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Recent discoveries indicate that the foamy virus (FV) (Spumavirus) ancestor may have been among the first retroviruses to appear during the evolution of vertebrates, demonstrated by foamy endogenous retroviruses present within deeply divergent hosts including mammals, coelacanth, and ray-finned fish. If they indeed existed in ancient marine environments hundreds of millions of years ago, significant undiscovered diversity of foamy-like endogenous retroviruses might be present in fish genomes. By screening published genomes and by applying PCR-based assays of preserved tissues, we discovered 23 novel foamy-like elements in teleost hosts. These viruses form a robust, reciprocally monophyletic sister clade with sarcopterygian host FV, with class III mammal endogenous retroviruses being the sister group to both clades. Some of these foamy-like retroviruses have larger genomes than any known retrovirus, exogenous or endogenous, due to unusually long gag-like genes and numerous accessory genes. The presence of genetic features conserved between mammalian FV and these novel retroviruses attests to a foamy-like replication biology conserved for hundreds of millions of years. We estimate that some of these viruses integrated recently into host genomes; exogenous forms of these viruses may still circulate.

Endogenous retroviruses (ERVs) are fossils of ancient retroviral infection in the germline. In primates they represent around 5% of the genome sequence. During time spent in the genome, being transmitted in a Mendelian fashion, copies of ERVs have accumulated mutations, which rendered them inactive. However, some of them (the most recently integrated ones) are still able to transcribe and produce viral proteins, although few are capable of re-infection. In the past often considered as unharmful 'junk DNA', recent evidence link ERVs with cancer and several inflammatory diseases. For example, a few reports demonstrate that ERVs are involved in tumour development using shRNA knock-down and over-expression systems, and their overexpression tends to correlate with inflammation status, generating the hypothesis that they can act as pathogen-associated molecular patterns (PAMPs) and bind to innate sensors. Focusing on the Human (Homo sapiens) and the rhesus macaque (Macaca mulatta), the main aims of this thesis are to look for further evidence linking ERVs to tumour development, with possible implications for therapies, and test the hypothesis that ERVs are PAMPs by seeing if individuals with higher levels of ERV expression exhibit a higher innate immune response. The work on ERVs in cancer involved the human ERV type-K HML2 lineage (HERV-K (HML2)), an ERV lineage found in humans, in Merlin-deficient tumours. These are schwannomas that arise from Schwann cells and for which effective drug therapy is urgently needed. The work on ERVs in inflammation involved the Papio cynocephalus ERV (PcEV), in rhesus macaques infected with simian immunodeficiency virus (SIV) infection. The main outcomes are as follows: regarding HERV-K (HML2) in human schwannomas, (i) HERV-K (HML2) proteins are overexpressed in schwannoma compared to Schwann cells; (ii) these proteins are released from the tumour; (iii) regulation of HERV-K (HML2) expression in the tumour appears to involve the transcription factor TEAD; (iv) schwannomas are potentially treatable using anti-HERV-K (HML2) monoclonal antibodies and antiretroviral drugs since both decreased proliferation in vitro. Regarding PcEV in SIV-infected macaques: (i) PcEV is transcriptionally active; (ii) PcEV can be retrieved at low levels in the blood of some macaque animals; (iii) the levels of PcEV in cells correlates strongly with the strength of the innate response as measured by cellular levels of STAT1 transcripts - an interferon-stimulated gene (ISG). Other recent research has shown that human ERV lineages, namely HERV-W and HERV-H, have been co-opted and are involved in placentation and pluripotency during development, respectively. The present work suggests that ERVs are involved in a wide range of biological process and supports the need for further research into the biological significance of ERVs for their hosts.

