Toxic shock events can be detrimental to wastewater treatment systems and can result in long-term losses of system performance. If warned of an impending toxic shock, operators would have the opportunity to implement process controls that could help mitigate the effects of the shock event. The objective of this project was to evaluate the effectiveness of a developed corrective action strategy (involving aerobic endogenous respiration) on an enhanced biological phosphorus removal (EBPR) wastewater treatment plant (WWTP) shocked with chlorine. Three identical, laboratory-scale systems were designed to mimic one train of the Long Creek Water Resources Reclamation Facility (WRRF, Gastonia, NC). The basis of this study is a comparative performance analysis among the three trains; a negative control (unshocked and operated normally), a positive control (shocked with hypochlorite and operated normally), and the corrective action (shocked with hypochlorite and process controls implemented). Comparative performance analysis among the three trains was based on effluent quality, performance stability, and biomass kinetics as indicated by rates of respiration and phosphate release and uptake. The shock event and corrective action strategy both inhibited EBPR. After an initial perturbation, the positive control matched the performance of the negative control. The corrective action, however, exhibited significant instability in EBPR performance. Regardless of whether aerobic or anaerobic sludge storage conditions are selected, endogenous respiration will still result in system instability. It is recommended, therefore, that measures be taken to avoid imposing endogenous conditions on isolated sludge during a short-term toxic shock event. / Master of Science

Le génome du bananier (Musa sp.) est envahi par un nombre important de séquences de Banana streak virus (BSV), virus à ADN double brin de la famille des Caulimoviridae qui n'a aucune étape d'intégration au génome hôte au cours de son cycle de multiplication. La majorité de ces intégrations eBSV (endogenous BSV) est défective mais certaines sont restées fonctionnelles et peuvent être à l'origine de particules virales suite à des stress. L'objectif de ce travail de thèse est de préciser si les eBSV sont maintenus ou non dans le génome de Musa balbisiana des bananiers et d'étudier les conséquences évolutives que cela engendre. Nous avons tout d'abord caractérisé les eBSV pour trois espèces de BSV (Banana streak goldfinger virus (BSGFV), Banana streak obino l'ewai virus (BSOLV), Banana streak imove virus (BSImV) présents dans le génome du bananier modèle M. balbisiana cv Pisang Klutuk Wulung (PKW). Nous avons montré que les intégrations eBSGFV et eBSOLV étaient di-alléliques avec un seul allèle fonctionnel à chaque fois, contrairement à eBSImV qui est mono-allélique et pour lequel nous n'avons pas pu identifier l'allèle à l'origine de l'infection. Leur contexte génomique d'intégration diffère avec une co-localisation d'eBSGFV et d'eBSOLV sur le chromosome 1 et d'eBSImV sur le chromosome 2. Ces résultats nous ont permis de développer les outils moléculaires nécessaires à la caractérisation de ces trois eBSV dans la diversité de M. balbisiana. Cette caractérisation a révélé la diversité de structures des eBSV et éclairé une partie encore inconnue de la phylogénie de l'espèce M. balbisiana. Dans un second temps nous avons étudié les mécanismes de régulation des eBSV. Ce travail a porté sur les mécanismes d'ARN interférent pouvant expliquer le maintien des eBSV dans le génome des bananiers. Cette analyse révèle que les eBSV sont effectivement sous contrôle d'un mécanisme de type ARNi et la forte production de petits ARNs de 24nt ciblant les eBSV suggère qu'il s'agit d'un silencing au niveau transcriptionnel (TGS). En parallèle, nous avons aussi recherché les mécanismes mis en place par les bananiers non-porteurs d'eBSV en cas d'infection afin de connaître les défenses constitutives des bananiers face à une attaque virale BSV. Nous avons, sur la base de ces résultats, proposé un modèle de régulation des eBSV et des BSV et discuté de l'impact que ces mécanismes auraient pu avoir sur l'évolution des eBSV. L'ensemble des données de ce travail ont permis de préciser les étapes évolutives qu'ont connues les eBSV dans le génome du bananier, expliquant le maintien que l'on observe aujourd'hui. / The nuclear genome of banana plants is invaded by numerous viral sequences of banana streak virus (BSV), a DNA virus belonging to the family Caulimoviridae which does not require integration for its replication. These endogenous BSV (eBSV) are mostly defective; however, some can release a functional viral genome following activating stresses. The objectives of this work were to identify if the eBSV are maintained or not in the M. balbisiana genome