VictorJuiz/thesis huggingface dataset:
Local Likelihood for Interval-censored and Aggregated Point Process Data
Keywords: Local likelihood
EMS algorithm
Disease mapping
Lupus

The use of the local likelihood method (Tibshirani and Hastie, 1987; Loader, 1996) in the presence of interval-censored or aggregated data leads to a natural consideration of an EM-type strategy, or rather a local EM algorithm. In the thesis, we consider local EM to analyze the point process data that are either interval-censored or aggregated into regional counts. We speciﬁcally formulate local EM algorithms for density, intensity and risk estimation and implement the algorithms using a piecewise constant function. We demonstrate that the use of the piecewise constant function at the E-step explicitly results in an iteration that involves an expectation, maximization and smoothing step, or an EMS algorithm considered in Silverman, Jones, Wilson and Nychka (1990). Consequently, we reveal a previously unknown connection between local EM and the EMS algorithm. From a theoretical perspective, local EM and the EMS algorithm complement each other. Although the statistical methodology literature often characterizes EMS methods as ad hoc, local likelihood suggests otherwise as the EMS algorithm arises naturally from a local likelihood consideration in the context of point processes. Moreover, the EMS algorithm not only serves as a convenient implementation of the local EM algorithm but also provides a set of theoretical tools to better understand the role of local EM. In particular, we present results that reinforce the suggestion that the pair of local EM and penalized likelihood are analogous to that of EM and likelihood. Applications include the analysis of bivariate interval-censored data as well as disease mapping for a rare disease, lupus, in the Greater Toronto Area.
Getting Behind the Grain: The Politics of Producer Opposition to GM Wheat on the Canadian Prairies
Keywords: agriculture
political economy and ecology

On May tenth, 2004 Monsanto announced that it would discontinue breeding and field level research of transgenic Roundup Ready (RR) wheat. This decision was heavily influenced by the widespread rejection of RR wheat by Canadian prairie producers who voiced their opposition through a diverse coalition of rural and urban organizations. With six of the nine member organizations representing rural and farm groups, this research departs from the most common representation of anti-GM movements as being urban and European-centred. This dissertation contrasts the general acceptance of Monsanto’s Roundup Ready canola just five years earlier (in the mid 90s) with the widespread opposition amongst prairie producers to RR wheat. It uses an updated version of the agrarian question and the production of nature thesis to show how capitalist relations are differentiated across place and commodities. The research finds that producer resistance to RR wheat hinged on the specificities of local histories and institutions, cultural conceptions of worth and economic fair treatment, and the character of wheat as a commodity with particular biophysical properties. The research is also concerned with the ways in which producers articulated their resistance with and through discourses of consumption, while at the same time rejecting the attempts made by proponents of RR wheat to relegate them to consuming subjects, who would best register their dissent by voting with their dollars on the market. For many prairie farm organizations, the fate of the family farm is tied up with the future of wheat farming and the capacity of farmers to collectively market their wheat in international markets. Monsanto’s vision for the future of prairie wheat crossed moral and cultural boundaries for producers and organizations that understood themselves as active subjects.
Modelling and Experimental Results on Stochastic Model Reduction, Protein Maturation, Macromolecular Crowding, and Time-varying Gene Expression.
Keywords: Gene expression
Noise and dynamics

Gene expression, which connects genomic information to functional units in living cells, has received substantial attention since the completion of The Human Genome Project. Quantitative characterization of gene expression will provide valuable information for understanding the behavior of living cells, and possibilities of building synthetic gene circuits to control or modify the behavior of naturally occurring cells. Many aspects of quantitative gene expression have been studied, including gene expression dynamics and noise in E. coli. The gene expression process itself is stochastic, and modelling approaches have been broadly used to study gene expression noise; however, stochastic gene expression models are usually large and time intensive to simulate. To speed up simulations, we have developed a systematic method to simplify gene expression models with fast and slow dynamics, and investigated when we can ignore the gene expression from the background genome when modelling the gene expression from plasmids. When modelling the noise in gene expression, one usually neglected aspect is the slow maturation process of fluorescent proteins, necessary for the protein to give out fluorescence after it is produced. By modelling, we show that the maturation steps can bring large changes to both the mean protein number and the noise in the model. An unstudied aspect of gene expression dynamics is the time dependent gene expression behavior in E. coli batch culture. Contrary to the usual assumption, we have found, in E. coli batch culture gene expression, that there is no steady state in terms of both the mean number of proteins and the noise. Negative feedback is thought to be able to reduce the noise in a system, and experiments have shown that negative feedback indeed suppresses the noise in gene expression, but the modelling shows that negative feedback will increase the noise. We have found that the increase of noise by feedback is due to the exclusion of extrinsic noise from the model, and that negative feedback will suppress the extrinsic noise while increasing the intrinsic noise. Living cells are crowded with macromolecules, which will, predicted by modelling, make the reaction constant time dependent. Our experimental observation has confirmed this prediction.
Functional Genomic Approaches to Study Cell Polarity Regulation by G1 Cyclins in Saccharomyces cerevisiae
Keywords: genomics
cell polarity