Abstract not available

Animal research suggests that exposure to inescapable stressors can lead to an endogenous opioid-mediated form of pain inhibition, known as stress-induced analgesia (SIA). Similar results have been found with humans, although the literature is much less extensive and at times contradictory where uncontrollable stressors have led to an increase, rather than a decrease in pain. More recently, there has been some suggestion that emotions play an important role in pain modulation, and that particular negative moods are associated with opioid-mediated hypoalgesia. This research aimed to clarify the psychological (cognitive and affective) factors underlying endogenous opioid-mediated pain inhibition in humans. The purpose of Study 1 was to examine the effects of stressor controllability and predictability on pain intensity (PI) and unpleasantness (UP) ratings during a cold pressor task (CPT) in 56 male and female subjects. The stressor involved a timed mental arithmetic task during which three moderately noxious electrical shocks were delivered. Although subjects were informed that shock delivery was contingent on math performance, the shock schedule was preset and identical across conditions. Perceived control over the shocks was manipulated between subjects by altering the difficulty of the math task. Shock predictability was manipulated by changing the colour of the computer screen to warn of an impending shock. Subjects were randomly allocated to four experimental conditions (controllable-predictable, controllable-unpredictable, uncontrollable-predictable, and uncontrollable-unpredictable shocks). Visual analogue ratings of ‘perceived self-efficacy’ (to avoid the shocks) and mood (anxiety, confusion, discouragement, anger, sluggishness, liveliness) were completed before, during and after the math task. Significantly greater discouragement and lower self-efficacy was reported in ‘uncontrollable’ conditions indicating that ‘controllability’ was manipulated effectively. Results indicated that a perceived lack of control over shocks during the math task led to significantly greater decreases in PI, but not UP, ratings during the last stages of a 4-minute fixed interval CPT after the math task. Shock predictability failed to influence subjective pain ratings alone; however, unpredictability interacted with lack of control to initially increase pain, followed by analgesia. Stress-induced increases in negative affect (anxiety, discouragement, anger) were associated with decreases in cold pressor PI, but with increased shock PI and UP during the math task. It was concluded that lack of control over an aversive event and negative affect led to SIA during a prolonged pain stimulus, whereas shock predictability had little influence on pain. In Study 2, 70 male and female subjects received either an opioid antagonist (naltrexone) or a placebo before the math task (using a double-blind, counterbalanced design), in order to determine the role of endogenous opioids in SIA. Subjects were randomly assigned to one of three experimental conditions to investigate whether the shocks themselves may have contributed to analgesia observed after the math task: (1) easy task-few shocks, (2) hard task-few shocks, (3) hard task-many shocks. Increases in systolic blood pressure (SBP), diastolic blood pressure (DBP), anxiety, anger and discouragement indicated that negative affect and sympathetic arousal were induced during the math task. Endogenous opioids inhibited the rise in anger, but not discouragement or anxiety, during the math task. There was some evidence that perceived lack of control over shocks, and not the shocks themselves, led to opioid-mediated decreases in cold pressor UP after the math task. In correlational analyses, discouraged subjects under opioid blockade reported more cold pressor UP after the math task than their placebo counterparts. However, this effect was not strong enough to reach statistical significance in regression analyses. Anxiety, anger, discouragement and lack of control over shocks increased shock PI and UP during the math task. A growing body of research with normotensive subjects has linked increased cardiovascular activity with insensitivity to pain, but the role of endogenous opioids remains contentious. In addition to the investigations outlined above, Study 2 aimed to examine the contribution of endogenous opioids in the cardiovascular-pain relationship. However, there was no evidence of an interaction between pain and cardiovascular activity in this study. Study 3 was carried out to investigate opioid involvement in the effects of an uncontrollable stressor and stress-induced negative mood on cold pressor PI, UP and pain tolerance, and onset/thresholds of the nociceptive flexion reflex (RIII). Forty-three male and female subjects were administered either naltrexone or a placebo using a double-blind, counterbalanced design before completing a timed mental arithmetic stressor (identical to the ‘hard task-many shocks’ condition in Study 2). Increases in physiological (SBP, DBP) and affective measures (anxiety, anger and discouragement) indicated that the math task induced a marked state of stress. Negative affect increased shock PI and UP during the task, whereas self-efficacious subjects taking the placebo experienced less shock pain. However, uncontrollable stress led to an opioid-antagonised increase in cold pressor UP. Stressor controllability had a similar, but marginal, effect on cold pressor PI, but not pain tolerance. Tolerance of cold pressor pain was not associated with subjective PI and UP ratings, but was positively associated with endurance to non-painful, but unpleasant tasks (Valsalva Manoeuvre, Letter-Symbol Matching Task), indicating that pain tolerance was measuring the ability to tolerate discomfort, in addition to pain. Results of hierarchical multiple regressions demonstrated that increases in discouragement were positively related to increases in cold pressor UP after the math task, for naltrexone recipients only. These findings suggest that discouragement inhibits the UP of a prolonged pain stimulus via opioid mechanisms. RIII latencies and thresholds were not affected by the math task or by opioid blockade; however, these null effects may be due to methodological limitations. Unlike Study 2, higher blood pressure was associated with shock and cold pressor pain inhibition in normotensive subjects, and this relationship appeared to be mediated by opioids. The strong association between chronic pain and depression has led to speculation that the endogenous opioid system and pain modulatory mechanisms may be impaired in depression. At the time that this research was carried out, no studies had examined whether this was the case. In Study 4, the effect of a cognitive stressor (math task used in Study 3) on foot cold pressor PI, UP and pain tolerance and the nociceptive, or R2 component, of the blink reflex was investigated in 61 participants with or without major depression (as met by DSM-IV diagnostic criteria and confirmed by psychometric testing). Naltrexone or placebo was administered to subjects an hour before the math task using a double-blind, counterbalanced design. Increases in physiological (SBP, DBP) and affective measures (anxiety, anger and discouragement) confirmed that the math task induced the targeted emotional state. An opioid-mediated reduction in anxiety occurred mid-way through the math task. Opioid-mediated decreases in foot cold pressor PI and UP were observed in depressed and non-depressed subjects after the math task. R2 onset to 10 mA was facilitated after the task regardless of opioid blockade, suggesting that endogenous opioids are not involved in the modulation of the BR. Increased anxiety and discouragement led to opioid-mediated inhibition of shock PI and UP during the task and, to a lesser extent, foot cold pressor PI and UP after the math task. Anger increased shock pain without being influenced by opioid blockade. Pain tolerance was not influenced by depression, opioid blockade or mood. These findings failed to support the idea that SIA is impaired in major depression, suggesting instead that uncontrollable aversive events and negative mood (anxiety, discouragement) lead to opioid activation and insensitivity to acute pain. Multiple regression analyses revealed that the inverse relationship between resting blood pressure and foot cold pressor PI and UP was opioid-mediated in controls only, suggesting that opioid dysregulation in depression might influence regulatory functions other than SIA. In Study 4, opioid involvement in hetero-segmental pain inhibitory phenomena termed diffuse noxious inhibitory controls (DNIC) was examined separately, before psychological stress. Specifically, the effect of a heterotopic noxious conditioning stimulus (CS i.e., hand CPT) on R2 onset latency was compared before and after drug absorption (before the math task). An inhibitory effect of the first CS was detected at each electrical stimulus intensity consistent with a DNIC effect. However, this effect was not detected during the second CS, suggesting that some other process masked the DNIC effect. In summary, the findings indicate that uncontrollable aversive events and negative emotion (primarily discouragement) activates endogenous opioids and inhibits pain in human subjects, whether depressed or not. Notably, opioids inhibited the affective component of pain perception, or pain UP, more consistently than PI, suggesting that the antinociceptive function of opioids may be secondary to an important emotional-modulatory role. Endogenous opioids also appeared to mediate the cardiovascular-pain relationship in normotensive non-depressed subjects, suggesting an important stress-regulatory role for these peptides. Opioid-mediated masking of this relationship in major depression suggests that functioning of the endogenous opioid system may be impaired in baroreceptor-mediated analgesia. This finding provides preliminary support for the notion that opioid antinociceptive system dysfunction may contribute to cardiovascular disease in depression.

