Scoring the charter: A twenty-year analysis of supreme court voting trends (Pierre Trudeau).

The Charter has transformed the way the policy process is conducted in Canada. It has ushered in a revolution focused on individual and collective group rights. The entrenchment of codified rights and freedoms has forced the legislatures to conform to the contents within the Charter and has reshaped Canadian socio-political values. Various studies have attempted to explain the Charters role in this process, however the question left unanswered is how has the Charter reshaped the policy process and what is the impact to Canadian constitutionalism? This thesis seeks to answer this question through a detailed quantitative analysis. The body of this thesis will focus on three tenets of constitutionalism: First, the Constitution Act, 1982 implemented constitutional supremacy in Canadian law and policy, however, this shift raised many questions as to the relationship between the Court and legislatures. Second, the Charter was manufactured by Pierre Trudeau with a centralizing theme. Trudeau shaped the Charter to implement universal standards across Canada, which in effect was expected to decrease provincial autonomy. Trudeau\u27s nation building project focused on three areas: Mobility rights, Language and Education rights and Equality rights. This study seeks to assess whether the Charter has had the centralizing effects that Trudeau originally sought. Third, the influence of the individual justice was analyzed to asses what role the each justice plays in the Court, and second whether ideological congruencies exist within the Court. The database for this study will be composed exclusively of Supreme Court Charter cases. This thesis produces an important and necessary contribution to Canadian judicial literature in that it updates the database an additional five years from James Kelly\u27s study. Moreover, this thesis created a more sophisticated approach to analyzing whether ideological congruencies and individual biases influence the Court\u27s decision making process. However, quite simply, this study is significant and unique because it is the first study to focus on the exclusive impact of the Charter, by only focusing on explicit Charter cases. Thus not only will this study update the previous studies, it has corrected and modified them.Dept. of History, Philosophy, and Political Science. Paper copy at Leddy Library: Theses & Major Papers - Basement, West Bldg. / Call Number: Thesis2005 .D35. Source: Masters Abstracts International, Volume: 44-03, page: 1214. Thesis (M.A.)--University of Windsor (Canada), 2005

Analysis of Salmonella enterica Serotype Paratyphi A Gene Expression in the Blood of Bacteremic Patients in Bangladesh

Salmonella enterica serotype Paratyphi A is a significant and emerging global public health problem and accounts for one fifth of all cases of enteric fever in many areas of Asia. S. Paratyphi A only infects humans, and the lack of an appropriate animal model has limited the study of S. Paratyphi A infection. In this study, we report the application of an RNA analysis method, Selective Capture of Transcribed Sequences (SCOTS), to evaluate which S. Paratyphi A genes are expressed directly in the blood of infected humans. Our results provide insight into the bacterial adaptations and modifications that S. Paratyphi A may need to survive within infected humans and suggest that similar approaches may be applied to other pathogens in infected humans and animals

Comparative Proteomic Analysis of the PhoP Regulon in Salmonella enterica Serovar Typhi Versus Typhimurium

Background: S. Typhi, a human-restricted Salmonella enterica serovar, causes a systemic intracellular infection in humans (typhoid fever). In comparison, S. Typhimurium causes gastroenteritis in humans, but causes a systemic typhoidal illness in mice. The PhoP regulon is a well studied two component (PhoP/Q) coordinately regulated network of genes whose expression is required for intracellular survival of S. enterica. Methodology/Principal Findings: Using high performance liquid chromatography mass spectrometry (HPLC-MS/MS), we examined the protein expression profiles of three sequenced S. enterica strains: S. Typhimurium LT2, S. Typhi CT18, and S. Typhi Ty2 in PhoP-inducing and non-inducing conditions in vitro and compared these results to profiles of $phoP^−/Q^−$ mutants derived from S. Typhimurium LT2 and S. Typhi Ty2. Our analysis identified 53 proteins in S. Typhimurium LT2 and 56 proteins in S. Typhi that were regulated in a PhoP-dependent manner. As expected, many proteins identified in S. Typhi demonstrated concordant differential expression with a homologous protein in S. Typhimurium. However, three proteins (HlyE, STY1499, and CdtB) had no homolog in S. Typhimurium. HlyE is a pore-forming toxin. STY1499 encodes a stably expressed protein of unknown function transcribed in the same operon as HlyE. CdtB is a cytolethal distending toxin associated with DNA damage, cell cycle arrest, and cellular distension. Gene expression studies confirmed up-regulation of mRNA of HlyE, STY1499, and CdtB in S. Typhi in PhoP-inducing conditions. Conclusions/Significance: This study is the first protein expression study of the PhoP virulence associated regulon using strains of Salmonella mutant in PhoP, has identified three Typhi-unique proteins (CdtB, HlyE and STY1499) that are not present in the genome of the wide host-range Typhimurium, and includes the first protein expression profiling of a live attenuated bacterial vaccine studied in humans (Ty800)

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

DOT1L as a therapeutic target for the treatment of DNMT3A-mutant acute myeloid leukemia