In the budding yeast Saccharomyces cerevisiae, the G1-specific cyclin-dependent kinases (Cdks) Cln1-, Cln2-Cdc28 and Pcl1-, Pcl2-Pho85 are essential for ensuring that DNA replication and cell division are properly linked to cell polarity and bud morphogenesis. However, like most genes in S. cerevisiae, individual cyclin genes are not required for viability, and the phenotypes associated with deletion of any single cyclin gene tend to be subtle. My goal was to dissect the cellular roles of the G1 cyclins by systematically identifying their genetic interactions. To do this, I conducted Synthetic Genetic Array (SGA) screens using strains deleted for different combinations of cyclin genes. The results of screens with strains deleted for the G1 cyclin pairs, CLN1, CLN2, or PCL1, PCL2, confirmed a role for these cyclins in cell polarity regulation and identified novel G1 Cdk substrates, which I examined in more detail. One cell polarity regulator that showed an interesting pattern of genetic interactions with G1 cyclins was BNI1, which encodes a yeast formin protein. Overexpression of BNI1 caused an Synthetic Dosage Lethal interaction in the absence of both G1 cyclin pairs while its deletion caused synthetic lethality specifically in the absence of PCL1, PCL2. Consistent with these genetic interactions, phosphorylation of Bni1 was partially dependent on CLN1, CLN2. It has been proposed that Bni1 is regulated by intramolecular interactions. In an effort to discover how phosphorylation might affect Bni1 function, I developed assays to test for intramolecular interactions. In my experiments I found no evidence that Bni1 is regulated by intramolecular binding, as was proposed from parallels with its mouse homolog mDia1. I also found that deletion of BNI4, which encodes an adaptor protein that targets several proteins to the bud neck, results in severe growth defects in the absence of the Cdc28 cyclins Cln1 and Cln2, and overexpression of BNI4 was toxic in yeast cells lacking the Pho85 cyclins Pcl1 and Pcl2. I discovered that Bni4 was phosphorylated by Pcl1- and Pcl2-Pho85 in vitro and that phosphorylation of Bni4 was dependent on PCL1 and PCL2 in vivo. Further analysis showed that phosphorylation of Bni4 by Pcl-Pho85 is necessary for its localization to bud neck, and the bud neck structure can be disrupted by overexpressing BNI4 in pcl1pcl2 mutant cells. I propose that if Bni4 cannot be regulated by phosphorylation, it may titrate away an essential component that resides at the bud neck, thus causing catastrophic morphogenesis defects. The relationship between G1 Cdk activity and the polarity regulator Bni4 serves as a bridge to link the cell cycle machine to the regulation of cell.
Multidrug Resistance Protein 1 (MDR1) and Glycosphingolipids Biosynthesis: Advantages for Therapeutics
Keywords: P-glycoprotein
Multidrug Resistance
glycosphingolipids
Fabry disease
Adamantyl Gb3

ABC drug transporter, MDR1, is a drug flippase that moves a variety of hydrophobic molecules from the inner to the outer leaflet of the plasma membrane. We have previously reported that MDR1 can function as a glycolipid flippase, being one of the mechanisms responsible for the translocation of glucosylceramide into the Golgi for neutral, but not acidic, glycosphingolipids (GSLs) synthesis. The interplay between GSLs and MDR1 could provide a whole new spectrum of innovative therapeutic options. We found that cell surface MDR1 partially co-localized with globotriaosyl ceramide (Gb3) in MDR1 transfected cells. Inhibition of GSL biosynthesis results in the loss of drug resistance and of cell surface MDR1. We speculated that an association of MDR1 and cell surface GSLs, in particular Gb3, may be functional at the cell surface, as MDR1 partitions into plasma membrane lipid rafts regulating MDR1 function. We therefore tested adamantyl Gb3 (adaGb3), a water soluble analog of Gb3, on MDR1 functions. AdaGb3 was able to inhibit MDR1-mediated rhodamine 123 drug efflux from MDR1 expressing cells, like cyclosporin A (CsA), a classical MDR1 inhibitor. AdaGb3 was also able to reverse vinblastine drug resistance in cell culture, whereas adamantyl galactosylceramide had no effect on drug resistance. The strong MDR1 reversal effects of adaGb3, as well as its favourable in vivo features make it a possible choice for inhibition of MDR1 to increase bioavailability of drugs across the intestinal epithelium (De Rosa et al., 2008). Thus, specific GSL analogs provide a new approach to MDR reversal. We have previously shown that MDR1 inhibitor CsA depletes Fabry cell lines of Gb3, the characteristic GSL accumulated in this disease, by preventing its de novo synthesis, and can also deplete Gaucher lymphoid cell lines of accumulated GlcCer (Mattocks et al., 2006). Liver and heart sections of Fabry mice treated with third generation MDR1 inhibitors showed significantly less Gb3 than liver and heart sections of untreated Fabry mice. Thus, MDR1 inhibition offers a potential alternative therapeutic approach not only for Fabry disease given the extraordinary cost of conventional enzyme replacement therapy, but also for other neutral GSL storage diseases, such as Gaucher disease.
Challenging the Behavioural Model: Exploring Individual, Interpersonal, and Structural Predictors of Adolescent Dual Protection Use
Keywords: Adolescent Health
Sexual Health