This thesis deals with different forms of strategic complementarities in industrial organization problems. Chapter 2 is an attempt to develop a unified approach to endogenous heterogeneity by constructing a general class of two-player symmetric games that possess only asymmetric pure-strategy Nash equilibria. These classes of games are characterized in some abstract sense by two general properties: payoff non-concavities and some form of strategic substitutability. While the second characteristic allows to show the existence of pure strategy Nash equilibria, the second precludes these equilibria to be symmetric. Other two classes of games that always possess asymmetric, but never symmetric, pure-strategy equilibria, although they are not of strategic substitutes are also studied. This chapter also generalizes a number of models dealing with two-stage games, with long term investment decisions in the first stage and product market competition in the second stage. Chapter 3 investigates the effects of forward looking behaviour in technology adoption. The setup is an overlapping generations model where agents choose between two alternative networks taking into consideration both the installed base and the expected base. The latter element is the distinctive feature of the approach. It is shown that a unique equilibrium exists, on which agents coordinate their expectations. While exhibiting hysteresis, the equilibrium adoption path does not comply with technologies locking in. Network choices are characterized both in terms of their long run properties and the expected time of adoption. Chapter 4 studies the problem of a monopolist who produces a good with network externalities and faces the possibility of selling a new higher quality. Within the vertical product differentiation it identifies the necessary and sufficient conditions for quality improvement to take place when a good, produced by a monopolist, exhibits positive network externalities. When network effects are not very strong, the monopolist produces both the high and the low quality and thus quality improvement takes place. In this case, he will use an introductory pricing strategy for the quality that benefits from network externalities, not maximizing however the network size. As the network effect becomes more important, the monopolist will have an incentive to practise introductory pricing and produce both qualities. Finally, if the network externality is higher than the intrinsic quality differential, quality improvement does not take place. Chapter 5 deals with the problem of an incumbent producing a low quality good with network externalities that faces the threat of entry by a higher quality good. In the framework of a vertical product differentiation model, it is identified a necessary and sufficient condition under which quality improvements are spontaneously adopted along, in spite of the existence of network effects. This condition says that the intensity of network effects on consumers' preferences should not exceed twice the differential of intrinsic qualities existing between the two variants. Finally, chapter 6 is concerned with the optimal path of prices of a monopolist who operates in a network industry for a finite horizon. Agents obtain intrinsic utility from the good and from the fact that in the past there have been other consumers using it. It is observed that the monopolist has an incentive to introduce the good at initially low prices and to increase the price as the time goes by. This chapter concludes with a necessary and sufficient condition under which the initial price, and only the initial one is zero. This condition is related both with the intensity of the preferences for the network and with the time horizon of the monopolist.

