研究背景： / 肝癌是全球常見的惡性腫瘤之一，世界上每年大約有50萬死亡病例，並且呈逐年上升之勢， 是全球第3位的腫瘤死亡原因。慢性乙型和丙型肝炎病毒感染是肝癌的主要成因。肝癌惡性程度高、預後差，並且目前的治療手段非常有限，術後易復發和轉移，迄今尚無正式獲准有效治療藥物。現階段，治療肝癌的主要方法是手術切除，但是隨之引起的併發症以及較高的復發機率嚴重影響了治療的療效，大大降低肝癌病人的存活期。 / 研究目的： / 分析TDP對肝癌細胞和肝腫瘤旁細胞生長的影響；分析TDP抑癌的分子靶標蛋白及其分子機理；驗證TDP對肝癌動物模型的抑制效果。開發一種新型有效的肝癌治療藥物。 / 研究方法： / 首先用MTT法從102種來源於嶺南山竹子的純複合物中分離出了TDP,它是一種甾醇類化合物。採用MTT法檢測TDP對腫瘤細胞生長的影響；流式細胞實驗驗證TDP能否引起腫瘤細胞的凋亡；採用蛋白組學和質譜分析找出TDP抑癌的分子靶標；進一步的蛋白功能增加和缺失實驗證明Hsp27的功能和作用；生物資訊學驗證HSP27和TDP的作用結果；最後利用動物模型驗證TDP對肝腫瘤的治療效果。 / 結果： / TDP不但能效率極高的抑制肝癌細胞的生長而且可以大量誘發肝癌細胞的凋亡，而對正常的肝癌旁細胞沒有影響。二維電泳以及質譜分析TDP處理的肝癌細胞對比DMSO處理的肝癌細胞發現了具有不同表達水準的18種蛋白，Hsp27是其中一個在TDP誘導下調變化倍數較大並且與細胞凋亡有密切關係的蛋白，Hsp27的過表達以及Knock-down都充分驗證了TDP通過調節Hsp27的表達參與了依賴於caspase的線粒體凋亡途徑，在Western Blotting以及RT-PCR中得到了充分的驗證。生物資訊學預測TDP可以與Hsp27結合，實驗結果表明TDP可以誘導Hsp27的聚集並導致功能喪失。動物實驗腫瘤生長結果以及免疫組化結果證明，TDP可以在很大程度上對肝癌有抑製作用。 / 結論： / 本研究首次表明，TDP如果不是完全的,最起碼也是部分通過誘導依賴於caspase的線粒體凋亡的途徑來抑制肝癌細胞的增值和分化, 具有明顯的抗腫瘤的功效，特別是對Hsp27高表達的腫瘤細胞有比較明顯的作用，是一種值得繼續深入研究的有較高潛在價值的藥物。 / Background： / Hepatocellular carcinoma (HCC), the most common primary hepatic malignancy, is a global public health problem that accounts for approximately 500,000 deaths annually. Chronic hepatitis B and hepatitis C infections are the major risk factors for the development of HCC. Due to the high rate of these infections, the incidence of HCC remains alarmingly high globally. Although great advances have been made in HCC treatment, poor prognosis and high risk of recurrence have been major challenges to patients. Currently, surgical resection is the main treatment option for HCC patients; however, complications arising from surgery can threaten its therapeutic effect and patients’ survival. / Objectives： / To characterize the functions of 1,3,5-trihydroxy-13,13-dimethyl-2H-pyran [7,6-b]Xanthone (TDP) in cell proliferation of HepG2 cells; to discover the molecular target genes and elucidate the underlying molecular mechanism of TDP; to examine the in vivo function of TDP in a nude mouse tumor model of HCC. Finally, to investigate TDP’s potential as an anti-HCC drug candidate. / Methods and Results： / In this study, we discovered that TDP, isolated from the Chinese medicinal herb, Garcinia oblongifolia, strongly inhibited cell growth and induced caspase-dependent mitochondrial apoptosis in HCC, as evidenced from MTT assay and flow cytometry analysis. Two-dimensional gel electrophoresis and mass spectrometry-based comparative proteomics were applied to find the molecular targets of TDP in HCC cells, and eighteen proteins were identified with altered expression, with Hsp27 protein being one of the proteins most significantly down-regulated by TDP. Further Hsp27-siRNA knockdown and Lenti-Hsp27 overexpression studies found that Hsp27 was involved in TDP induced mitochondrial apoptosis, with bioinformatics predictions and biological results revealing that TDP might cause Hsp27 protein form dimer and consequent degradation via the ubiquitin-proteasome system. Finally, subcutaneously injecting cancer cells with Hsp27 expression vector into the dorsal flank of nude mice tumor model also demonstrated the suppressive effect of TDP on HCC. / Conclusions： / In summary, our study discovered that TDP, a natural xanthone, was a potent inhibitor of Hsp27 in HCC. TDP inhibited cell growth and induced apoptosis by inducing Hsp27 degradation, which stimulated mitochondrial cytochrome C release which resultantly activated caspase-3 and caspase-9. These data combined with the results of the animal model strongly supported TDP’s potential as a novel anti-cancer drug candidate, especially for cancers with an abnormally high expression of Hsp27. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Fu, Weiming. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2012. / Includes bibliographical references (leaves 111-151). / Abstract also in Chinese. / Abstract (English) --- p.i / Abstract (Chinese) --- p.iiv / Acknowledgment --- p.vi / Publications --- p.viii / List of Contents --- p.ix / List of Tables --- p.xii / List of Figures --- p.xiii / List of Abbreviations --- p.xv / Chapter Chapter 1 --- Introduction --- p.1 / Chapter 1.1 --- General Introduction --- p.1 / Chapter 1.1.1 --- Overview of HCC --- p.1 / Chapter 1.1.2 --- Epidemiology of HCC in China and Hong Kong --- p.3 / Chapter 1.2 --- Etiology of HCC --- p.7 / Chapter 1.2.1 --- Cirrhosis --- p.8 / Chapter 1.2.2 --- HBV infection --- p.9 / Chapter 1.2.3 --- HCV infection --- p.10 / Chapter 1.2.4 --- Viral Co-Infection --- p.11 / Chapter 1.2.5 --- Fatty Liver Disease and Cryptogenic Cirrhosis --- p.12 / Chapter 1.2.6 --- Alcohol --- p.13 / Chapter 1.2.7 --- Iron --- p.13 / Chapter 1.2.8 --- Aflatoxin --- p.14 / Chapter 1.2.9 --- Others --- p.14 / Chapter 1.3 --- Diagnosis of HCC --- p.14 / Chapter 1.4 --- Prognosis of HCC --- p.17 / Chapter 1.5 --- Treatment of HCC --- p.19 / Chapter 1.5.1. --- Early stage --- p.19 / Chapter 1.5.2. --- Intermediate and advanced stage --- p.24 / Chapter 1.5.3. --- Terminal stage --- p.28 / Chapter 1.6 --- Signaling pathways in HCC --- p.28 / Chapter 1.6.1 --- Proliferation signaling pathways --- p.29 / Chapter 1.6.2 --- Signaling pathways frequently dysregulated in HCC --- p.30 / Chapter 1.6.3 --- Pathways involved in liver development and cell differentiation --- p.34 / Chapter 1.6.4 --- Inflammation pathways involved in hepatocarcinogenesis --- p.35 / Chapter 1.6.5 --- Pathways involved in neoangiogenesis --- p.37 / Chapter 1.6.6 --- The P53 tumor suppressor --- p.38 / Chapter 1.6.7 --- Heat shock proteins in HCC --- p.39 / Chapter 1.7 --- The roles of microRNAs in liver cancer progression --- p.42 / Chapter 1.8 --- TCM in the treatment of HCC --- p.45 / Chapter 1.8.1 --- Introduction --- p.45 / Chapter 1.8.2 --- Garcinia --- p.49 / Chapter 1.9 --- Objectives of the study --- p.51 / Chapter Chapter 2 --- Materials and Methods --- p.52 / Chapter 2.1 --- Preparation of the pure compounds --- p.52 / Chapter 2.2 --- Liver cell lines and tissue culture --- p.52 / Chapter 2.3 --- Human tissue samples --- p.52 / Chapter 2.4 --- Cell viability assessment with MTT assay --- p.53 / Chapter 2.5 --- Apoptosis analysis --- p.53 / Chapter 2.6 --- Two-dimensional electrophoresis (2-DE), protein visualization and image analysis --- p.54 / Chapter 2.6.1 --- Materials --- p.54 / Chapter 2.6.2 --- Protein extraction --- p.54 / Chapter 2.6.3. --- 2-DE protein profiling --- p.55 / Chapter 2.6.4. --- Gel staining and image analysis --- p.55 / Chapter 2.6.5. --- In-gel protein digestion with trypsin --- p.56 / Chapter 2.6.6. --- MALDI-TOF mass spectrometric analysis --- p.56 / Chapter 2.6.7. --- Database search --- p.57 / Chapter 2.7.1 --- Sample preparation --- p.58 / Chapter 2.7.2 --- SDS-PAGE --- p.58 / Chapter 2.7.3 --- Protein transfer --- p.58 / Chapter 2.7.4 --- Blocking --- p.59 / Chapter 2.7.5 --- Incubation with primary and secondary antibodies --- p.59 / Chapter 2.7.6 --- Proteins Visualization --- p.59 / Chapter 2.8 --- Real-time PCR --- p.60 / Chapter 2.9 --- Vector construction and lentivirus production --- p.61 / Chapter 2.9.1 --- Lenti-vector construction for Hsp27 expression --- p.61 / Chapter 2.9.2 --- Lentivirus production --- p.62 / Chapter 2.9.3 --- Lentivirus infection --- p.63 / Chapter 2.10 --- SiRNAs transfection. --- p.63 / Chapter 2.11 --- Identification of potential protein targets for TDP --- p.64 / Chapter 2.12 --- In Vivo Tumorigenesis --- p.64 / Chapter 2.13 --- Assay of chaperone activity of Hsp27 using lysozyme as substrate --- p.65 / Chapter 2.14 --- Mitochondria and cytosolic proteins preparation --- p.66 / Chapter 2.15 --- Immunohistochemistry (IHC) --- p.67 / Chapter 2.15.1 --- Preparation of paraffin tissue sections --- p.67 / Chapter 2.15.2 --- Immunostaining --- p.67 / Chapter 2.16 --- Methodology of this study --- p.68 / Chapter 2.17 --- Statistical analysis --- p.68 / Chapter CHAPTER 3 --- Results --- p.69 / Chapter 3.1 --- Introduction --- p.69 / Chapter 3.2 --- TDP significantly suppressed cell growth and induced apoptosis in HCC cells. --- p.69 / Chapter 3.2.1 --- TDP was identified from 102 pure compounds by using MTT assay --- p.69 / Chapter 3.2.2 --- TDP significantly suppressed HCC cell growth --- p.73 / Chapter 3.2.3 --- TDP induced the apoptosis of HCC cells --- p.74 / Chapter 3.3 --- Study of the molecular mechanism of TDP on HCC --- p.76 / Chapter 3.3.1 --- The comparative proteomic profiling --- p.76 / Chapter 3.3.2 --- Hsp27 was one of the molecular targets of TDP in HepG2 cells. --- p.80 / Chapter 3.3.3 --- TDP induced apoptosis through the caspase-dependent mitochondrial pathway. --- p.82 / Chapter 3.3.4 --- Hsp27 involved in the mitochondrial apoptosis induced by TDP --- p.84 / Chapter 3.3.5 --- Enforced Hsp27 overexpression rescued the mitochondrial apoptosis induced by TDP in HepG2 cells --- p.87 / Chapter 3.3.6 --- The possible regulatory signaling by TDP --- p.91 / Chapter 3.4 --- TDP directly targeted Hsp27 and destroyed its chaperone action --- p.92 / Chapter 3.5 --- Degradation of Hsp27 aggregation stimulated by TDP was mediated by ubiquitin-proteasome system (UPS) pathway --- p.96 / Chapter 3.6 --- Nude mice model demonstrated the suppressive effect of TDP on HCC --- p.97 / Chapter Chapter 4 --- Discussion and Conclusions --- p.100 / Chapter 4.1 --- Discussion --- p.100 / Chapter 4.2 --- Conclusion --- p.110 / Reference --- p.111