The optimal model to support adolescent sexual health is the concurrent use of hormonal birth control and condoms. This dual protection approach prioritizes protection against unplanned pregnancy as well as sexually transmitted diseases (STDs) and human immunodeficiency virus (HIV). In order to explore individual, interpersonal and structural factors that influence adolescent protection use, multivariate Chi-squared Automatic Interaction Detector (CHAID) analysis was completed with a national sample of adolescents (n=2320) from the 2002 Canadian Youth, Sexual Health, and HIV/AIDS Study. CHAID is a decision tree method which assesses interactions between significant independent variables to optimize prediction of the dependent variable (i.e. safer-sex protection method). Among adolescent females, the following factors were associated with dual protection use: high condom intentions; having lived with both biological parents; having accessed a medical professional or media as the primary source of HIV/AIDS information; having utilized a medical professional as the primary source of sexual health information; having never had unwanted sex; having not consumed alcohol and/or drugs before sex; frequent sexual activity; having identified a medical professional as the primary source of STD advice; having been tested for STDs; and having supported the importance of talking about condoms with a partner. Among adolescent males, dual protection was associated with: high condom intentions; frequent sexual activity; the belief that both partners are responsible for condom use; having been born in Canada; having noted uncertain or high levels of religiosity; having been older than 14 at first sexual intercourse; having been able to speak with their father about sex; having accessed a medical professional or media as the primary source of HIV/AIDS information; and having reported a peer group that did not use tobacco. The results indicate that structural factors, in concert with individual and interpersonal factors, play a vital role in understanding adolescent safer-sex practices. Policy and practice implications include revisions to sexual health curricula, sexual health service accessibility for all adolescents, and targeted prevention programming for adolescents at highest risk. Further research into the sexual health of male adolescents and the influence of structural factors on sexual health among diverse samples should be prioritized.
Heraldry in the Trecento Madrigal
Keywords: medieval music
heraldry
Italy

This study investigates a repertoire of eighteen madrigals whose texts refer to heraldry, all of which were composed in trecento Italy. The hereditary and personal arms cited in the song texts are those of the Visconti, Della Scala and Carrara families of northern Italy. Though these madrigals have been used in the past as a means for dating manuscripts and reconstructing composer biographies, they have never been studied as a discrete repertoire. This study applies musicological, heraldic and art historical approaches to the repertoire in order to investigate the heraldic madrigal as a manifestation of political authority in trecento Italy. Part One offers background information necessary to the understanding of the heraldic madrigal repertoire. Chapter 1 presents a glossary of heraldic terminology, and an overview of the role of heraldry in late medieval life, art and literature, focusing on heraldry as a means of representing ideas of authority and identity in the late Middle Ages. Chapter 2 defines the heraldic madrigal and discusses the stylistic features unique to this repertoire. This chapter also considers the heraldic madrigal in the context of contemporary musical repertoires such as the Italian motet and the songs of the French ars subtilior. Chapter 3 presents a critical edition of heraldic madrigal texts with translations. Part Two consists of case studies. Chapter 4 explores the link between Jacopo da Bologna’s madrigal Aquila altera and the references to the Holy Trinity in the heraldry of its dedicatees, Giangaleazzo Visconti and Isabelle de Valois. Chapter 5 offers a re-evaluation of the poem La fiera testa, challenging the common opinion that the text is condemnatory. Chapter 6 considers non-musical models for the the madrigal texts Inperiale sedendo and Per quella strada, based on manuscripts owned by and dedicated to the Carrara family. The Conclusion of this study touches briefly on the legacy of the heraldic madrigal, giving a summary of later Italian songs containing references to the heraldry of noble families, such as the Malatesta and Medici.
Marketing Institutions of Afforestation Generated Carbon Offsets in Canada: Political Sustainability, Ideology and the New Institutional Economics
Keywords: afforestation
new institutional economics
policy
ideology
carbon offset