Mutations in DNA methyltransferase 3A (DNMT3A) are common in acute myeloid leukemia and portend a poor prognosis; thus, new therapeutic strategies are needed. The likely mechanism by which DNMT3A loss contributes to leukemogenesis is altered DNA methylation and the attendant gene expression changes; however, our current understanding is incomplete. We observed that murine hematopoietic stem cells (HSCs) in which Dnmt3a had been conditionally deleted markedly overexpress the histone 3 lysine 79 (H3K79) methyltransferase, Dot1l. We demonstrate that Dnmt3a(-/-) HSCs have increased H3K79 methylation relative to wild-type (WT) HSCs, with the greatest increases noted at DNA methylation canyons, which are regions highly enriched for genes dysregulated in leukemia and prone to DNA methylation loss with Dnmt3a deletion. These findings led us to explore DOT1L as a therapeutic target for the treatment of DNMT3A-mutant AML. We show that pharmacologic inhibition of DOT1L resulted in decreased expression of oncogenic canyon-associated genes and led to dose- and time-dependent inhibition of proliferation, induction of apoptosis, cell-cycle arrest, and terminal differentiation in DNMT3A-mutant cell lines in vitro. We show in vivo efficacy of the DOT1L inhibitor EPZ5676 in a nude rat xenograft model of DNMT3A-mutant AML. DOT1L inhibition was also effective against primary patient DNMT3A-mutant AML samples, reducing colony-forming capacity (CFC) and inducing terminal differentiation in vitro. These studies suggest that DOT1L may play a critical role in DNMT3A-mutant leukemia. With pharmacologic inhibitors of DOT1L already in clinical trials, DOT1L could be an immediately actionable therapeutic target for the treatment of this poor prognosis disease

Camphene-Assisted Fabrication of Free-Standing Lithium-Ion Battery Electrode Composites

Free-standing electrode (FSE) architectures hold the potential to dramatically increase the gravimetric and volumetric energy density of lithium-ion batteries (LIBs) by eliminating the parasitic dead weight and volume associated with traditional metal foil current collectors. However, current FSE fabrication methods suffer from insufficient mechanical stability, electrochemical performance, or industrial adoptability. Here, we demonstrate a scalable camphene-assisted fabrication method that allows simultaneous casting and templating of FSEs comprising common LIB materials with a performance superior to their foil-cast counterparts. These porous, lightweight, and robust electrodes simultaneously enable enhanced rate performance by improving the mass and ion transport within the percolating conductive carbon pore network and eliminating current collectors for efficient and stable Li+ storage (>1000 cycles in half-cells) at increased gravimetric and areal energy densities. Compared to conventional foil-cast counterparts, the camphene-derived electrodes exhibit ∼1.5× enhanced gravimetric energy density, increased rate capability, and improved capacity retention in coin-cell configurations. A full cell containing both a free-standing anode and cathode was cycled for over 250 cycles with greater than 80% capacity retention at an areal capacity of 0.73 mA h/cm2. This active-material-agnostic electrode fabrication method holds potential to tailor the morphology of flexible, current-collector-free electrodes, thus enabling LIBs to be optimized for high power or high energy density Li+ storage. Furthermore, this platform provides an electrode fabrication method that is applicable to other electrochemical technologies and advanced manufacturing methods

Brainwide Genetic Sparse Cell Labeling to Illuminate the Morphology of Neurons and Glia with Cre-Dependent MORF Mice

Cajal recognized that the elaborate shape of neurons is fundamental to their function in the brain. However, there are no simple and generalizable genetic methods to study neuronal or glial cell morphology in the mammalian brain. Here, we describe four mouse lines conferring Cre-dependent sparse cell labeling based on mononucleotide repeat frameshift (MORF) as a stochastic translational switch. Notably, the optimized MORF3 mice, with a membrane-bound multivalent immunoreporter, confer Cre-dependent sparse and bright labeling of thousands of neurons, astrocytes, or microglia in each brain, revealing their intricate morphologies. MORF3 mice are compatible with imaging in tissue-cleared thick brain sections and with immuno-EM. An analysis of 151 MORF3-labeled developing retinal horizontal cells reveals novel morphological cell clusters and axonal maturation patterns. Our study demonstrates a conceptually novel, simple, generalizable, and scalable mouse genetic solution to sparsely label and illuminate the morphology of genetically defined neurons and glia in the mammalian brain

The Nup107-160 nucleoporin complex promotes mitotic events via control of the localization state of the chromosome passenger complex

The human Nup107-160 nucleoporin complex plays a major role in formation of the nuclear pore complex and is localized to kinetochores in mitosis. Here we report that Seh1, a component of the Nup107-160 complex, functions in chromosome alignment and segregation by regulating the centromeric localization of Aurora B and other chromosome passenger complex proteins. Localization of CENP-E is not affected by Seh1 depletion and analysis by electron microscopy showed that microtubule kinetochore attachments are intact. Seh1-depleted cells show impaired Aurora B localization, which results in severe defects in biorientation and organization of the spindle midzone and midbody. Our results indicate that a major function of the Nup107 complex in mitosis is to ensure the proper localization of the CPC at the centromere