by Lo Ka-Man. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1997. / Includes bibliographical references (leaves 175-197). / Chapter I --- Title page --- p.i / Chapter II --- Thesis committee --- p.ii / Chapter II --- Acknowledgment --- p.iii-iv / Chapter III --- Abstract --- p.v-vi / Chapter IV --- Table of content --- p.vii-xiv / Chapter V --- List of figures --- p.xv-xviii / Chapter VI --- List of tables --- p.xix-xx / Forewords: / Overall objectives --- p.1 / Introduction on the fish used in this research study --- p.2 / Chapter Chapter 1: --- Literature Review on Biomarkers of Stress in Teleosts --- p.5 / Chapter 1.1 --- Definition of stress --- p.7 / Chapter 1.2 --- Classification of stress indicators --- p.8 / Chapter 1.2.1 --- Primary stress indicators --- p.8 / Chapter 1.2.1.1 --- Molecular stress indicators --- p.8 / Chapter 1.2.1.2 --- Hormonal stress indicators --- p.9 / Chapter (I) --- Corticosteroid --- p.9 / Chapter (II) --- Catecholamines --- p.11 / Chapter 1.2.2 --- Secondary stress indicators --- p.12 / Chapter 1.2.2.1 --- Metabolic changes --- p.12 / Chapter (I) --- Glucose metabolism --- p.13 / Chapter (II) --- Lactic acid --- p.14 / Chapter 1.2.2.2 --- Osmoregulatory changes --- p.15 / Chapter 1.2.2.3 --- Haematological changes --- p.16 / Chapter 1.2.2.4 --- Reproductive changes --- p.17 / Chapter 1.2.3 --- Tertiary stress indicators --- p.18 / Chapter 1.2.3.1 --- Histopathological indicators --- p.18 / Chapter 1.2.3.2 --- Ecological indicators --- p.19 / Chapter 1.3 --- Recent trends on the study of biomarkers --- p.20 / Chapter 1.3.1 --- Use of detoxification enzymes for specific indication of toxic pollutants in aquatic environment --- p.20 / Chapter 1.3.1.1 --- Metallothioneins (MTs) --- p.20 / Chapter 1.3.1.2 --- Cytochrome P450 monoxygenase (CYP450) --- p.21 / Chapter 1.3.2 --- Use of HSP 70 as a biomarker in teleost --- p.22 / Chapter 1.4 --- Future perspectives on the study of biomarkers in fish --- p.24 / Chapter Chapter 2: --- Literature Review on Heat Shock Proteins (HSPs) --- p.28 / Chapter 2.1 --- General Characteristics of HSPs --- p.29 / Chapter 2.1.1 --- HSP90 family --- p.30 / Chapter 2.1.2 --- HSP70 family --- p.31 / Chapter 2.1.3 --- HSP60 family (Chaperonin-60) --- p.32 / Chapter 2.1.4 --- Low-molecular weight HSPs (HSP20) --- p.33 / Chapter 2.2 --- Structure of HSP70 encoding gene --- p.33 / Chapter 2.2.1 --- General characteristics of HSP70-encoding gene --- p.33 / Chapter 2.2.2 --- Heat shock transcription factor (HSF) --- p.35 / Chapter 2.2.3 --- Heat shock elements (HSE) --- p.35 / Chapter 2.3 --- Stress-mediated control of HSP70 transcription --- p.36 / Chapter 2.4 --- Characterization of HSP70 expression in teleost --- p.38 / Chapter 2.4.1 --- Tissues-specific expression of HSP70 in teleost --- p.39 / Chapter 2.4.2 --- Inter-relationship of HSP70 expression with seasonal variation and thermotolerance of teleost --- p.40 / Chapter 2.4.3 --- Induction of HSP70 in teleost upon acute thermal stress --- p.41 / Chapter 2.4.4 --- Induction of HSP70 in teleost by non-thermal stressors --- p.43 / Chapter 2.4.4.1 --- Heavy metal-induced HSP70 expression --- p.43 / Chapter 2.4.4.2 --- Handling stress-induced HSP70 expression --- p.43 / Chapter Chapter 3: --- "Induction of HSP70 in blood cells of seabream, Sparus sarba subjected to in vivo and in vitro thermal stress" --- p.48 / Chapter 3.1 --- Introduction --- p.49 / Chapter 3.2 --- Materials and Methods --- p.52 / Chapter 3.2.1 --- Overall experimental design --- p.52 / Chapter 3.2.2 --- Fish --- p.53 / Chapter 3.2.3 --- Blood sampling --- p.53 / Chapter 3.2.4 --- Preparation of blood cells --- p.54 / Chapter 3.2.5 --- Thermal stress regimes --- p.54 / Chapter 3.2.5.1 --- Time couse of HSP70 induction profile in blood cells after in vitro exposure to thermal stress --- p.54 / Chapter 3.2.5.2 --- HSP70 synthesis in blood cells taken from fish subjected to in vivo hyper- thermic stress --- p.55 / Chapter 3.2.5.3 --- Transcriptional inhibitory effect of actinomycin D on the synthesis of HSP70 in blood cells subjected to in vitro thermal stress --- p.55 / Chapter 3.2.6 --- Protein analysis --- p.56 / Chapter 3.2.7 --- Gel electrophoresis --- p.57 / Chapter 3.2.8 --- Immunoblotting (Western blot analysis) --- p.57 / Chapter 3.2.9 --- Autroradiography --- p.58 / Chapter 3.3 --- Results --- p.59 / Chapter 3.3.1 --- Time course of HSP70 induction profile in blood cells subjected to in vitro thermal treatments --- p.59 / Chapter 3.3.1.1 --- Results of immunoblotting from blood cells of fish acclimated to 26°C --- p.59 / Chapter 3.3.1.2 --- Results of immunoblotting in blood cells from 18°C-acclimated fish --- p.60 / Chapter 3.3.1.3 --- Results of immunoblotting in blood cells from fish acclimated to 20°C --- p.60 / Chapter 3.3.1.4 --- 35S-methionine labelling of de novo protein synthesis in blood cells of fish acclimated to 15 and 20°C --- p.61 / Chapter 3.3.2 --- Blood cell HSP70 levels in 20°C-acclimated fish subjected to in vivo hyperthermic stress --- p.61 / Chapter 3.3.3 --- Transcriptional inhibitory effect of actinomycin D on HSP70 induction in blood cells subjected to in vitro thermal stress --- p.62 / Chapter 3.4 --- Discussions --- p.60 / Chapter 3.4.1 --- Characteristics of HSP70 induction in blood cells of seabream subjected to in vitro temperature stress --- p.72 / Chapter 3.4.1.1 --- Induction profile of HSP70 in blood cells --- p.72 / Chapter 3.4.1.2 --- Time course ofHSP70 induction in blood cells --- p.75 / Chapter 3.4.1.3 --- Effect of acclimation temperature of fish on the induction of HSP70 --- p.76 / Chapter 3.4.2 --- Comparison of HSP70 induction in in vitro and in vivo thermal treatment on blood cells --- p.78 / Chapter 3.4.3 --- "Effect of transcriptional inhibitor, actinomycin D, on the de novo synthesis of HSP70" --- p.80 / Chapter 3.5 --- Conclusions --- p.70 / Chapter Chapter 4: --- "Effects of seasonal variation and transportation stress on level of HSP70, serum glucose and serum Cortisol in seabream, Sparus sarba" --- p.86 / Chapter 4.1 --- Introduction --- p.87 / Chapter 4.2 --- Materials and methods --- p.90 / Chapter 4.2.1 --- Overall experimental design --- p.90 / Chapter 4.2.2 --- Fish and blood sampling --- p.91 / Chapter 4.2.3 --- Preparation of blood samples --- p.92 / Chapter 4.2.4 --- Determination of HSP70 levels in blood cells sampled from seabream upon different seasons --- p.92 / Chapter 4.2.5 --- Immunoblotting analysis --- p.92 / Chapter 4.2.6 --- Enzyme-linked Immnosorbent Assay (ELISA) --- p.93 / Chapter 4.2.7 --- Measurement of serum parameter in seabream --- p.95 / Chapter 4.2.7.1 --- Serum glucose --- p.95 / Chapter 4.2.7.2 --- Serum Cortisol --- p.96 / Chapter 4.3 --- Results --- p.96 / Chapter 4.3.1 --- Determination of HSP70 levels in blood cells sampled from seabream in different seasons --- p.96 / Chapter 4.3.1.1 --- Immunoblotting analysis --- p.96 / Chapter 4.3.1.2 --- Enzyme-linked immunosorbent assay (ELISA) --- p.96 / Chapter 4.3.2 --- Serum analysis of seabream sampled from fish farm in different seasons --- p.98 / Chapter 4.3.2.1 --- Serum glucose --- p.98 / Chapter 4.3.2.2 --- Serum Cortisol --- p.99 / Chapter 4.4 --- Discussions --- p.117 / Chapter 4.4.1 --- Characterization of HSP70 expression in blood cells of seabream --- p.117 / Chapter 4.4.2 --- Dynamicity of HSP70 content and thermo- tolerance of fish in different seasons --- p.118 / Chapter 4.4.3 --- Effect of transportation stress on HSP70 induction in blood cells of seabream --- p.121 / Chapter 4.4.4 --- Dynamicity of serum glucose level in seabream subjected to seasonal variations --- p.123 / Chapter 4.4.5 --- Effect of transportation stress on the serum glucose level of seabream in different seasons --- p.124 / Chapter 4.4.6 --- Dynamicity of senam Cortisol level in seabream subjected to seasonal variations --- p.125 / Chapter 4.4.7 --- Effect of transportation stress on the serum Cortisol level of seabream in different seasons --- p.126 / Chapter 4.4.8 --- "Comments on the use of HSP70, serum Cortisol and serum glucose as biomarkersin environmental supervision" --- p.126 / Chapter 4.5 --- Conclusions --- p.129 / Chapter Chapter 5: --- "In vitro and in vivo effects