Institutionalism, Rawls, and Political Development: Theorizing about the Ideal of Institution Building

Philosophers usually seek for and justify moral and political orders by two methodologies. Rationalism claims that social organization of human beings should fit with human nature, and believes that a predefined conception of human nature, defined in terms of human capacities for the exercise of reason, can be established as the independent criterion for choosing and justifying the proper moral and political order. Institutionalism, on the other hand, believes that human nature is at least significantly shaped by the actual construction of moral and political orders by human beings, and by internalizing the social institutions in which they live, they create themselves. In this essay, I argue that rationalism is not a good methodology because it does not reflect the correct relationship between human beings and their institutional life. I will develop a philosophical theory of institutionalism, and argue that an institutionalist justification of the ideal of liberal democracy will encourage a political development towards liberalization and democratization. I will also argue that Rawls‘s justification of liberal democracy is such an institutionalist justification, and although it might seem to suggest otherwise, it not only speaks to citizens of western democracies, but also speaks to all moral persons from all other societies. The political development towards liberalization and democratization is a normative demand for any human society, if such a society strives to be a well-ordered society with long term legitimacy and stability. The exact degree of liberalization and democratization for any particular society will depend on the available means of communication and organization, but the normative demand for such a political development is present in every human society. Institutionalism represents human freedom in human beings‘ creation and justification of social institutions, which are man-made rules and norms aimed at guaranteeing social order among interacting human agents. As a ―liberalism of freedom,‖ institutionalism is therefore committed to a highest ideal of human institution building: institutions of a society should be justified to, and be obeyed by, all the members of this society, so that such a society is a political autonomy. In these terms, Rawls‘s justification of liberal democracy, although dependent on a public political culture of modern western democracies, is nevertheless not limited to this context. As an instantiation of institutionalism, Rawls‘s theory has a dimension of universalism. Ultimately, Rawls‘s justification of liberal democracy encourages every other human society on this earth to develop towards the ideal of liberal democracy

Do more mergers and acquisitions create value for the firm?

This thesis was submitted for the award of Doctor of Philosophy and was awarded by Brunel University LondonThis thesis is aimed to empirically investigate the performance impact of frequent acquisitions as an aggressive merger and acquisition (M&A) strategy for an acquiring firm. In literature related to the study of M&A, a common question is whether acquisitions improve the performance of acquirers. Neither theoretical nor empirical studies have a clear view on the performance effect of M&A. Some argue positively and some are opposite. Although existing research are mixed for their arguments, a takeover is commonly perceived as a shock to the firm with a constant effect on changing business performance. This static perception of M&A creates a difficulty in explaining why firms acquire others when the performance effect is negative. To address the issue, this thesis examines the M&A effect dynamically with taking into account the role of merger frequency in affecting performance. On the basis of a large sample that consists of about 14,000 acquisitions from more than 100 countries over last 12 years, the thesis finds that the investors perceive a lower value if the acquiring firm is involved in frequent mergers. This is because more mergers are expected to attract considerable amount of management attention away from profitable activities in order to digest the challenges of new business integration at least in the short run. This “digesting constraint” argument is evident by our estimations. Firm becomes less profitable in the short run after a merger shock, and this adverse effect can be more severe if the firm is involved in more frequent mergers. Evidence of the thesis further show that, the effect of merger shocks is not static and persistent, and it changes with time. The shock affects adversely profitability in the short run, usually lasting a couple of years, and then the negative effect on performance could be turned either oppositely if the firm digests the shock successfully, or otherwise, continuously but diminishing over time if the digestion takes longer such as for frequent acquisition. This finding implies that the pace of firm resilience to a merger shock can be affected by its merger strategies. The pace can be slow if the firm pursues frequent mergers aggressively. The performance effect of a merger shock is dynamic and changes with time. The dynamic view for merger shocks from this study opens a new vision for literature in merger studies. Overall the market expectation to a merger effect on changing firm performance is quite consistently related to what has actually happened to the firm after the merger shock

Targeting Mll1 H3K4 methyltransferase activity to guide cardiac lineage specific reprogramming of fibroblasts

Generation of induced cardiomyocytes (iCMs) directly from fibroblasts offers a great opportunity for cardiac disease modeling and cardiac regeneration. A major challenge of iCM generation is the low conversion rate. To address this issue, we attempted to identify small molecules that could potentiate the reprogramming ability towards cardiac fate by removing inhibitory roadblocks. Using mouse embryonic fibroblasts as the starting cell source, we first screened 47 cardiac development related epigenetic and transcription factors, and identified an unexpected role of H3K4 methyltransferase Mll1 and related factor Men1 in inhibiting iCM reprogramming. We then applied small molecules (MM408 and MI503) of Mll1 pathway inhibitors and observed an improved efficiency in converting embryonic fibroblasts and cardiac fibroblasts into functional cardiomyocyte-like cells. We further observed that these inhibitors directly suppressed the expression of Mll1 target gene Ebf1 involved in adipocyte differentiation. Consequently, Mll1 inhibition significantly decreased the formation of adipocytes during iCM induction. Therefore, Mll1 inhibitors likely increased iCM efficiency by suppressing alternative lineage gene expression. Our studies show that targeting Mll1 dependent H3K4 methyltransferase activity provides specificity in the process of cardiac reprogramming. These findings shed new light on the molecular mechanisms underlying cardiac conversion of fibroblasts and provide novel targets and small molecules to improve iCM reprogramming for clinical applications

