Understanding the meaning of the human genome codes is one of the keys to unlock the secrets of life. Despite having a fairly good grasp of the sequences of the human genome, we are still far from... Show moreUnderstanding the meaning of the human genome codes is one of the keys to unlock the secrets of life. Despite having a fairly good grasp of the sequences of the human genome, we are still far from understanding the functions of most parts of the genome and their involvement in diseases. The application of the CRISPR-Cas9 genome-editing systems revolutionized the way to study the function of the genome, not only the coding genes but also the non-coding genome. In this thesis, multiple CRISPR screening systems were designed and used to study the transport of chemotherapeutic drugs and the functions of non-coding regulatory elements in distinct biological pathways. Using the CRISPR screening systems, we identified previously known drug exporters such as ABCB1 and ABCG2 and a new doxorubicin importer gene SLC2A3 (GLUT3). We used an innovative dual-CRISPR system to study the functions of noncoding regulatory elements (NCREs) in their endogenous genomic environment. We provide the broad research community with a new tool to study the functions of NCREs in different biological aspects, and it is expected many more important NCREs will be discovered in the future, which would not only be relevant to fundamental biology but also to human diseases. Show less
In this thesis, we identify and/or analyse a couple of regulators of the TGF-β and Wnt signal transduction pathways that play important roles in breast cancer. Our aim was to understand how these... Show moreIn this thesis, we identify and/or analyse a couple of regulators of the TGF-β and Wnt signal transduction pathways that play important roles in breast cancer. Our aim was to understand how these regulators affect the different steps of these pathways, including receptor activation, post-translational modification of other transducing molecules, target gene transcription, as well as crosstalk with other cell signaling pathways. Insight in these mechanisms is expected to help to design strategies for therapeutic intervention in TGF-β and Wnt mediated breast cancer progression. Show less
This dissertation explores the relationship among creditors in sovereign debt restructuring and specifically focuses on the issue of inter-creditor equity. It consists of five ar ticles focusing... Show moreThis dissertation explores the relationship among creditors in sovereign debt restructuring and specifically focuses on the issue of inter-creditor equity. It consists of five ar ticles focusing on the core issues regarding inter-creditor equity in the context of domestic insolvency law. It is largely inspired by international developments on the legal reform and practice of sovereign debt restructuring in the past three years. Overall, this disser tation argues that a multilateral legal framework for sovereign debt restructuring should not take the form of a collective proceeding and should not include debt claims with all types of maturities. In the context of a cram-down, a safeguard procedure should be put in place to ensure that any amendment of the contract terms imposed by majority bondholders is fair and equitable with respect to minority bondholders who have voted against the amendment. Arbitral tr ibunals established pursuant to international investment treaties could serve as an appropriate forum to develop such a safeguard provision. A new arbitral tribunal, preferably modelled after the tribunal concerning the Bank for International Settlements, could apply the safeguard provision once developed, because not all Show less