of Cortisol, dexamethasone and adrenaline on the induction of HSP70 in seabream, Sparus sarba" --- p.131 / Chapter 5.1 --- Introduction --- p.132 / Chapter 5.2 --- Materials and methods --- p.133 / Chapter 5.2.1 --- Overall experimental design --- p.133 / Chapter 5.2.2 --- Acclimation of fish and regimes of treatment --- p.133 / Chapter 5.2.3 --- Serum Cortisol and adrenaline analysis --- p.135 / Chapter 5.2.4 --- "Protein analysis, gel electrophoresis, immuno- blotting and ELISA analysis" --- p.136 / Chapter 5.3 --- Results --- p.137 / Chapter 5.3.1 --- "HSP70 level in blood cells treated with Cortisol, dexamethasone and adrenaline in vitro" --- p.137 / Chapter 5.3.2 --- "Serum hormones and HSP70 level in tissues of fish injected with Cortisol, adrenaline and dexamethasone invivo" --- p.137 / Chapter 5.3.2.1 --- Serum Cortisol and adrenaline level of fish after hormone injections --- p.137 / Chapter 5.3.2.2 --- "HSP70 level in blood cells, brain and liver tissue of fish after hormone injections" --- p.138 / Chapter (I) --- Level of HSP70 in blood cells of fish after hormone injections --- p.138 / Chapter 5.4 --- Discussions --- p.156 / Chapter 5.4.1 --- In vitro and in vivo study of the hormonal effect on HSP70 level in blood cells of seabream --- p.156 / Chapter 5.4.2 --- Hypothetical mechanism of hormone-receptor mediated HSP70 regulation --- p.158 / Chapter 5.4.3 --- In vivo study of the hormonal effect on HSP70 level in blood cells of seabream --- p.160 / Chapter 5.4.4 --- In vivo study on the hormonal effect of HSP70 synthesis in liver of seabream --- p.163 / Chapter 5.4.5 --- In vivo study on the hormonal effect of HSP70 synthesis in brain tissue of seabream --- p.165 / Chapter 5.4.6 --- HSP70 level in different tissues of fish in relation to the induction and sensitivity against stress --- p.166 / Chapter 5.5 --- Conclusions --- p.169 / Chapter Chapter 6: --- Summary --- p.171 / References --- p.175

The purpose of this thesis is to test the extended industry shock hypothesis, which accounts for a macro-economic capital liquidity element, in determining the drivers of merger waves. Various theories have been extended by the literature and these are broadly classified under the neo-classical theory of merger waves and the behavioural theory of merger waves. Behavioural theories have explained merger waves by taking into account the psychology of stock markets and the occurrence of merger waves during a stock market boom. The industry shock hypothesis (a neo-classical theory) however, argues that merger waves are due to the clustering of industry shocks that affect an industry’s operating environment. Along with this shock, the mis-valuation caused by a stock market boom increases asset values, thereby lowering transaction costs and hence increasing capital liquidity in the economy. This capital liquidity factor causes merger waves to cluster even if industry shocks do not. The findings in this study show that industry level merger waves exist in Australia and they occur when there is sufficient capital liquidity in the economy. The industry shock variables are found to be insignificant; however they do improve the explanatory power of the explanatory variables used in predicting the start of a merger wave. The mis-valuation variables used in this study: market-to-book ratio, 3-year return and standard deviation of the 3-year return, are insignificant and do not have any explanatory powers in predicting the start of a merger wave. Merger and acquisition announcements made to acquire Australian firms listed on the Australian Stock Exchange (ASX), are collected and analysed for the period from 1996 to 2007. The methodology used in this study is adopted from Harford (2005), which uses legit models to predict the start of merger waves. The explanatory variables are also adopted from Harford’s (2005) study and include proxies for mis-valuation, industry shock and capital liquidity. Overall, the results obtained for the Australian merger and acquisition data are inconclusive as to whether industry shocks because industry merger waves as Harford (2005) documented for the US merger and acquisition data. However, industry level merger waves do exist, as there is clustering in time of firm-level mergers within industries. Moreover, sufficient capital liquidity must be present to accommodate the necessary transactions.