Exploring Hierarchical Visualization Designs Using Phylogenetic Trees

Ongoing research on information visualization has produced an ever-increasing number of visualization designs. Despite this activity, limited progress has been made in categorizing this large number of information visualizations. This makes understanding their common design features challenging, and obscures the yet unexplored areas of novel designs. With this work, we provide categorization from an evolutionary perspective, leveraging a computational model to represent evolutionary processes, the phylogenetic tree. The result — a phylogenetic tree of a design corpus of hierarchical visualizations — enables better understanding of the various design features of hierarchical information visualizations, and further illuminates the space in which the visualizations lie, through support for interactive clustering and novel design suggestions. We demonstrate these benefits with our software system, where a corpus of two-dimensional hierarchical visualization designs is constructed into a phylogenetic tree. This software system supports visual interactive clustering and suggesting for novel designs; the latter capacity is also demonstrated via collaboration with an artist who sketched new designs using our system

Pyrimido[4,5‐ d ]pyrimidin‐4(1 H )‐one Derivatives as Selective Inhibitors of EGFR Threonine 790 to Methionine 790 (T790M) Mutants

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/99673/1/8545_ftp.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/99673/2/ange_201302313_sm_miscellaneous_information.pd

Pyrimido[4,5‐ d ]pyrimidin‐4(1 H )‐one Derivatives as Selective Inhibitors of EGFR Threonine 790 to Methionine 790 (T790M) Mutants

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/99681/1/8387_ftp.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/99681/2/anie_201302313_sm_miscellaneous_information.pd

A Dual-Readout F2 Assay That Combines Fluorescence Resonance Energy Transfer and Fluorescence Polarization for Monitoring Bimolecular Interactions

Forster (fluorescence) resonance energy transfer (FRET) and fluorescence polarization (FP) are widely used technologies for monitoring bimolecular interactions and have been extensively used in high-throughput screening (HTS) for probe and drug discovery. Despite their popularity in HTS, it has been recognized that different assay technologies may generate different hit lists for the same biochemical interaction. Due to the high cost of large-scale HTS campaigns, one has to make a critical choice to employee one assay platform for a particular HTS. Here we report the design and development of a dual-readout HTS assay that combines two assay technologies into one system using the Mcl-1 and Noxa BH3 peptide interaction as a model system. In this system, both FP and FRET signals were simultaneously monitored from one reaction, which is termed -Dual-Readout F2 assay- with F2 for FP and FRET. This dual-readout technology has been optimized in a 1,536-well ultra-HTS format for the discovery of Mcl-1 protein inhibitors and achieved a robust performance. This F2 assay was further validated by screening a library of 102,255 compounds. As two assay platforms are utilized for the same target simultaneously, hit information is enriched without increasing the screening cost. This strategy can be generally extended to other FP-based assays and is expected to enrich primary HTS information and enhance the hit quality of HTS campaigns.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90469/1/adt-2E2010-2E0292.pd

A covalently bound inhibitor triggers EZH2 degradation through CHIP‐mediated ubiquitination

Abstract Enhancer of zeste homolog 2 (EZH2) has been characterized as a critical oncogene and a promising drug target in human malignant tumors. The current EZH2 inhibitors strongly suppress the enhanced enzymatic function of mutant EZH2 in some lymphomas. However, the recent identification of a PRC2‐ and methyltransferase‐independent role of EZH2 indicates that a complete suppression of all oncogenic functions of EZH2 is needed. Here, we report a unique EZH2‐targeting strategy by identifying a gambogenic acid (GNA) derivative as a novel agent that specifically and covalently bound to Cys668 within the EZH2‐SET domain, triggering EZH2 degradation through COOH terminus of Hsp70‐interacting protein (CHIP)‐mediated ubiquitination. This class of inhibitors significantly suppressed H3K27Me3 and effectively reactivated polycomb repressor complex 2 (PRC2)‐silenced tumor suppressor genes. Moreover, the novel inhibitors significantly suppressed tumor growth in an EZH2‐dependent manner, and tumors bearing a non‐GNA‐interacting C668S‐EZH2 mutation exhibited resistance to the inhibitors. Together, our results identify the inhibition of the signaling pathway that governs GNA‐mediated destruction of EZH2 as a promising anti‐cancer strategy