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The primary objectives of this thesis are to clarify and distinguish the existence of regulatory expropriation from other types of indirect expropriation and to propose alternative ways to rescrutinise regulatory expropriation in light of its establishment and justification in international law. In pursuing the first objective, the research delves into certain national, regional, and international contexts, identifying the key features of regulatory expropriation – for instance, regulatory autonomy and regulatory interference – and conducts an extensive exploration of the relevant principles of international law. This exploration concentrates especially on the doctrine of police power and on principles that can contribute to an elaborated application of the doctrine for the identification of regulatory expropriation. With regard to the second objective, the research examines the principle of necessity in international law that functions to preclude the wrongfulness of a state’s act and also takes into account the interacting relationship between customary international law and bilateral investment agreements. In addition, the research goes a step further by means of its analysis of the necessity exception in WTO law. This thesis puts forward the conclusion that an arbitral approach to bona fide regulatory expropriation that can be justified in international law, if it is based on the elaborated application of the doctrine of police power and on the application of the principle of proportionality within the framework of the ends-means and the cause-effect, will be more desirable for investment treaty arbitration given that arbitration is a type of public law adjudication.

Hematopoietic stem cells (HSCs) maintain themselves throughout life by undergoing self-renewing divisions and by differentiating to generate all the blood and immune system cells in the body. Tumor suppressors play an important role in regulating signaling pathways that maintain HSCs while avoiding leukemogenesis. Deficiency in the tumor suppressor Pten depletes HSCs but expands leukemia-initiating cells. Understanding this mechanistic difference could lead to anti-leukemia therapies with less toxicity to HSCs. Indeed, the mTOR inhibitor, rapamycin, blocks HSC depletion and leukemogenesis in Pten-deficient cells, raising the question of how mTOR activation depletes HSCs. In contrast to what occurs after FoxO1/3/4 deletion, we found that the depletion of Pten-deficient HSCs was not caused by oxidative stress and could not be blocked by N-acetyl-cysteine. Instead, Pten deletion induced the expression of p16Ink4a and p53 in HSCs, and p19Arf and p53 in other hematopoietic cells. Rapamycin treatment attenuated these increases. Analysis of compound mutant mice indicated that p53 suppressed leukemogenesis and promoted HSC depletion after Pten deletion. p16Ink4a also promoted HSC depletion but had a limited role suppressing leukemogenesis. p19Arf suppressed leukemogenesis but did not deplete HSCs. Pten deficiency and FoxO deficiency therefore deplete HSCs by different mechanisms. These results provide functional evidence that mTOR activation depletes stem cells by inducing a tumor suppressor response. Little is known about whether autophagic processes are active in HSCs and whether they contribute to HSC maintenance. FIP200 plays important roles in mammalian autophagy and other cellular functions, but its role in hematopoiesis has not been examined. We found that conditional deletion of FIP200 in hematopoietic cells led to impaired autophagy in the fetal liver, severe anemia, and perinatal lethality. FIP200 was also cell-autonomously required for the maintenance of fetal HSCs as FIP200-deleted HSCs were unable to reconstitute lethally irradiated recipients. FIP200 ablation increased the rate of cell-cycling in HSCs, which may have contributed to HSC depletion. Interestingly, FIP200-deleted HSCs exhibited increased mitochondrial mass and elevated reactive oxygen species levels. Our data identify FIP200 as a key intrinsic regulator of fetal HSCs and implicate a potential role for autophagy in the maintenance of fetal hematopoiesis and HSCs.

