VictorJuiz/thesis huggingface dataset:
Management of Uncertainties in Publish/Subscribe System
Keywords: publish/subscribe
uncertainty
filtering
routing

In the publish/subscribe paradigm, information providers disseminate publications to all consumers who have expressed interest by registering subscriptions. This paradigm has found wide-spread applications, ranging from selective information dissemination to network management. However, all existing publish/subscribe systems cannot capture uncertainty inherent to the information in either subscriptions or publications. In many situations the large number of data sources exhibit various kinds of uncertainties. Examples of imprecision include: exact knowledge to either specify subscriptions or publications is not available; the match between a subscription and a publication with uncertain data is approximate; the constraints used to define a match is not only content based, but also take the semantic information into consideration. All these kinds of uncertainties have not received much attention in the context of publish/subscribe systems. In this thesis, we propose new publish/subscribe models to express uncertainties and semantics in publications and subscriptions, along with the matching semantics for each model. We also develop efficient algorithms to perform filtering for our models so that it can be applied to process the rapidly increasing information on the Internet. A thorough experimental evaluation is presented to demonstrate that the proposed systems can offer scalability to large number of subscribers and high publishing rates.
Improvements to Field-Programmable Gate Array Design Efficiency using Logic Synthesis
Keywords: Logic Synthesis
Computer-Aided Design
Field-Programmable Gate Array
Boolean Satisfiability
Binary-Decision Diagram

As Field-Programmable Gate Array (FPGA) capacity can now support several processors on a single device, the scalability of FPGA design tools and methods has emerged as a major obstacle for the wider use of FPGAs. For example, logic synthesis, which has traditionally been the fastest step in the FPGA Computer-Aided Design (CAD) flow, now takes several hours to complete in a typical FPGA compile. In this work, we address this problem by focusing on two areas. First, we revisit FPGA logic synthesis and attempt to improve its scalability. Specifically, we look at a binary decision diagram (BDD) based logic synthesis flow, referred to as FBDD, where we improve its runtime by several fold with a marginal impact to the resulting circuit area. We do so by speeding up the classical cut generation problem by an order-of-magnitude which enables its application directly at the logic synthesis level. Following this, we introduce a guided partitioning technique using a fast global budgeting formulation, which enables us to optimize individual “pockets” within the circuit without degrading the overall circuit performance. By using partitioning we can significantly reduce the solution space of the logic synthesis problem and, furthermore, open up the possibility of parallelizing the logic synthesis step. The second area we look at is the area of Engineering Change Orders (ECOs). ECOs are incremental modifications to a design late in the design flow. This is beneficial since it is minimally disruptive to the existing circuit which preserves much of the engineering effort invested previously in the design. In a design flow where most of the steps are fully automated, ECOs still remain largely a manual process. This can often tie up a designer for weeks leading to missed project deadlines which is very detrimental to products whose life-cycle can span only a few months. As a solution to this, we show how we can leverage existing logic synthesis techniques to automatically modify a circuit in a minimally disruptive manner. This can significantly reduce the turn-around time when applying ECOs.
Essays on Environmental Policy, Heterogeneous Firms, Employment Dynamics and Inflation
Keywords: Macroeconomics
Environmental Economics
Employment Dynamics
Inflation

