Econometric models in foreign exchange market

According to the significance of the econometric models in foreign exchange market, the purpose of this research is to give a closer examination on some important issues in this area. The research covers exchange rate pass-through into import prices, liquidity risk and expected returns in the currency market, and the common risk factors in currency markets. Firstly, with the significant of the exchange rate pass-through in financial economics, the first empirical chapter studies on the degree of exchange rate pass-through into import in emerging economies and developed countries in panel evidences for comparison covering the time period of 1970-2009. The pooled mean group estimation (PMGE) is used for the estimation to investigate the short run coefficients and error variance. In general, the results present that the import prices are affected positively, though incompletely, by the exchange rate. Secondly, the following study addresses the question whether there is a relationship between cross-sectional differences in foreign exchange returns and the sensitivities of the returns to fluctuations in liquidity, known as liquidity beta, by using a unique dataset of weekly order flow. Finally, the last study is in keeping with the study of Lustig, Roussanov and Verdelhan (2011), which shows that the large co-movement among exchange rates of different currencies can explain a risk-based view of exchange rate determination. The exploration on identifying a slope factor in exchange rate changes is brought up. The study initially constructs monthly portfolios of currencies, which are sorted on the basis of their forward discounts. The lowest interest rate currencies are contained in the first portfolio and the highest interest rate currencies are in the last. The results performs that portfolios with higher forward discounts incline to contain higher real interest rates in overall by considering the first portfolio and the last portfolio though the fluctuation occurs.

The role of miRNAs in stroke

Stroke is currently one of the leading causes of death and disability worldwide. Despite recent advances in the treatment of stroke there is a major unmet clinical need for novel therapeutics for intervention. miRNAs are small coding RNAs which act to post-transcriptionally inhibit expression of genes. Emerging evidence has supported the view that miRNAs play an important role in the development and progression of ischaemic stroke, although understanding remains relatively poor. This research uses several models to investigate the effects of miRNAs in the context of stroke in vivo and in vitro, as well as assessment of patient serum samples in order to identify biomarkers for stroke. miR-29b was found to be significantly upregulated in SHRSP rat brain peri-infarct at 72h following stroke, and downregulated in ischaemic core at 24h and 72h following stroke, whilst miR-29c was significantly downregulated in remainder tissue at 24h following stroke and in infarct at 72h following stroke. The upreglation of miR-29b at 72h corresponded to a significant downregulation of miR-29 target genes MMP2, MMP9 and TGF-β1 in peri-infarct tissue at 72h following stroke. Modulation of miR-29b and miR-29c was achieved in a rat neuronal cell line but suppression of genes of interest was not observed following oxygen glucose deprivation. Several candidate miRNAs were then identified by microRNA Openarray analysis in stroke patient serum samples. Validation of these miRNAs was not demonstrated in the population studied, but assessment of these miRNAs in rat serum and isolated exosomes demonstrated that several of these miRNAs were significantly altered in SHRSP rats following stroke. Finally miR-21 was demonstrated to be significantly upregulated in SHRSP rat peri-infarct following stroke. This was associated with a change in miR-21 localization as determined by in situ hybridization. Modulation of miR-21 via the use of CAG-miR-21 mice demonstrated no difference in infarct size as measured by T2 -weighted MRI scan nor was any difference present in behavioural tests versus wild type. KO of miR-21 resulted in a reduction of survival rate compared with wild type. This thesis demonstrates that miR-29 and miR-21 are modulated following stroke in animal models, and these are potential candidates for therapeutic intervention in the future. Analysis of clinical samples has illustrated difficulties in the identification of serum miRNA profiles and suggests that looking at the exosomal component of serum may provide better information regarding miRNA profiles after stroke.

Using induced pluripotent stem cells (IPSCS) as a replacement for in vivo models to screen novel therapies in chronic myeloid leukaemia (CML)

Tyrpsine kinase inhibitors (TKIs) effectively target progenitors and mature leukaemic cells but prove less effective at eliminating leukaemic stem cells (LSCs) in patients with chronic myeloid leukaemia (CML). Several reports indicate that the TGFβ superfamily pathway is important for LSC survival and quiescence. We conducted extensive microarray analyses to compare expression patterns in normal haemopoietic stem cells (HSC) and progenitors with CML LSC and progenitor populations in chronic phase (CP), accelerated phase (AP) and blast crisis (BC) CML. The BMP/SMAD pathway and downstream signalling molecules were identified as significantly deregulated in all three phases of CML. The changes observed could potentiate altered autocrine signalling, as BMP2, BMP4 (p<0.05), and ACTIVIN A (p<0.001) were all down regulated, whereas BMP7, BMP10 and TGFβ (p<0.05) were up regulated in CP. This was accompanied by up regulation of BMPRI (p<0.05) and downstream SMADs (p<0.005). Interestingly, as CML progressed, the profile altered, with BC patients showing significant over-expression of ACTIVIN A and its receptor ACVR1C. To further characterise the BMP pathway and identify potential candidate biomarkers within a larger cohort, expression analysis of 42 genes in 60 newly diagnosed CP CML patient samples, enrolled on a phase III clinical trial (www.spirit-cml.org) with greater than 12 months follow-up data on their response to TKI was performed. Analysis revealed that the pathway was highly deregulated, with no clear distinction when patients were stratified into good, intermediate and poor response to treatment. One of the major issues in developing new treatments to target LSCs is the ability to test small molecule inhibitors effectively as it is difficult to obtain sufficient LSCs from primary patient material. Using reprogramming technologies, we generated induced pluripotent stem cells (iPSCs) from CP CML patients and normal donors. CML- and normal-derived iPSCs were differentiated along the mesodermal axis to generate haemopoietic and endothelial precursors (haemangioblasts). IPSC-derived haemangioblasts exhibited sensitivity to TKI treatment with increased apoptosis and reduction in the phosphorylation of downstream target proteins. 4 Dual inhibition studies were performed using BMP pathway inhibitors in combination with TKI on CML cell lines, primary cells and patient derived iPSCs. Results indicate that they act synergistically to target CML cells both in the presence and absence of BMP4 ligand. Inhibition resulted in decreased proliferation, irreversible cell cycle arrest, increased apoptosis, reduced haemopoietic colony formation, altered gene expression pattern, reduction in self-renewal and a significant reduction in the phosphorylation of downstream target proteins. These changes offer a therapeutic window in CML, with intervention using BMP inhibitors in combination with TKI having the potential to prevent LSC self-renewal and improve outcome for patients. By successfully developing and validating iPSCs for CML drug screening we hope to substantially reduce the reliance on animal models for early preclinical drug screening in leukaemia.