and to study the impacts of this on the evolution of banana plants. First, we characterized three functional eBSV sequences present within the Musa balbisiana cv PKW genome: (Banana streak goldfinger virus (BSGFV) ; Banana streak obino l'ewai virus (BSOLV) ; and, Banana streak imove virus (BSImV). We show that eBSOLV and eBSGFV are di-allelic with just one functional allele contrary to eBSImV which are mono-allelic and for which we cannot reveal the functional allele. Their genomic areas of integration are different and we also observe that eBSOLV and eBSVGFV are both on chromosome 2 whereas eBSImV is on chromosome 1. These results allowed us to develop the molecular tools required for the characterization of these 3 functional eBSVs within the diversity of M. balbisiana. This characterization has revealed the structural diversity of eBSV and has thus clarified previously unresolved details of M. balbisiana phylogeny. Secondly, we studied the regulatory mechanism of eBSV expression. This work investigated if RNA interference (RNAi) mechanisms could explain the maintenance of eBSV in the Musa genome. Our analyses have shown that, as expected, eBSV was under the control of RNAi mechanisms and the strong production of 24nt small RNAs that target eBSV suggests that Transcriptional Gene Silencing (TGS) was involved in this control. In parallel, we investigated the mechanisms implicated in the anti-viral defense during a BSV infection on a banana plant without eBSV in order to understand the constitutive defense of banana plants. On the basis of these results we have proposed a regulation model of eBSV and BSV and we discuss the impact of silencing regulation on eBSV evolution. Data accumulated during this work have clarified several steps in the co-evolutionary history of Musa sp. and eBSV and explain the maintenance of eBSVs in Musa genomes that we observe today.

京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第20764号 / 工博第4416号 / 新制||工||1686(附属図書館) / 京都大学大学院工学研究科合成・生物化学専攻 / (主査)教授 浜地 格, 教授 跡見 晴幸, 教授 秋吉 一成 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DFAM

After numerous renewals and reignitions since the initiation of the "War on Cancer" more than five decades ago, the recent reignition of "Moonshot to Cure Cancer" points to the systemic persistence of cancer as a major cause of loss of life and livelihood. Literature points to the diminishing returns of cancer research through time, as well as heterogeneities in cancer research centers' innovation strategies. This dissertation focuses on the strategic decision by cancer research centers to invest their resources in conducting early phases of clinical trials on new candidate drugs/treatments (resembling exploration) or late phases of clinical trials that push established candidates towards acquiring FDA approvals (resembling exploitation). The extensive clinical trials data suggests that cancer research centers are not only different in their emphasis on exploratory trials, but also in how their emphasis is changing over time. This research studies the dynamics of this heterogeneity in cancer research centers' innovation strategies, how experiential learning and capability development interact to cause dynamics of divergence among learning agents, and how the heterogeneity among cancer research centers' innovation strategies is affected by the dynamics of learning from experience and capability development. The findings of this dissertation shows that endogenous heterogeneities can arise from the process of learning from experience and accumulation of capabilities. It is also shown that depending on the sensitivity of the outcome of decisions to the accumulated capabilities, such endogenous heterogeneities can be value-creating and thus, justified. Empirical analysis of cancer clinical trials data shows that cancer research centers learn from success and failure of their previous trials to adopt more/less explorative tendencies. It also demonstrates that cancer research centers with a history of preferring exploratory or FDA trials have the tendency to increase their preference and become more specialized in one specific type (endogenous specialization). These behavioral aspects of the cancer research centers' innovation strategies provide some of the tools necessary to model the behavior of the cancer research efforts from a holistic viewpoint. / Doctor of Philosophy / The "Moonshot to Cure Cancer" was renewed most recently in September 2022. However, renewal and reignition of this national collective effort is nothing new; this effort started as "War on Cancer" in 1971 and has been reignited numerous times. After more than 50 years of our collective battle to cure cancer, it claims almost 600,000 lives annually and remains as the second leading cause of death in the US. There are a wide variety of cancer