasonality, nor by bonobo population structure, diet or gut microbiota. Thus, the geographic restriction of bonobo Plasmodium reflects still unidentified factors that likely influence parasite transmission

Genomes of cryptic chimpanzee Plasmodium species reveal key evolutionary events leading to human malaria

African apes harbour at least six Plasmodium species of the subgenus Laverania, one of which gave rise to human Plasmodium falciparum. Here we use a selective amplification strategy to sequence the genome of chimpanzee parasites classified as Plasmodium reichenowi and Plasmodium gaboni based on the subgenomic fragments. Genome-wide analyses show that these parasites indeed represent distinct species, with no evidence of cross-species mating. Both P. reichenowi and P. gaboni are 10-fold more diverse than P. falciparum, indicating a very recent origin of the human parasite. We also find a remarkable Laverania-specific expansion of a multigene family involved in erythrocyte remodelling, and show that a short region on chromosome 4, which encodes two essential invasion genes, was horizontally transferred into a recent P. falciparum ancestor. Our results validate the selective amplification strategy for characterizing cryptic pathogen species, and reveal evolutionary events that likely predisposed the precursor of P. falciparum to colonize humans