Should Investment Treaties Contain Public Policy Exceptions?

The increasing inclusion of exceptions in newly concluded investment treaties, together with the divergent manner in which tribunals and annulment committees have approached these provisions, suggests that a greater understanding of their role and purpose is needed. In particular, the question whether exceptions operate as permissions or as defenses is a crucial but unaddressed issue that has significant implications for both litigation and practice and, in turn, implications for the stability of the regime. This Essay argues that as a starting point, exceptions should be understood as permissions that limit the scope of the substantive treaty obligations, and not as defenses invoked to justify prima facie unlawful conduct. Understanding exceptions as permissions has several advantages, including the avoidance of double-counting a government’s motivation for its conduct or, more problematically, failing to take regulatory purpose into account when determining whether a government has complied with the treaty’s substantive obligations. Understanding exceptions as permissions also sends signals to adjudicators in relation to issues such as the appropriate standard of review. The Essay also explores the desirability of including exceptions in treaties in light of recent innovations that clarify the substantive content of investment obligations. Although the uncertain analytic character of existing exceptions risks constraining rather than preserving regulatory space, they may be an important failsafe in light of current institutional arrangements for investor-state dispute settlement, which effectively preclude review for error of law. The Essay concludes that the relationship between standards of investment protection and exceptions needs further consideration, and suggests that governments negotiating investment treaties ought to more holistically consider the aims of the regime and the role of exceptions therein

Regulation of Matrix Metallopeptidase-1 in Breast Cancer Metastasis

Matrix Metallopeptidase 1 (MMP-1) expression has repeatedly been correlated to tumorigenesis and metastasis. Yet, MMP-1 regulation in a metastatic context remains largely unknown. Here we confirm differential MMP-1 expression in mammary carcinoma cells with varied metastatic potentials and identify a mechanism differentially regulating MMP-1. We show that MMP-1 expression is regulated by an AP-1 element in its promoter in highly metastatic MDA-MB-231 mammary carcinoma cell derivatives. Fra-1, an AP-1 family transcription factor, differentially binds this element in highly metastatic derivatives compared to low-metastatic cells and is required for MMP1 expression. Fra-1 mRNA levels are unchanged in the cell variants, however its protein levels are higher in the metastatic cells. There was no change in protein degradation rates, while protein synthesis rates of Fra-1 increased. These results suggest that protein translation of Fra-1 is differentially regulated in these cells. Consistent with the importance of Fra-1 for tumor growth, we found that Fra-1 overexpression is sufficient to increase cell motility and anchorage independent growth. These results suggest that Fra-1 regulation is critical for regulation of MMP-1 and metastasis

Variations on a Theme: Comparing the Concept of Necessity in International Investment Law and WTO Law

The concept of necessity is used in many legal systems to delimit permissible from prohibited measures where such measures negatively affect the regime\u27s primary values, such as human rights, liberalized trade, and protection of foreign investment. International investment tribunals have adopted a variety of approaches to the question of whether a measure is necessary to achieve its objective in relation to a number of provisions of investment treaties, including non-precluded measures clauses and fair and equitable treatment. Yet their approaches to this form of analysis are inconsistent and generally not analytically robust. By comparison, WTO tribunals have developed relatively sophisticated methods for analyzing a measure\u27s necessity to achieve its objective in the context of general exceptions, sanitary and phytosanitary measures and technical regulations. The WTO approach generally takes into account a number of factors, including the importance of a measure\u27s objective, a measure\u27s effectiveness at achieving that objective, and the availability of alternative measures. Importantly, WTO tribunals generally undertake this analysis with a degree of deference, in recognition of the right of governments to set their own policy priorities. Investment tribunals could usefully employ aspects of the WITO approach to necessity\u27 in the context of non-precluded measures, fair and equitable treatment, non-discrimination, and non-expropriation. Such an approach would go some way toward the development of a consistent, coherent bod of cases in relation to the concept of necessity in international investment law, providing greater certainty for both host states and investors

Investigations on the Turbulent Wake of a Generic Space Launcher Geometry in the Hypersonic Flow Regime