Creating effective cellular interfaces that can provide specific cellular signals is important for a number of fields ranging from tissue engineering to biosensors. Electroconducting polymers, especially polypyrrole (PPy), have attracted much attention for use in numerous biomedical applications since they provide a potential platform for local delivery of electrical stimuli to target tissues. To effectively modulate cellular functions at neural interfaces, it is essential to incorporate a range of extracellular cues into conducting polymers according to specific applications, such as nerve guidance conduits and implantable neural probes. For nerve regeneration scaffolds, three dimensional forms are desired for control of critical properties, such as porosity, mechanical strength, and topography. However, most researchers have worked on conventional two-dimensional PPy films, which cannot mimic a native three-dimensional architecture. Thus, a portion of my work has focused on introducing three-dimensional nanofibrous features into PPy. I have investigated various coating conditions to obtain uniform and conductive nanofibers. Effectiveness of electrical stimulation through the conducting nanofibers was confirmed by in vitro PC12 cell culture. The effects of different conducting nanofiber topographies (random and aligned) on cell adhesion and neurite outgrowth were examined in conjunction with electrical stimulation. The benefits of immobilized-NGF could be combined with electrical stimuli, which could be an ideal platform for neural tissue engineering scaffolds. Thus, I have modified conducting polymers to display neurotrophic activity. Nerve growth factor (NGF) was chemically immobilized on two dimensional and three dimensional PPy substrates. Specific chemical conjugation was achieved and characterized using diverse techniques. Immobilized NGF was as effective as exogenous NGF in medium in inducing neurite development and extension. NGF immobilized on functionalized PPy substrates was stable in a physiological solution and under electrical stimulation, indicating effective prolonged activity. I also investigated another important application of conducting polymer-based materials for neural interfacing - passivating electrodes with a biocompatible polysaccharide, hyaluronic acid (HA). I synthesized electrically polymerizable HA by chemically conjugating amine-functionalized pyrrole derivatives with HA. This coating was stable under physiological conditions for three months and resistant to enzymatic degradation. In vitro studies have shown the minimal adhesion and migration of astrocytes on the HA-coated electrodes. Implantation of HA-coated commercial probes into rat cortices for three weeks revealed attenuated reactive astrocyte responses from the coated wires, and the importance of glial interaction with non-conducting sites was demonstrated.

In many countries, the payment structure in the telecommunications market is based on the Calling Party Pays Principle (CPP), in which only callers pay for calls. Since the CPP model has been generally accepted, little attention has been paid to the fact that call-receivers benefit from the calls without having to pay, except in telecommunications studies in 1970s. This “call externality” has been examined recently in research dealing with the Receiver Pays Principle (RPP). In this paper, I study the interconnection between a regulated fixed-line network and competitive mobile networks. Previous literature says that, under the CPP regime, mobile networks have an incentive to charge monopoly access charges, the profits from which are used to attract their own subscribers. However, taking into consideration the receiver’s utility reduces the mobile networks’ incentive for above-cost access charges. I consider this phenomenon to be a welfare transfer from fixed-line users to mobile users. I show that the welfare transfer is reversed as mobile networks take into account the receiving-utility of their own subscribers. This reversed welfare effect increases with the size of the receiver’s utility. However, the market outcome is still inefficient because the mobile access charges are not sufficiently low given the receiver’s utility. These results urge the introduction of a different payment regime into the telecommunications market to incorporate call externalities and remove access market distortions. I show that by introducing a new regime, “Bill-and-Keep”, which includes a Receiving Party Pays system and no access charges, efficient allocation can be achieved. Proper meet-points corresponding to receiver’s utilities are required for the efficient allocation. Theoretically, if a regulator is able to collect information about the costs of networks and the receiver’s utility, an optimal Bill-and-Keep regime can be introduced to the economy. But, because it’s nearly impossible to obtain this information, two practical Bill-and-Keep regimes are suggested: Central Office Bill-and-Keep and Meet-Point Bill-and-Keep. They only require information about transport costs, which are relatively easy to detect. Using a example model, I examine the welfare effect of the practical Bill-andKeep regimes for a range of values for the receiver’s utility. I show that for a Bill-and-Keep regime to be superior to a CPP regime the receiver’s utility should be fairly large. When receiver’s utility is small, a practical Bill-andKeep regime might not provide better total surplus than a market-driven CPP regime.

A new method of element decomposition is introduced in the formulation of a new shell finite element. The actual element is decomposed into a translational element defined completely by the nodal translations and a difference element representing the difference between the actual element and the translational element. An alternative form of coordinate transformation is also suggested to achieve a simple and systematic formulation. Three different types of elements, designated as types I, II and III, are derived by employing different assumptions on the displacement field of each component element. The type III element, in which the rotation of the translational element and the translation of the difference element are suppressed, gives the most favorable results. The element has properties similar to Ahmad's degenerate shell element, but shows better performance than the latter for all test problems considered in this study.