This thesis covers three issues: the aggregate and welfare effects of environmental policies when plants are heterogeneous; what causes the different patterns of employment dynamics in small versus large firms over business cycles; and the welfare costs of expected and unexpected inflation. In the first chapter, we show that accounting for plant heterogeneity is important for the evaluation of environmental policies. We develop a general equilibrium model in which monopolistic competitive plants differ in productivity, produce differentiated goods and choose optimally a discrete emission-reduction technology. Emission-reduction policies affect both the fraction of plants adopting the advanced emission-reduction technology and the market shares of those with high levels of productivity. Calibrated to the Canadian data, the model shows that the aggregate costs of an emission tax to implement the Kyoto Protocol are 40 percent larger than the costs that would result with homogenous plants. In the second chapter, we incorporate labor search frictions into a model with lumpy investment to explain a set of firm-size-related facts about the United States labor market dynamics over business cycles. Contrary to the predictions of standard models, we observe that job destruction is procyclical in small firms but countercyclical in large ones. Calibrated to U.S. data, the model generates this asymmetric pattern of employment dynamics in small versus large firms. This is because a favorable aggregate productivity shock tightens the labor market. A tighter labor market hurts investing small firms. As a result, workers move from small to large firms during booms. In the third chapter, we analyze the welfare costs of inflation when money is essential to facilitate trades among anonymous agents and information about nominal shocks is incomplete as in Lucas (1972). In the model, the transactions in which money is essential coincide with those in which agents are affected by monetary shocks. Consequently, the average value of money and its variation in value in different markets affect agents simultaneously when the supply of money changes. Calibrated to U.S. data, we find that the welfare costs of expected inflation are almost three orders higher than the welfare costs of unexpected inflation.
Agobard of Lyon: An Exploration of Carolingian Jewish-Christian Relations
Keywords: Agobard of Lyon
Jewish-Christian relations
anti-Judaism
Carolingians

Agobard of Lyon has usually been studied because of his writings about Jews. This dissertation likewise began from a desire to understand Agobard’s anti-Jewish writings, their content, motives, and impact. Approaching that topic from the basis of Agobard’s whole corpus of writings, however, forces an acknowledgment that Agobard cannot be reduced to simply “Agobard and the Jews,” although the subject clearly created a great amount of anxiety for him. Also, by beginning with Agobard’s own works, this dissertation discusses him on his own terms first, without relying on the historiographical tradition which defines him as a Visigoth, a tradition ultimately found wanting. This dissertation effectively dismantles the model of Agobard as a Visigoth working in the Carolingian world, and replaces it with a model of Agobard as a Carolingian. As such, this study explores his anti-Judaism in terms of his immediate historical context and links it with his other anxieties and the Carolingian desire for a perfect, Christian, society. Doing so also opens the door for a re-evaluation of the traditional interpretation of the Carolingian period as the last “golden age” of European Jews outside of Muslim Spain. At its conclusion, this study argues that the Carolingians, by deliberately attempting to create a Christian society, however “well” they treated Jews in their own time, laid some of the ideological groundwork for the later isolation and persecution of Jews in Europe. The introduction begins the exploration of Agobard’s historical context by discussing the history of both Louis’s empire and Agobard’s Lyon. The first chapter provides a quick summary of his life and works. From there, the dissertation turns to its in-depth study of Agobard in the second through fourth chapters. An analysis of his main anti-Jewish work, De iudaicis superstitionibus et erroribus in Chapter 3 is prefaced by a study of the character and possible roots of his anti-Judaism in Chapter 2. The last chapter looks at Agobard’s other concerns, how they relate to his writings on Judaism, and finally how his great amount of worry around Judaism can help shape our understanding of medieval Jewish-Christian relations.
The Role of the Glutamatergic System in Psychiatric Behavioral Endophenotypes in Mice: Implications for Schizophrenia
Keywords: NMDA receptor
D-serine
genetic animal models
behavioral neuroscience
schizophrenia

