Effectively Enforcing Minimality During Backtrack Search

Constraint Processing is an expressive and powerful framework for modeling and solving combinatorial decision problems. Enforcing consistency during backtrack search is an effective technique for reducing thrashing in a large search tree. The higher the level of the consistency enforced, the stronger the pruning of inconsistent subtrees. Recently, high-level consistencies (HLC) were shown to be instrumental for solving difficult instances. In particular, minimality, which is guaranteed to prune all inconsistent branches, is advantageous even when enforced locally. In this thesis, we study two algorithms for computing minimality and propose three new mechanisms that significantly improve performance. Then, we integrate the resulting algorithms in a portfolio that operates both locally and dynamically during search. Finally, we empirically evaluate the performance of our approach on benchmark problems. Adviser: Berthe Y. Choueir

The Truly Disadvantaged: Structuring an Agenda for Change

This manuscript addresses the question as to how we may best structure an agenda for change aimed at improving the economic situation for the truly disadvantaged. I have chosen to address this question within the limits set by existing political circumstances. Policy proposals are presented because they are believed to be achievable and would be effective if implemented. It is impossible to think about this question without considering the proposals presented by William J. Wilson in his pathbreaking book, The Truly Disadvantaged (1987). Consequently, I briefly describe the intellectual context within which Wilson wrote his book and analyze the basic assumptions which underlay his proposals. On the whole, I believe Wilson\u27s analysis to be sound and the proposals that he presents to be invaluable. Nevertheless, there are some difficulties with his formulation of the problem. Some of his assumptions are flawed and, consequently, his proposals, while pointed in the right direction, do not go far enough

The yeast protein kinase Mps1p is required for assembly of the integral spindle pole body component Spc42p

Saccharomyces cerevisiae MPS1 encodes an essential protein kinase that has roles in spindle pole body (SPB) duplication and the spindle checkpoint. Previously characterized MPS1 mutants fail in both functions, leading to aberrant DNA segregation with lethal consequences. Here, we report the identification of a unique conditional allele, mps1–8, that is defective in SPB duplication but not the spindle checkpoint. The mutations in mps1-8 are in the noncatalytic region of MPS1, and analysis of the mutant protein indicates that Mps1-8p has wild-type kinase activity in vitro. A screen for dosage suppressors of the mps1-8 conditional growth phenotype identified the gene encoding the integral SPB component SPC42. Additional analysis revealed that mps1-8 exhibits synthetic growth defects when combined with certain mutant alleles of SPC42. An epitope-tagged version of Mps1p (Mps1p-myc) localizes to SPBs and kinetochores by immunofluorescence microscopy and immuno-EM analysis. This is consistent with the physical interaction we detect between Mps1p and Spc42p by coimmunoprecipitation. Spc42p is a substrate for Mps1p phosphorylation in vitro, and Spc42p phosphorylation is dependent on Mps1p in vivo. Finally, Spc42p assembly is abnormal in a mps1-1 mutant strain. We conclude that Mps1p regulates assembly of the integral SPB component Spc42p during SPB duplication

ERK and MMPs Sequentially Regulate Distinct Stages of Epithelial Tubule Development

AbstractEpithelial cells undergo tubulogenesis in response to morphogens such as hepatocyte growth factor (HGF). To organize into tubules, cells must execute a complex series of morphogenetic events; however, the mechanisms that underlie the timing and sequence of these events are poorly understood. Here, we show that downstream effectors of HGF coordinately regulate successive stages of tubulogenesis. Activation of extracellular-regulated kinase (ERK) is necessary and sufficient for the initial stage, during which cells depolarize and migrate. ERK becomes dispensable for the latter stage, during which cells repolarize and differentiate. Conversely, the activity of matrix metalloproteases (MMPs) is essential for the late stage but not the initial stage. Thus, ERK and MMPs define two regulatory subprograms that act in sequence. By inducing these reciprocal signals, HGF directs the morphogenetic progression of tubule development

Epstein-Barr Virus LMP2A Reduces Hyperactivation Induced by LMP1 to Restore Normal B Cell Phenotype in Transgenic Mice