Anthropogenically forced climate change has emerged as one of the most important, and polarizing, issues of our time. Afforestation generated carbon offset projects hold a position in Canada as potentially influential, yet frustratingly under-utilized, options to mitigate climate change. This dissertation responds to the question, “what are the economic implications of afforestation generated carbon offset institutions in Canada – and how appropriate are the tools of the New Institutional Economics (NIE) in their identification?” I establish the context for discussion by arguing that the NIE, as practiced, seems incapable of providing rigorous analysis while simultaneously responding to questions of power and distribution. The case of afforestation generated carbon offset marketing is presented as an appropriate context for exploring this point. A literature review is then used to establish general patterns regarding aggregating institutions for offset production and marketing, and aggregating institutions are presented as a response to the effects of transaction costs on the Canadian offset market. I then develop supply and demand curves to describe the equilibrium state of the Canadian offset market, into which the transaction costs borne by three aggregators are integrated. Their performance in fulfilling various policy objectives is evaluated. The results indicate that the primary variation between scenarios is the distribution of benefits. This focus on the distribution of benefits continues through demonstrating how subtle variations in modeling coefficients affect the regional distribution of afforestation projects within Canada, identifying the power associated with policy maker ideology. The role of policy maker ideology is then explicitly examined through a survey of government analysts and technicians and the application of discriminant analysis. The primary axes of afforestation ideology are identified, and demonstrated to be independent of concerns of transaction costs and aggregation. These results are integrated to argue that distributional concerns, particularly when ideologies are active in informing policy maker preferences, are critical to achieving sustainable policy outcomes, and that the NIE can respond to such concerns, but only if reform takes place to legitimate these techniques as part of the standard economic discourse.
The Impact of GB Virus C co-infection on Mother to Child transmission of Human Immunodeficiency Virus
Keywords: HIV
GBV-C
vertical transmission
mother-to-child
Thailand
perinatal

GB virus C (GBV-C) is a common, apathogenic virus that can inhibit human immunodeficiency virus (HIV) replication in vitro. Persistent coinfection with GBV-C has been associated with improved survival among HIV-infected adults while loss of GBV-C viremia has been associated with poor survival. If GBV-C does inhibit HIV replication, it is possible that GBV-C infection may reduce mother-to-child-transmission (MTCT) of HIV. This study investigated whether maternal or infant GBV-C infection was associated with reduced MTCT of HIV infection. The study population consisted of 1,783 pregnant women from three Bangkok perinatal HIV transmission studies (1992-94, 1996-7, 1999-2004). We tested plasma collected at delivery for GBV-C RNA, GBV-C antibody, and GBV-C viral genotype. If maternal GBV-C RNA was detected, the four- or six-month infant specimen was tested for GBV-C RNA. Rates of MTCT of HIV in GBV-C-infected and GBV-C-uninfected women and infants were compared using multiple logistic regression as were associations with MTCT of GBV-C and prevalence of GBV-C infection. The prevalence of GBV-C infection (i.e. presence of RNA or antibody) was 33% among HIV-infected women and 15% among HIV-uninfected women. Forty-one percent of GBV-C-RNA-positive women transmitted GBV-C to their infants. Only two of 101 (2.0%) GBV-C-RNA-positive infants acquired HIV infection compared to 162 (13.2%) of 1,232 of GBV-C-RNA-negative infants (RR 0.15, p<0.0001). This association remained after adjustment for maternal HIV viral load, antiretroviral prophylaxis, CD4+ count and other covariates. MTCT of HIV was not associated with presence of maternal GBV-C RNA or maternal GBV-C antibody. Maternal receipt of antiretroviral therapy was associated with increased MTCT of GBV-C, as was high GBV-C viral load, vaginal delivery and absence of infant HIV infection. GBV-C infection among women was independently associated with more than one lifetime sexual partner, intravenous drug use and HIV-infection. We observed a higher prevalence of GBV-C infection among HIV-infected compared to HIV-uninfected pregnant women in Thailand, likely due to common risk factors. Antiretroviral therapy appears to increase MTCT of GBV-C. Infant GBV-C acquisition, but not maternal GBV-C infection, was significantly associated with reduced MTCT of HIV. Mechanisms for these later two associations are unknown.