Reduced activity of the N-methyl-D-aspartate receptor (NMDAR) has been implicated in the pathophysiology of schizophrenia. The NMDAR contains a glycine site on the NR1 subunit that may be a promising therapeutic target for psychiatric illness. Recently, D-serine has been discovered to be a high-affinity endogenous activator of the NMDAR glycine site. Levels of D-serine in the brain are controlled by its synthesis enzyme serine racemase (Srr) and its catabolic enzyme D-amino acid oxidase (DAO). This work investigates the NMDAR glycine site, D-serine, and D-serine-regulatory enzymes Srr and DAO in the pathophysiology and treatment of symptomatology relevant to schizophrenia and other psychiatric disorders. Pharmacological and genetic mouse models were used to alter glycine site function and D-serine availability. Behavioral responses in these models were assessed. Administration of exogenous D-serine and the glycine transporter 1 (GlyT-1) inhibitor ALX-5407 improved performance of C57BL/6J mice in behavioral tests examining prepulse inhibition (PPI) or latent inhibition (LI). These compounds also reversed impairments induced by the NMDAR antagonist MK-801, and produced similar beneficial effects to the classical atypical antipsychotic clozapine. Mice carrying a point mutation that leads to diminished NMDAR glycine site function demonstrated abnormally persistent LI and deficits in social approach and spatial recognition that were reversible by D-serine or clozapine administration. Similarly, mutant mice that lacked Srr function and had a severe reduction in D-serine displayed impairments in sociability, PPI, spatial recognition and memory. Behavioral deficits in mice without Srr were exacerbated by MK-801 and rescued by treatment with D-serine or clozapine. A genetically-induced loss of DAO function in mice resulted in the elevation of brain D-serine levels, and produced improvements in spatial reversal memory and extinction of a learned response in the Morris water maze, consistent with the effects of exogenous D-serine application in wild-type mice. Thus, deficiencies in NMDAR glycine site function and D-serine availability produce behavioral disturbances that are relevant to the negative and cognitive symptoms of schizophrenia. Activation of the NMDAR glycine site by D-serine, GlyT-1 inhibition, or diminished DAO activity may be beneficial for the treatment of schizophrenia and other psychopathologies involving cognitive dysfunction and persistent repetitive behaviors.
The Role of Munc18 Proteins in Physiologic and Pathologic Exocytoses in the Pancreatic Acinar Cell
Keywords: Pancreatitis
Exocytosis
Acinar Cell
Molecular Biology
SNARE proteins
Munc18

Distinct membrane fusion events in the polarized pancreatic acinar cell involve highly specific interactions between distinct sets of SNARE proteins forming exocytotic complexes, whose assembly is modulated by distinct Munc18 proteins. The Munc18 isoform responsible for these exocytotic events in the acinar cell is unknown. Here, I postulate Munc18b to regulate apical exocytosis in the acinar cell. Current dogma for the pathogenesis of acute pancreatitis, including alcoholic pancreatitis, is mis-targeting and deregulated fusion of zymogen granules with lysosomal bodies in the acinar cells. This derangement results in premature activation of proteolytic zymogens and autophagic digestion of cellular contents. I have hypothesized an alternate mechanism, which is pathologic exocytosis occurring at the basolateral plasma membrane, and further propose Munc18c to mediate this process in alcoholic pancreatitis. The aims of this thesis are to demonstrate the roles of Munc18b and Munc18c in regulated apical exocytosis and pathologic basolateral exocytosis underling alcoholic pancreatitis, respectively. In Chapter Three, using both real-time and static imaging techniques and biochemical tools, I demonstrated that Munc18c is dissociated from the acinar basal plasma membrane (BPM) when stimulated with postprandial CCK8 preceding preincubation of acini with postprandial 20-50mM ethanol concentrations. This activated Syntaxin (Syn)-4 and SNAP-23 on the BPM to complex with VAMP proteins on the granule to form the exocytotic SNARE complex that triggered basolateral exocytosis. This molecular mechanism of pathologic basolateral exocytosis was recapitulated in an Ethanol-diet rat model of pancreatitis. In Chapter Four, I determined Munc18b to be in the apical pole of the acinar cell to appropriately bind cognate Syn-2 and Syn-3 in the apical PM and ZGs. Here, I examined the structure-function of Munc18b on amylase secretion by employing Munc18b mutants with distinct affinities to Syn-2 and Syn-3. In Chapter Five, I discovered a novel EF-hand Ca2+-binding protein called Cab45b, which binds Munc18b to regulate its membrane targeting and interactions with Syntaxins in the acinar cell in a manner that influenced Ca2+-induced amylase release. Taken together, these studies clarify our understanding of the role of Munc18 proteins involved in regulated and pathologic membrane fusion events underlying physiologic digestive enzyme secretion and clinical alcoholic pancreatitis.
Activity-based Functional Annotation of Unknown Proteins: HAD-like hydrolases from E. coli and S. cerevisiae
Keywords: Biochemical proteomics
enzymatic activity
haloacid dehalogenase-like hydrolases
substrate specificity
phosphatases
uncharacterized proteins