Epstein-Barr virus (EBV) latently infects most of the human population and is strongly associated with lymphoproliferative disorders. EBV encodes several latency proteins affecting B cell proliferation and survival, including latent membrane protein 2A (LMP2A) and the EBV oncoprotein LMP1. LMP1 and LMP2A signaling mimics CD40 and BCR signaling, respectively, and has been proposed to alter B cell functions including the ability of latently-infected B cells to access and transit the germinal center. In addition, several studies suggested a role for LMP2A modulation of LMP1 signaling in cell lines by alteration of TRAFs, signaling molecules used by LMP1. In this study, we investigated whether LMP1 and LMP2A co-expression in a transgenic mouse model alters B cell maturation and the response to antigen, and whether LMP2A modulates LMP1 function. Naïve LMP1/2A mice had similar lymphocyte populations and antibody production by flow cytometry and ELISA compared to controls. In the response to antigen, LMP2A expression in LMP1/2A animals rescued the impairment in germinal center generation promoted by LMP1. LMP1/2A animals produced high-affinity, class-switched antibody and plasma cells at levels similar to controls. In vitro, LMP1 upregulated activation markers and promoted B cell hyperproliferation, and co-expression of LMP2A restored a wild-type phenotype. By RT-PCR and immunoblot, LMP1 B cells demonstrated TRAF2 levels four-fold higher than non-transgenic controls, and co-expression of LMP2A restored TRAF2 levels to wild-type levels. No difference in TRAF3 levels was detected. While modulation of other TRAF family members remains to be assessed, normalization of the LMP1-induced B cell phenotype through LMP2A modulation of TRAF2 may be a pathway by which LMP2A controls B cell function. These findings identify an advance in the understanding of how Epstein-Barr virus can access the germinal center in vivo, a site critical for both the genesis of immunological memory and of virus-associated tumors

Protest participation and economic crisis: The conditioning role of political opportunities

The economic crisis that started in 2008 has negatively affected European nations to different degrees. The sudden rise in demonstrations particularly in those countries most hard hit by the crisis suggests that grievance theories, dismissed in favour of resource-based models since the 1970s, might have a role to play for explaining protest behaviour. While most previous studies have tested these theories at the individual or contextual level, it is likely that mechanisms at both levels are interrelated. To fill this lacuna, we examine the ways in which individual-level grievances interact with macro-level factors to impact on protest behaviour. In particular, we examine whether the impact of individual subjective feelings of deprivation is conditional on contextual macroeconomic and policy factors. We find that while individual-level relative deprivation has a direct effect on the propensity to have protested in the last year, this effect is greater under certain macroeconomic and political conditions. We interpret both significant results for the cross-level interactions in terms of their role for opening up political opportunities for protest amongst those who felt they had been most deprived in the current crisis. These findings suggest that the interaction of the contextual and individual level should continue to be explored in future studies in order to further clarify the mechanisms underlying protest behaviour

Effectively Enforcing Minimality During Backtrack Search

Constraint Processing is an expressive and powerful framework for modeling and solving combinatorial decision problems. Enforcing consistency during backtrack search is an effective technique for reducing thrashing in a large search tree. The higher the level of the consistency enforced, the stronger the pruning of inconsistent subtrees. Recently, high-level consistencies (HLC) were shown to be instrumental for solving difficult instances. In particular, minimality, which is guaranteed to prune all inconsistent branches, is advantageous even when enforced locally. In this thesis, we study two algorithms for computing minimality and propose three new mechanisms that significantly improve performance. Then, we integrate the resulting algorithms in a portfolio that operates both locally and dynamically during search. Finally, we empirically evaluate the performance of our approach on benchmark problems. Adviser: Berthe Y. Choueir

A systematic approach to the development of fluorescent contrast agents for optical imaging of mouse cancer models

In the past decade, our increased elucidation of the molecular basis of cancer has led to the development of novel targeted strategies for specific inhibition of cancer signaling pathways that control growth, proliferation, apoptosis, and angiogenesis. Several monoclonal-antibody-based therapeutics and small-molecule drugs have received clearance for use as human therapeutics [1]. However, among these successes are many candidate drugs that have failed in clinical trials despite promising preclinical results [2]. The development of targeted therapeutics is expensive and time consuming. In their Critical Path Initiative, the United States Food and Drug Administration emphasized the need for more effective tools to facilitate the rapid development of improved cancer therapeutics. One such tool is the use of targeted molecular optical imaging probes or contrast agents to visualize the underlying processes in cancer. Optical imaging, also known as molecular imaging, is a rapidly developing field of research aimed at noninvasively interrogating animals for disease progression, evaluating the effects of a drug, assessing the pharmacokinetic behavior of a drug, or identifying molecular biomarkers of disease. A prerequisite of molecular imaging is the development of specific, targeted imaging contrast agents to assess these biological processes. Several optical aids have shown great utility in animal studies, including bioluminescence, fluorescent proteins, and fluorochrome-labeled agents. However, only the latter have the advantage of being potentially relevant to human clinical applications. The complexity of developing robust fluorochrome-labeled optical agents is often underestimated. Many studies describe the use of these agents, but guidelines for their development and testing are not readily available. The purpose of this review is to outline some of the considerations for developing and using fluorochrome-labeled optical contrast agents in animals. For simplicity, we have focused on the use of organic fluorochromes as labeling agents. These types of probes are generally the most straightforward to develop and have the greatest potential for translation to human clinical use. Nanoparticles such as quantum dots, while useful for some animal studies, are hampered by clearance issues and toxicity and will not be specifically discussed. However, the principles described here are generally applicable to any fluorescent optical imaging agent