research centers from all around the world contributing to this collective effort and they make considerably different decisions regarding their investment in research. There is evidence suggesting that some of the research centers' investment decisions are not optimal and can be improved. It has been shown that systems such as patent regulations can be revised to encourage such improved decisions among cancer research centers. This dissertation focuses on the process of clinical trials for new drugs/treatments for cancer. New drugs/treatments have to pass different phases of trials to ensure that they are safe and effective before they can acquire FDA approvals. Cancer research centers decide whether to invest in early phases of clinical trials for new drug/treatment candidates or invest in late phases of trials for candidates that have already passed the early phases. The clinical trials data show that there has been a sharp rise in number of early phases of trials on new drugs/treatments; however, the same rise cannot be seen in the late phases of trials resulting in approvals. It can also be seen that different research centers put different levels of emphasis on initiating early phases of trials for new drugs/treatments (exploration). In this dissertation, the hypothesis is that this ongoing dilemma that cancer research centers face to invest on how much emphasis to put on exploration in their clinical trials is affected by learning from experience. To test this hypothesis, a mathematical model is used to show differences in decisions can be causes solely by learning from experience, when the decision maker is learning "what to do" from success/failure of previous efforts and learning "how to do it" from practicing and accumulating the required skills. Then, the hypothesis is formally tested using the clinical trials data. The results show that cancer research centers learn from the success and failure of their previous exploratory trials when deciding on their emphasis on exploration. Also, they accumulate skills, resources, and capabilities relevant to the type of research the conduct more often and specialize in either of late- or early-phases of trials. The findings of this dissertation show that learning from experience can cause in differences in decisions. It also finds evidence that cancer research centers learn to place different levels of emphasis on exploration in their clinical trials. These findings can later be used in models of the cancer research ecosystem to study how funding structures and policies can be changed to improve the outcomes of our collective effort to cure cancer.

Background: Platelets provide the initial haemostatic plug at sites of vascular injury. They also participate in pathological thrombosis that leads to myocardial infarction, stroke and peripheral vascular disease. The outcome of an acute myocardial infarction depends not only on the formation and stability of an occlusive thrombus, but also on the efficacy of the endogenous thrombolytic process, which allows reperfusion of the infarct related artery and prevents recurrent ischaemic episodes. Various platelet function tests are available to measure the thrombogenic potential of an individual, but the sensitivity of these tests remain questionable as most of these tests use citrated blood and measure response to a particular agonist. Endogenous thrombolysis has been a neglected entity, and its beneficial effects on cardiovascular outcomes has not been studied in depth in the past, possibly as until recently there has been no available technique to measure spontaneous thrombolytic activity in native blood. The Global Thrombosis Test (GTT) is a new point of care tests that allows us to measure time to thrombus formation (Occlusion time: OT) using native blood, avoiding the use of agonists and making the test results more physiological. The GTT also measures the time to lyse this formed thrombi without use of any lytic agents (Lysis time: LT), allowing us to measure the patient’s endogenous thrombolytic potential. Aim: Our aim in this study was to detect patients who are at risk of future thrombotic events despite dual antiplatelet therapy, either due to prothrombotic tendency or due to impaired endogenous thrombolysis, and to determine if these two parameters were correlated. Methods: GTT was used to assess the thrombotic and thrombolytic activity in healthy volunteers, and in different patient populations. 100 healthy volunteers were tested using the GTT, and a normal range was established. 