The turbulent wake flow of generic rocket configurations is investigated experimentally and numerically at a freestream Mach number of 6.0 and a unit Reynolds number of 10 x 10^6. The flow condition is based on the trajectory of Ariane V at an altitude of 50 km, which is used as baseline to address the overarching tasks of wake flows in the hypersonic regime like fluid-structural coupling, reverse hot jets and base heating. Experiments using pressure transducers and high-speed schlieren measurement technique were conducted to gain insight into the local pressure fluctuations on the base and the oscillations of the recompression shock. This experimental configuration features a wedge-profiled strut orthogonally mounted to the main body. Additionally, the influence of cylindrical nozzle extensions attached to the base of the rocket is investigated, which is the link to the numerical investigations. Here, the axisymmetric model possesses a cylindrical sting support of the same diameter as the nozzle extensions. The sting support allows investigations of a undisturbed wake flow. A time-accurate zonal RANS/LES approach was applied to identify shocks, expansion waves, and the highly unsteady recompression region numerically. Subsequently, experimental and numerical results in the strut-averted region are opposed with regard to the wall pressure and recompression shock frequency spectra. For the compared configurations, experimental pressure spectra exhibit dominant Strouhal numbers at about S rD = 0.03 and 0.27 and the recompression shock oscillates at 0.2. In general, the numerical pressure and recompression shock fluctuations agree satisfactorily to the experimental results. The experiments with a blunt base reveal base-pressure spectra with dominant Strouhal numbers at 0.08 at the center position and 0.145, 0.21 − 0.22 and 0.31 − 0.33 at the outskirts of the base

Mid-channel proteolysis of the L-type voltage gated calcium channel and the potential role of amyloid-β precursor protein

L-type voltage-gated calcium channels are involved in many important physiological processes, including muscle contraction, hormone secretion and neuronal gene expression. These channels are regulated by many different mechanisms to tightly control calcium influx. Our lab has uncovered a new form of L-type channel regulation that involves the proteolysis of the channel in the main body of the alpha1 subunit in response to increased intracellular calcium, channel activity and age. I investigated the immediate and long-term functional impact of mid-channel proteolysis on the CaV1.2 channel. Mid-channel proteolysis causes an acute change in gating and a decrease in channel activity over a longer time scale. Fragment channels result from proteolysis, and these fragments associate on the plasma membrane to form functional channels. These L-type fragment channels exhibit different biophysical properties than full-length CaV1.2. While fragment channels must combine so that all four domains are present to be functional, non-complimentary pairs containing more than four domains still produce discernible current. L-type fragment channels co-immunoprecipitate with the full-length CaV1.2, indicating that fragments bind to either the alpha1 subunit or the channel complex. Some of these fragments cause a shift in inactivation and in the I-V curve of the channel, and one fragment comprising Domain IV and the C-terminus (fragment C2) inhibits full-length CaV1.2 in a dominant negative manner. These results demonstrate the functional effects of mid-channel proteolysis. L-type mid-channel proteolysis increases with animal age. Therefore, to identify the protease responsible for mid-channel proteolysis, I turned to proteases involved in aging diseases. Amyloid-β precursor protein (APP), a protein implicated in Alzheimer's disease (AD), modulates L-type channels and is itself extensively proteolyzed. One of those proteases is presenilin, the catalytic component to gamma-secretase. I found that APP dramatically reduced human CaV1.2 current in Xenopus oocytes. The current-voltage relationship and inactivation profiles of CaV1.2 in the presence of APP mirrored those of the fragment channels. Moreover, a gamma-secretase inhibitor, DAPT, completely reversed this effect. When an AD APP mutant was co-expressed with CaV1.2, currents were further diminished. Astonishingly, an APP mutant that protects against AD had the opposite effect, allowing larger CaV1.2 currents than wild-type APP. Western blots stained with an antibody against CaV1.2 revealed a ~100 kD band when APP was coexpressed with the channel, which was absent in oocytes solely expressing CaV1.2. DAPT application reversed this effect, indicating the band was a product of presenilin proteolysis. A putative cut site was found on the alpha1 subunit that would produce a band similar in size to the one observed in Western blots. When this site was mutated, the ~100 kD band no longer appeared when CaV1.2 was coexpressed with APP. Unfortunately, the CaV1.2 II-III loop antibody was later found to cross-react with APP. Therefore, additional experiments are necessary to determine whether the ~100 kD band is CaV1.2 Interestingly, APP induced mid-channel proteolysis was detected in primary neurons using imaging techniques. While the mechanism for APP-induced inhibition of the channel is still unresolved, my data clearly shows this effect is mediated by presenilin. Whether or not presenilin is responsible for cutting CaV1.2 remains to be resolved