A prerequisite for aeroelastic stability prediction inturbomachines is the understanding of the fluctuatingaerodynamic forces acting on the blades. Unsteady transonicflows are complex because of mutual interactions betweentravelling pressure waves, outlet disturbances, shock motion,and fluctuating turbulent boundary layers. Complex phenomenaappear in the shock/boundary layer region and produce phaselags and high time harmonics, which can give a significantcontribution to the overall unsteady lift and torque, andtherefore affect flutter boundaries, cause large localstresses, or even severely damage the turbomachine. The present research work is concerned with theunderstanding of phenomena associated with travelling waves innon-uniform transonic flows and how they affect the unsteadypressure distribution on the surface as well as the far fieldradiated sound. In similitude with turbomachines potentialinteraction, the emphasis was put on the unsteady interactionof upstream propagating acoustic waves with an oscillatingshock in 2D and 3D nozzle flows. Both numerical andexperimental studies are carried out and compared with eachother. Results shows that the unsteady pressure distribution, bothon the bump surface and within the channel, results from thesuperposition of upstream and downstream propagating waves. Itis believed that outlet pressure perturbations propagateupstream in the nozzle, interact in the high subsonic flowregion according to the acoustic blockage theory, and arepartly reflected or absorbed by the oscillating shock,depending on the frequency of the perturbations and theintensity of the SBLI. Furthermore the shock motion amplitudeis found to be related to the mean flow gradients and localwave length of the perturbations rather than to the shockboundary layer interaction. The phase angle between incomingpressure perturbations and the shock motion increases with theperturbation frequency but also depends on the intensity of theSBLI. Additionally the phase angle "shift" observed underneaththe shock location linearly increases with the perturbationfrequency and the shock strength. Such phase shift is criticalregarding aeroelastic stability and might have a significantimpact on the phase angle of the overall aerodynamic forceacting on the blade and shift the aerodynamic damping fromstable to exciting. <b>Keywords:</b>Shock Boundary Layer Interaction, ShockMotion, Unsteady Flows, Nozzle Flows, Potential Interaction,Back Pressure Perturbations.

As one category of energetic materials, impact-initiated reactive materials are able to release a high amount of stored chemical energy under high strain rate impact loading, and are used extensively in civil and military applications. In general, polymers are introduced as binder materials to trap the reactive metal powders inside, and also act as an oxidizing agent for the metal ingredient. Since critical attention has been paid on the metal / metal reaction, only a few types of polymer / reactive metal interactions have been studied in the literature. With the higher requirement of materials resistant to different thermal and mechanical environments, the understanding and characterization of polymer / reactive metal interactions are in great demand. In this study, PTFE (Polytetrafluoroethylene) 7A / Ti (Titanium) composites were studied under high strain rates by utilizing the Taylor impact and SHPB tests. Taylor impact tests with different impact velocities, sample dimensions and sample configurations were conducted on the composite, equipped with a high-speed camera for tracking transient images during the sudden process. SHPB and Instron tests were carried out to obtain the stress vs. strain curves of the composite under a wide range of strain rates, the result of which were also utilized for fitting the constitutive relations of the composite based on the modified Johnson-Cook strength model. Thermal analyses by DTA tests under different flow rates accompanied with XRD identification were conducted to study the reaction mechanism between PTFE 7A and Ti when only heat was provided. Numerical simulations on Taylor impact tests and microstructural deformations were also performed to validate the constitutive model built for the composite system, and to investigate the possible reaction mechanism between two components. The results obtained from the high strain rate tests, thermal analyses and numerical simulations were combined to provide a systematic study on the reaction mechanism between PTFE and Ti in the composite systems, which will be instructive for future energetic studies on other polymer / reactive metal systems.