In all sequenced genomes, a large fraction of predicted genes encodes proteins of unknown biochemical function and up to 15% of the genes with ‘‘known’’ function are mis-annotated. Several global approaches are being employed to predict function, including sequence similarity searches, analysis of gene expression, protein interaction, and protein structure. Enzymes comprise a group of target proteins that require experimental characterization for accurate functional annotations. Here I applied enzyme genomics to identify new enzymes by screening individually purified proteins for enzymatic activity under relaxed reaction conditions, which allowed me to identify the subclass or sub-subclasses of enzymes to which the unknown protein belongs. Further biochemical characterization of proteins was facilitated by the application of secondary screens with natural substrates (substrate profiling). Application of general enzymatic screens and substrate profiling greatly sped up the identification of biochemical function of unknown proteins and the experimental verification of functional predictions produced by other functional genomics approaches. As a test case, I used this approach to characterize the members of the haloacid dehalogenase (HAD)-like hydrolase superfamily, which consists mainly of uncharacterized enzymes, with a few members shown to possess phosphatase, beta-phosphoglucomutase, phosphonatase, and dehalogenase activities. Low sequence similarity between the members of the HAD superfamily precludes the computational prediction of their substrates and functions. Using a representative set of 80 phosphorylated substrates I characterized the phosphatase activities of 21 soluble HADs from Escherichia coli and seven soluble HADs from Saccharomyces cerevisiae. E. coli HADs show broad and overlapping substrate specificity against a wide range of phosphorylated metabolites. The yeast enzymes were more specific, and one protein also showed protein phosphatase activity. Comparison of HAD substrate profiles from two model organisms showed several “functional niches” that are occupied by HADs, which include hydrolysis of nucleotides, phosphoglycolate, phosphoserine, and pyridoxal phosphate. I proposed the cellular function for a number of HADs from both organisms based on substrate specificities. The physiological relevance of the phosphatase activity with the preferred substrate was validated in vivo for one of the HADs, E. coli YniC.
Pre-quantization of the Moduli Space of Flat G-bundles
Keywords: Symplectic Geometry
Homotopy Theory

This thesis studies the pre-quantization of quasi-Hamiltonian group actions from a cohomological viewpoint. The compatibility of pre-quantization with symplectic reduction and the fusion product are established, and are used to understand the necessary and sufficient conditions for the pre-quantization of M(G,S), the moduli space of at flat G-bundles over a closed surface S. For a simply connected, compact, simple Lie group G, M(G,S) is known to be pre-quantizable at integer levels. For non-simply connected G, however, integrality of the level is not sufficient for pre-quantization, and this thesis determines the obstruction, namely a certain 3-dimensional cohomology class, that places further restrictions on the underlying level. The levels that admit a pre-quantization of the moduli space are determined explicitly for all non-simply connected, compact, simple Lie groups G. Partial results are obtained for the case of a surface S with marked points. Also, it is shown that via the bijective correspondence between quasi-Hamiltonian group actions and Hamiltonian loop group actions, the corresponding notions of prequantization coincide.
A Two-colour Reporter Screen and Application to Cell Cycle Transcription
Keywords: Saccharomyces cerevisiae
functional genomics