300 patients admitted to hospital with a diagnosis of acute coronary syndrome (ACS) were included in the study, and tested using the GTT after they had been stabilized on dual antiplatelet therapy (Aspirin and Clopidogrel). All these patients were followed up for a year, to determine if their baseline GTT results were a predictor of recurrent cardiac events. The primary endpoint of the study was major adverse cardiovascular events (MACE), which was a composite of cardiovascular death, nonfatal myocardial infarction, or stroke at 12 months. Results: All results were analysed using statistical package SPSS version 16.0 (SPSS Inc., Chicago, Illinois). The 100 healthy volunteers were all non-smokers, and were not taking any medications. There were 55 males and 45 females, and mean age was 38±11 years (range 22-76, IQR 11). OT was normally distributed with mean OT 377.80s, and using mean ± 2SD, we derived a normal range of 185-569s (200-550s). LT demonstrated a skewed distribution with values ranging between 457 – 2934s. Using log transformation, a normal range of 592 – 1923 (600- 2000s) was established for LT. OT and LT were both prolonged in ACS patients compared to normal volunteers (p< 0.001). No association was observed between OT and risk of major adverse cardiovascular events. LT was noted to be a significant and independent predictor of MACE in a multivariate model adjusted for cardiovascular risk factors. LT ≥ 3000 s was the optimal cutoff value for predicting 6 month MACE [hazard ratio (HR): 2.48, 95% CI: 1.2-4.8, P= 0.008] and cardiovascular death [HR: 4.04, 95% CI : 1.3-12.0, P= 0.012 ] and 12 month MACE [HR:1.9, 95% CI: 1.04- 3.5,P= 0.03] and cardiovascular death [HR: 3.9,95% CI: 1.34-11.9, P= 0.013 ]. LT ≥ 3000 s was observed in 23% of ACS patients. Conclusions: Our study suggests that endogenous thrombolytic activity based on lysis of platelet rich thrombi can be assessed by the point of care GTT assay, which can help in identification of ACS patients at high risk of future cardiac events. Prolongation of OT may be explained by the antiplatelet effects of Aspirin and Clopidogrel, as both these drugs prolong time to thrombus formation and hence increase OT. Further large studies are required to study factors which can reduce thrombogenic potential, and improve endogenous thrombolytic activity, which can be monitored using the GTT to improve cardiovascular outcomes.

Atherosclerotic and restenotic lesions develop as a result of an excess inflammatory response to vascular injury. Glucocorticoid hormones have widely-recognised anti-inflammatory and anti-proliferative properties which appear to make them ideal candidates for inhibition of vascular lesion development. Indeed, administration of glucocorticoids to experimental animals does inhibit the growth of vascular lesions in some models. In addition, glucocorticoids are currently being trialled clinically as anti-restenotic agents. However, glucocorticoid excess in patients, either as a result of Cushing’s syndrome or chronic steroid therapy, is associated with enhanced CVD risk. Therefore, the effects of glucocorticoids on vascular lesion development remain imperfectly understood. The overall objective of these studies was to explore the influence of endogenous and exogenous glucocorticoids on vascular lesion development using murine models of atherosclerosis (ApoE-/- mice fed a “western” diet) and neointimal hyperplasia (wireinduced femoral artery injury). The work described in this thesis addresses the hypothesis that glucocorticoids are pro-atherogenic, yet anti-restenotic. Mice were bilaterally adrenalectomised to investigate the role of endogenous glucocorticoids on vascular lesion development. Removal of the adrenal glands had no influence on atherogenesis or neointima development. The influence of exogenous glucocorticoids on lesion development was assessed by orally administering dexamethasone (0.1 or 0.8mg/kg/day). Atherosclerotic lesion burden was augmented by dexamethasone administration. Conversely, fibro-proliferative neointimal proliferation was inhibited by dexamethasone. However, this effect was obscured by thrombotic lesion development. It was proposed that this thrombotic effect is attributable to increased plasminogen activator inhibitor-1 (PAI-1), which was tested using PAI-1 deficient mice. Although PAI-1 was found to mediate the systemic pro-thrombotic effect of dexamethasone, it is not required for the enhanced development of thrombotic lesions at the site of intra-luminal injury. These results suggest that physiological levels of endogenous glucocorticoids play a limited role in vascular lesion development. Conversely, although exogenous glucocorticoids inhibit fibro-proliferative intimal hyperplasia, they appear to have significant detrimental influences on lesion development, augmenting atherosclerosis and inducing thrombotic neointimal lesion formation following vascular injury. Further research is therefore required to improve the cardiovascular outcome of patients requiring glucocorticoid therapy and for the use of glucocorticoids as antirestenotic agents.