The current study addresses the stability of shock waves propagating through dissipative media, analogous to both granular media and molecular gases undergoing endothermic reactions. In order to investigate the stability, a simple molecular dynamics model was developed to observe shock waves and their structures with the inclusion of energy dissipation. For this, an Event Driven Molecular Dynamics model was implemented in a 2D environment, where a molecule is represented by a disk. The simulations addressed the formation of a shock wave in a gas by the sudden acceleration of a piston. Inelastic collisions were assumed to occur only if an impact velocity threshold is surpassed, representing the activation energy of the dissipative reactions. Parametric studies were conducted for this molecular model, by varying the strength of the shock wave, the activation threshold and the degree of inelasticity in the collisions. The resulting simulations showed that a shock structure does indeed become unstable with the presence of dissipative collisions. This instability manifests itself in the form of distinctive high density non-uniformities behind the shock wave, which take the form of convective rolls. The spacing and size of this ``finger-like" unstable pattern was shown to be dependent on the degree of inelasticity, the activation energy, and the strength of the driving piston. The mechanism responsible for the instability was addressed by studying the time evolution of the material undergoing the shock wave compression and further relaxation. It is found that the gas develops the instability on the same time scales as the clustering instability in homogeneous gases, first observed by Goldhirsch and Zanetti in granular gases. This confirmed that the clustering instability is the dominant mechanism.

Aquesta tesi doctoral proposa formulacions de Galerkin Discontinu (DG) d’alt ordre per la captura de shocks, obtenint alhora solucions altament precises per problemes de flux compressible. En les últimes dècades, la investigació en els mètodes de DG ha estat en constant creixement. L'èxit dels mètodes DG en problemes hiperbòlics ha conduit el seu desenvolupament en lleis de conservació no lineals i problemes de convecció dominant. Entre els avantatges dels mètodes DG, destaquen la seva estabilitat inherent i les propietats locals de conservació. D'altra banda, els mètodes DG estan especialment dissenyats per l’ús aproximacions d'ordre superior. De fet, en els últims anys s'ha demostrat que la resolució de problemes de convecció dominant ja no es restringeix només a elements d'ordre inferior. De fet, es necessiten models numèrics d'alta precisió per aconseguir prediccions altament fiables dins la dinàmica de fluids computacional (CFD). En aquest context es presenten i discuteixen dos tècniques de captura de shocks. En primer lloc, es presenta una tècnica novedosa i senzilla basada en la introducció d'una nova base de funcions de forma. Aquesta base té la capacitat de canviar a nivell local entre una interpolació contínua o discontínua, depenent de la suavitat de la funció que es vol aproximar. En presència de xocs, les discontinuïtats introduïdes dins l’element permeten incloure l'estabilització necessària gràcies a l’ús dels fluxos numèrics, i alhora exploten les propietats intrínsiques del mètodes DG. En conseqüència, es poden utilitzar malles grolleres amb elements d’ordre superior. Amb aquestes discretitzacions i, utilitzant el mètode proposats, els xocs queden continguts a l’interior de l’element i per tant, és possible evitar l’ús de tècniques de refinament adaptatiu de la malla, alhora que es manté la localitat i compacitat dels esquemes DG. En segon lloc, es proposa una tècnica clàssica i, aparentment simple: la introducció de la viscositat artificial. Primerament es realitza un estudi detallat per al cas unidimensional. S’obté una viscositat d’alta precisió que escala segons el valor hk amb 1 ≤ k ≤ p i essent h la mida de l’element. En conseqüència, s’obté un xoc amb amplitud del mateix ordre. Seguidament, l'estudi de la viscositat unidimensional obtenida s'extén al cas multidimensional per a malles triangulars. L'extensió es basa en la projecció de la viscositat unidimensional en unes determinades direccions espacials dins l’element. Es demostra de manera consistent que la viscositat introduïda és, com a molt, del mateix ordre que la resolució donada per la discretització espacial, és a dir, h/p. El mètode és especialment eficient per aproximacions de Galerkin discontinu d’alt ordre, per exemple p≥ 3. Les dues metodologies es validen mitjançant una àmplia selecció d’exemples numèrics. En alguns exemples, els mètodes proposats permeten una reducció en el nombre de graus de llibertat necessaris per capturar xocs acuradament de fins i tot un ordre de magnitud, en comparació amb mètodes estàndar de refinament adaptatiu amb aproximacions de baix ordre. / This thesis proposes shock-capturing methods for high-order Discontinuous Galerkin (DG) formulations providing highly accurate solutions for compressible flows. In the last decades, research in DG methods has been very active. The success of DG in hyperbolic problems has driven many studies for nonlinear conservation laws and convection-dominated problems. Among all the advantages of DG, their inherent stability and local conservation properties are relevant. Moreover, DG methods are naturally suited for high-order approximations. Actually, in recent years it has been shown that convection-dominated problems are no longer restricted to low-order elements. In fact, highly accurate numerical models for High-Fidelity predictions in CFD are necessary. Under this rationale, two shock-capturing techniques are presented and discussed. First, a novel and simple technique based on on the introduction of a new basis of shape functions is presented. It has the ability to change locally between a continuous or discontinuous interpolation depending on the smoothness of the approximated function. In the presence of shocks, the new discontinuities inside an element introduce the required stabilization thanks to the numerical fluxes, thus exploiting DG inherent properties. Large high-order elements can therefore be used and shocks are captured within a single element, avoiding adaptive mesh refinement and preserving the locality and compactness of the DG scheme. Second, a classical and, apparently simple, technique is advocated: the introduction of artificial viscosity. First, a one-dimensional study is perfomed. Viscosity of the order O(hk) with 1≤ k≤ p is obtained, hence inducing a shock width of the same order. Second, the study extends the accurate one-dimensional viscosity to triangular multidimensional meshes. The extension is based on the projection of the one-dimensional viscosity into some characteristic spatial directions within the elements. It is consistently shown that the introduced viscosity scales, at most, withthe DG resolutions length scales, h/p. The method is especially reliable for highorder DG approximations, say p≥3. A wide range of different numerical tests validate both methodologies. In some examples the proposed methods allow to reduce by an order of magnitude the number of degrees of freedom necessary to accurately capture the shocks, compared to standard low order h-adaptive approaches.