Development of genome-wide reagents has allowed systematic analysis of gene function. The experimental accessibility of budding yeast makes it a test-bed for technology development and application of new functional genomic tools and resources that pave the way for comparable efforts in higher eukaryotes. In this Thesis, I describe a two-color GFP-RFP reporter system I developed to assess the consequences of genetic perturbations on a promoter of interest. The dual-reporter system is compatible with the synthetic genetic array methodology, an approach that enables marked genetic elements to be introduced into arrays of yeast mutants via an automated procedure. I use this approach to probe cell cycle-regulation of histone gene transcription by introducing an HTA1 promoter-GFP reporter gene construct into an ordered array of ~4500 yeast deletion mutants. I scored defects in reporter gene expression for each mutant, generating a quantitative analysis of histone promoter activity. The results of my screen motivated a number of follow-up experiments, including chromatin immunoprecipitation, transcript profiling and genome-wide analysis of nucleosome positions, which revealed a previously unappreciated pathway that specifies regions of repressed chromatin in a cell cycle-sensitive manner. A novel aspect of this pathway is that it involves histone chaperones and a chromatin boundary element. Specifically, we discovered that the histone chaperone Rtt106 works with two other chaperones, Asf1 and the HIR complex, to create a repressive chromatin structure at histone promoters which is bound by the protein Yta7. It was clear from previous work that Asf1 and HIR repress transcription at HTA1 and that HIR localizes to and functions through a specific element in histone promoters. However, there was no previous data demonstrating a role for Rtt106 in cell cycle-dependent gene transcription. In sum, I describe a new genomic screen that I used to discover a novel pathway regulating cell cycle-dependent transcription. While I examined histone gene expression as proof-of-principle, my screening system could be applied to virtually any pathway for which a suitable reporter can be devised. I anticipate this methodology will enable yeast researchers to collect quantitative data on hundreds of gene expression pathways.
Investigation of the Mechanisms of Drug-induced Agranulocytosis
Keywords: idiosyncratic drug reactions
drug-induced agranulocytosis

Idiosyncratic drug reactions (IDRs) are unpredictable adverse drug reactions. Their exact mechanisms are unknown but most appear to be immune-mediated. Mechanistic studies require valid animal models, but there are very few available and none for the study of drug-induced agranulocytosis. Thus, the first part of my thesis has focused on the development of an animal model of agranulocytosis. We pursued many attempts to develop one in rabbits, guinea pigs, and rats by treatment with aminopyrine, amodiaquine, and clozapine and manipulating the factors hypothesized to be involved in the mechanism of IDRs such as reactive metabolite formation/detoxication and immune stimulation. Clozapine-induced agranulocytosis is not associated with immune memory, which suggests that it may not be immune-mediated. Therefore, other factors, specifically selenium and vitamin C deficiencies, were assessed as possible risk factors for clozapine-induced agranulocytosis. Despite many attempts, we were not able to develop an animal model of idiosyncratic drug-induced agranulocytosis. The second part of this thesis was focused on investigating the effects of clozapine on neutrophils. It is known that the reactive metabolite of clozapine increases neutrophil apoptosis in vitro; however, it was not clear that the conditions of these experiments reflect in vivo conditions. Therefore, the effect of clozapine on neutrophil kinetics in vivo was examined. We found that clozapine treatment decreased the half-life of circulating neutrophils and increased the rate of release of neutrophils in rabbits. Thus, even though these animals did not develop agranulocytosis clozapine did appear to cause neutrophil damage that was compensated for by an increased production of neutrophils. Failure of the bone marrow to keep up with the increased rate of neutrophil destruction in certain individuals could result in agranulocytosis. Alternatively, damage to neutrophils could lead to an immune response in some patients that results in agranulocytosis. The failure to develop an animal model of drug-induced agranulocytosis despite many attempts using interventions based on the current mechanistic hypotheses suggests that these hypotheses are wrong. However, it is also possible that we are just unable to overcome the default response of immune tolerance; future studies will examine this possibility and the mechanism of clozapine-induced neutrophil damage.