Host cellular regulatory networks in dengue virus-human interactions

Dengue fever is one of the most important mosquito-borne diseases worldwide and is caused by infection with dengue virus (DENV). The disease is endemic in tropical and sub-tropical regions and has increased remarkably in the last few decades. At present, there is no antiviral or approved vaccine against the virus. Treatment of dengue patients is usually supportive, through oral or intravenous rehydration, or by blood transfusion for more severe dengue cases. Infection of DENV in humans and mosquitoes involves a complex interplay between the virus and host factors. This results in regulation of numerous intracellular processes, such as signal transduction and gene transcription which leads to progression of disease. To understand the mechanisms underlying the disease, the study of virus and host factors is therefore essential and could lead to the identification of human proteins modulating an essential step in the virus life cycle. Knowledge of these human proteins could lead to the discovery of potential new drug targets and disease control strategies in the future. Recent advances of high throughput screening technologies have provided researchers with molecular tools to carry out investigations on a large scale. Several studies have focused on determination of the host factors during DENV infection in human and mosquito cells. For instance, a genome-wide RNA interference (RNAi) screen has identified host factors that potentially play an important role in both DENV and West Nile virus replication (Krishnan et al. 2008). In the present study, a high-throughput yeast two-hybrid screen has been utilised in order to identify human factors interacting with DENV non-structural proteins. From the screen, 94 potential human interactors were identified. These include proteins involved in immune signalling regulation, potassium voltage-gated channels, transcriptional regulators, protein transporters and endoplasmic reticulum-associated proteins. Validation of fifteen of these human interactions revealed twelve of them strongly interacted with DENV proteins. Two proteins of particular interest were selected for further investigations of functional biological systems at the molecular level. These proteins, including a nuclear-associated protein BANP and a voltage-gated potassium channel Kv1.3, both have been identified through interaction with the DENV NS2A. BANP is known to be involved in NF-kB immune signalling pathway, whereas, Kv1.3 is known to play an important role in regulating passive flow of potassium ions upon changes in the cell transmembrane potential. This study also initiated a construction of an Aedes aegypti cDNA library for use with DENV proteins in Y2H screen. However, several issues were encountered during the study which made the library unsuitable for protein interaction analysis. In parallel, innate immune signalling was also optimised for downstream analysis. Overall, the work presented in this thesis, in particular the Y2H screen provides a number of human factors potentially targeted by DENV during infection. Nonetheless, more work is required to be done in order to validate these proteins and determine their functional properties, as well as testing them with infectious DENV to establish a biological significance. In the long term, data from this study will be useful for investigating potential human factors for development of antiviral strategies against dengue.

Management accounting and supply chains: actions, concerns, and networks

What does this thesis do? This thesis uses Actor-Network Theory (ANT) to examine how a UK retailer’s organization and strategy, and, in turn, its form of management accounting was shaped by its supply chain. The thesis does this by reporting on four related themes in the form of four inter-connected essays. The first essay undertakes a state-of-the-art review of the literature. It examines how accounting issues within supply chains permeate ‘matters of concern’. In accordance with this idea of ANT, the essay illustrates how issues emerged, controversies developed, and matters evolved through an actor-network of accounting researchers within the supply chain domain. This leads on to the second essay, which exemplifies the nature of the UK’s retailing industry within which the supply chain case organization emerged and developed. The purposes of the essay are twofold: to introduce the contextual ramifications of the case organization; and to illustrate the emergence of a new market logic, which led to the creation of a global supply chain and a new form of management accounting therein. The third essay reports on a qualitative case study. It analyses the dualistic relation between ostensive and performative aspects of supply chain strategy, reveals how accounting numbers act as an obligatory passage point within this dualism, and makes a contribution to the ANT debate around the issue of whether and how a dualism between ostensive and performative aspects exists. The final essay reports on another case analysis of institutionalizing a heterarchical form of management accounting: a distributed form of intelligence that penetrates through lateral accountable relations. The analysis reveals a new form of management accounting characterised by ambiguity; it emphasizes the possibilities of compromises and negotiations, and it thus contributes to knowledge by combining an aspect of ANT with heterarchical tendencies in the world of contemporary organizations. Finally, the thesis concludes that it is the supply chain that organises today’s neoliberal capitalism; and it is management accounting that unites both human and non-human actors within such supply chains, despite that form of management accounting being ambiguous. The thesis comprises the introduction, these four essays, and the conclusion.