FDI inflow to developing countries has shown a drastic increase in the past few decades. Accordingly, many policy makers and academics are concerned about policies that attract FDI inflows to enhance economic growth from the positive spillover effects of FDI. Hence this study examines the general impact of FDI on the economic growth of 56 developing countries for the period 1985-2014. In order to analyze the growth effect of FDI into different macroeconomic situations, the sample countries are grouped into 24 low-income developing countries and 32 upper middle-income countries. The overall panel data analysis based on endogenous growth theory supported the positive growth effect of FDI for the pooled 56 countries and upper middle- income countries. However the growth effect of FDI for low-income countries tend to be statistically significant but negative. Moreover, to investigate the absorptive capacity of the host country an interactive term of FDI and human capital is included to estimate the general model. The regression results from the interactive term denote that the growth effect of FDI is dependent on the level of human capital in the host country. Hence a minimum level of human capital is essential in order to maximize and absorb the positive growth effect of FDI.

Human endogenous retroviruses are the remnants of ancient retroviral infections present within our genome. These molecular fossils show similarities with present day exogenous retroviruses but act as typical Mendelian elements that are passed vertically between generations. Despite being repeatedly linked to a number of autoimmune diseases and disorders, no conclusive proof has been identified. Rheumatoid arthritis (RA) is one such disease which has been associated with an increase in HERV expression, compared to controls. In order to elucidate a clear role for HERVs in RA pathogenesis, autoantigens implicated in disease pathogenesis were scanned for sequence homology to retroviral genes. Such epitopes would induce antibodies cross reactive with host proteins, resulting in disease. Short peptides mimicking these regions were synthesised and the prevalence of anti-HERV antibodies was determined in RA patients and disease controls. Additionally, a novel real-time Polymerase Chain Reaction (PCR) assay was developed to accurately quantify levels of HERV-K (HML-2) gag expression, relative to normalised levels of housekeeping gene expression. Both serological and molecular assays showed significant increases in HERV-K (HML-2) activity in RA patients compared to disease controls with CD4+ lymphocytes harbouring the highest activity. The real-time assay was also used to determine whether factors within the synovium could modulate HERVs, resulting in their upregulation. Exogenous viral protein expression and pro-inflammatory cytokines were shown to exert a significant modulatory effect over HERV-K (HML-2) transcription. From this data, it is clear that RA patients have increased levels of HERV-K (HML-2) gag activity compared to controls. Despite this it is likely that factors within the synovium such as exogenous viral expression and pro-inflammatory cytokines also influence HERV-K (HML-2) transcription possibly contributing to a role of bystander activation, i.e. being influenced by external factors, rather than actively contributing to disease processes. The exact role of HERVs in RA pathology remains elusive; however this research proposes several mechanisms by which HERV-K (HML-2) may contribute to disease.