The paper provides a model that assesses the set of complementary components of varying compatibility and its effect towards consumer adoption decisions. The smartphone market is a system good which utilizes the device and a set of compatible applications (apps). The amount of switching costs may vary depending upon the consumer’s decision to switch devices or across platforms. Analyzing the Android ecosystem, the process of custom ROMs (and rooting) and the large set of games, news, etc. apps justify the existence of device-specific and platform-specific apps. The model reinforces the findings of a survey conducted by UBS suggesting the retention rate (i.e. level of switch costs) of Apple users is higher than Android users. The retention among Android devices is much lower in comparison as well. The model observes that the product fragmentation and the interdependence of apps lead to the noticeably lower retention rates across Android devices and platforms.

Taiwan is usually considered as a small open economy. Trade and exchange rate policies in Taiwan have substantially changed since 1990s.Not only has trade been liberalized, but exchange rates of the New Taiwan Dollar(NTD) were also allowed to fluctuate. This paper applies the Threshold Regression with Endogenous Threshold Variables(THRET) Model that puted forward Kourtellos, Stengos and Tan (2007) and combines the expectation-augmented Phillips curve with a threshold for the pass-through. The paper examines whether the short-run magnitude of the pass-through is affected by the business cycle. For that purpose, the important variable is tested as thresholds: output gap change. The results indicate that the short-run pass-through is higher when the the economy is booming, as well as the exchange rate depreciates above some threshold. And showed in this has conformed to the business cycle theory which Goldfajn and Werlang (2000) , Carneiro, Monteiro and Wu (2002) , Muinhos (2001) proposed.

The implication of credit rationing models states that the effect of monetary policy on output may be stronger when credit conditions are tight than when they are loose. Therefore, there may be a thresholde effect on the relation between real money supply and output. Existing empirical studies on testing threshold effects ignore the fact that the monetary policy and the credit conditions are endogenous, which are follow some optimal rules. Seeing that the past studies considering the endogenous monetary policy only cannot provide substantial evidence of the credit rationing theory, this article provides an extending test of threshold effects when monetary policy and the indicator of credit conditions are endogenous. Moreover, this study finds that the US aggregate data can still provide significant evidence of a threshold effect on the relation between money and output, comparing to the endogenous monetary policy partially considered.

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