In the current research, a framework based on classical molecular dynamics (MD) is developed for computational mechanical analyses of complex nanoscale materials. The material system of focus is a combination of fcc-Al and and #945;-Fe₂O₃. The framework includes the development of an interatomic potential, a scalable parallel MD code, nanocrystalline composite structures, and methodologies for the quasistatic and dynamic strength analyses. The interatomic potential includes an embedded atom method (EAM) cluster functional, a Morse type pair function, and a second order electrostatic interaction function. The framework is applied to analyze the nanoscale mechanical behavior of the Al+Fe₂O₃ material system in two different settings. First, quasistatic strength analyses of nanocrystalline composites with average grain sizes varying from 3.9 nm to 7.2 nm are carried out. Second, shock wave propagation analyses are carried out in single crystalline Al, Fe₂O₃, and one of their interfaces. The quasistatic strength analyses reveal that the deformation mechanisms in the analyzed nanocrystalline structures are affected by a combination of factors including high fraction of grain boundary atoms and electrostatic forces. The slopes as well as the direct or inverse nature of observed Hall-Petch (H-P) relationships are strongly dependent upon the volume fraction of the Fe₂O₃ phase in the composites. The compressive strengths of single phase nanocrystalline structures are two to three times the tensile strengths owing to the differences in the movement of atoms in grain boundaries during compressive and tensile deformations. Analyses of shock wave propagation in single crystalline systems reveal that the shock wave velocity (US) and the particle velocity (UP) relationships as well as the type and the extent of shock-induced deformation in single crystals are strongly correlated with the choice of crystallographic orientation for the shock wave propagation. Analyses of shock wave propagation through an interface between Al and Fe2O3 point to a possible threshold UP value beyond which a shock-induced structural transformation that is reactive in nature in a region surrounding the interface may be taking place. Overall, the framework and the analyses establish an important computational approach for investigating the mechanical behavior of complex nanostructures at the atomic length- and time-scales.

<p>A prerequisite for aeroelastic stability prediction inturbomachines is the understanding of the fluctuatingaerodynamic forces acting on the blades. Unsteady transonicflows are complex because of mutual interactions betweentravelling pressure waves, outlet disturbances, shock motion,and fluctuating turbulent boundary layers. Complex phenomenaappear in the shock/boundary layer region and produce phaselags and high time harmonics, which can give a significantcontribution to the overall unsteady lift and torque, andtherefore affect flutter boundaries, cause large localstresses, or even severely damage the turbomachine.</p><p>The present research work is concerned with theunderstanding of phenomena associated with travelling waves innon-uniform transonic flows and how they affect the unsteadypressure distribution on the surface as well as the far fieldradiated sound. In similitude with turbomachines potentialinteraction, the emphasis was put on the unsteady interactionof upstream propagating acoustic waves with an oscillatingshock in 2D and 3D nozzle flows. Both numerical andexperimental studies are carried out and compared with eachother.</p><p>Results shows that the unsteady pressure distribution, bothon the bump surface and within the channel, results from thesuperposition of upstream and downstream propagating waves. Itis believed that outlet pressure perturbations propagateupstream in the nozzle, interact in the high subsonic flowregion according to the acoustic blockage theory, and arepartly reflected or absorbed by the oscillating shock,depending on the frequency of the perturbations and theintensity of the SBLI. Furthermore the shock motion amplitudeis found to be related to the mean flow gradients and localwave length of the perturbations rather than to the shockboundary layer interaction. The phase angle between incomingpressure perturbations and the shock motion increases with theperturbation frequency but also depends on the intensity of theSBLI. Additionally the phase angle "shift" observed underneaththe shock location linearly increases with the perturbationfrequency and the shock strength. Such phase shift is criticalregarding aeroelastic stability and might have a significantimpact on the phase angle of the overall aerodynamic forceacting on the blade and shift the aerodynamic damping fromstable to exciting.</p><p><b>Keywords:</b>Shock Boundary Layer Interaction, ShockMotion, Unsteady Flows, Nozzle Flows, Potential Interaction,Back Pressure Perturbations.</p>

Source: Masters Abstracts International, Volume: 47-06, page: 3510. Adviser: Irwin B. Horwitz. Includes bibliographical references.