The aims of the thesis were to examine i) whether the endogenous opioid system (EOS) is lateralized in human brain areas involved in processing of emotions and pain; ii) whether EOS responses to unilateral brain injury depend on side of lesion, and iii) whether in human alcoholics, this system is involved in molecular adaptations in brain areas relevant for cognitive control of addictive behavior and habit formation. The main findings were that (1) opioid peptides but not opioid receptors and classic neurotransmitters are markedly lateralized in the anterior cingulate cortex involved in processing of  positive and negative emotions and affective component of pain. The region-specific lateralization of neuronal networks expressing opioid peptides may underlie in part lateralization of higher functions in the human brain including emotions and pain. (2) Analysis of the effects of traumatic brain injury (TBI) demonstrated predominant alteration of dynorphin levels in the hippocampus ipsilateral to the injury, while injury to the right hemisphere affected dynorphin levels in the striatum and frontal cortex to a greater extent than that to the left hemisphere. Thus, trauma reveals a lateralization in the mechanisms mediating the response of dynorphin expressing neuronal networks in the brain. These networks may differentially mediate effects of left or right brain injury on lateralized brain functions. (3) In human alcoholics, the enkephalin and dynorphin systems were found to be downregulated in the caudate nucleus and / or putamen that may underlie in part changes in goal directed behavior and formation of a compulsive habit in alcoholics. In contrast to downregulation in these areas, PDYN mRNA and dynorphins in dorsolateral prefrontal cortex, k-opioid receptor mRNA in orbitofrontal cortex, and dynorphins in hippocampus were upregulated in alcoholics. Activation of the k-opioid receptor by upregulated dynorphins may underlie in part neurocognitive dysfunctions relevant for addiction and disrupted inhibitory control. We conclude that the EOS exhibits region-specific lateralization in human brain and brain-area specific lateralized response after unilateral TBI in mice; and that the EOS is involved in adaptive processes associated with specific aspects of alcohol dependence.

Ökonomen wie Wirtschaftspolitiker berufen sich auf die Neutralitätstheorie des Geldes, wenn sie eine Entpolitisierung der Geldpolitik fordern. Sowohl die Theorie der Geldneutralität als auch das Paradigma der Entpolitisierung der Geldpolitik sind jedoch problematisch. Die politökonomischen Entwicklungen nach der globalen Finanz- und Wirtschaftskrise 2007/2008 und die jüngsten Kontroversen über die Rolle und Bedeutung von Geld haben dies deutlich vor Augen geführt. Die vorliegende Arbeit diskutiert zunächst die konzeptionellen Grundlagen und theoretischen Modelle der Geldneutralität. Anschließend werden die zentralen theoretischen Annahmen und Aussagen der Neutralitätstheorie aus einer kritischen heterodoxen Perspektive hinterfragt. Es wird argumentiert, dass Geld eine nicht-neutrale Produktionskraft ist, die weder ökonomisch noch sozial neutral ist. Die Bedingungen, unter denen Geld verfügbar ist und zirkuliert, sind richtungsweisend für die ökonomische Entwicklung. Daher kann es auch kein neutrales Geld oder gar eine apolitische Geldpolitik geben. / The assumption of the neutrality of money is a widespread belief in mainstream economics. Accordingly, money is regarded as a neutral means of exchange that has no lasting effects on the real side of the economy. This study questions the conceptual validity of the neutrality assumption and its theoretical models arguing that its basic insights and predictions are problematic because they misrepresent the circumstances and conditions of the real economy. First, it discusses the conceptual grounds of the neutrality argument, which is based on the classical dichotomy approach and the notion of exogenous money. In a second step, it exposes the theoretical weaknesses of both the traditional and the contemporary versions of the neutral money models, that is, of the quantity theory and the rational-choice theory, by questioning its basic assumptions and implications. Finally, it argues from a critical heterodox perspective that rather than exogenous and neutral, money is endogenous and non-neutral, both in economic and social terms.