A Portrait of Freedom: A Bakhtinian Interpretation of Henry James\u27 The Portrait of a Lady

Few issues in the Jamesian corpus have been more controversial than Isabel Archer’s decision to return to her cruel husband Gilbert Osmond at the end of The Portrait of a Lady. While critics have often thought of Isabel’s decision as either unrealistic, unjustifiable, or misguided, her choice becomes more rational when viewed within the context of a Bakhtinian polyphonic novel. By seeing the novel as a free-flowing novel of voices about the nature of freedom, Isabel’s choice can be explained as holding true to her belief that “freedom” means holding steadfast to one’s responsibilities, a conclusion she reaches by synthesizing other ideas about freedom she has learned from other female characters in the novel. Portrait therefore is a “novel of voice”, where characters like Isabel reach self-actualization by interacting with speech, unrestrained and unprivileged, and creating a new, autonomous, unified self out of it

Statistical Process Control and Medical Surveillance. An Application with Liver Function Tests

Traditionally, medical surveillance of liver disease generally involves a battery of tests. This research used multivariate analysis techniques to reduce the number of measures required to identify liver dysfunction and found using a Transferase Index (a combination of three tests; ALT, AST, and GGT) provided the most satisfying assessment, but the single best indicator, ALT, may be sufficient. Transferase Index and ALT criterion were both applied to SPC control charts. Through the use of statistical process control (SPC), this research identified work zones possessing signs of adverse effects to an individual\u27s liver as a possible result of their work environment and demonstrated SPC as an excellent way to conduct medical surveillance. Industry has embraced SPC, and control charts, this research extended their scope and demonstrated their effective use in medical surveillance of the liver. This research showed they provide easy, efficient ways to monitor work environments

Fiscal and economic stability in the eurozone.

yesEvery day the news is filled with increasingly depressing news about the economy. The recent Autumn Statement (29 November 2011) to the House of Commons by UK Chancellor of the Exchequer, George Osborne, confirmed that the cause of a potential ?double dip? recession in the British economy lay largely at the doors of the European Union and, in particular, the eurozone. It is easy to understand why some commentators feel that perhaps the European single currency is in its death-throes, and that the European Union itself needs major structural revisions. But for the sake of perspective it is important to remember the underlying rationale behind the ?European project? which remains as relevant today as it did in the 1950s

Defining the Molecular Mechanisms of the Cerebral Cavernous Malformation Proteins

Cerebral cavernous malformations (CCM) are the second most common class of cerebrovascular brain malformations affecting .1-.5% of the population. The disease is manifested in endothelial cells as lesions of thin, dilated, and leaky capillaries lacking normal blood vessel-stromal interactions. Lesions cause varied symptoms ranging from minor headaches to seizure and hemorrhagic stroke. CCMs can be incurred sporadically or inherited in an autosomal dominant manner from loss of function mutations in one of three genes, CCM1/Krit1, CCM2/OSM, or CCM3/PDCD10. These mutations affect the actin cytoskeleton due to deregulated RhoA/ROCK signaling, which increases stress fiber incidence, reduces endothelial cell barrier function, and decreases angiogenesis in vitro. We demonstrate through global kinome profiling that numerous kinases controlling the actin cytoskeleton are deregulated. Of these, we demonstrate that the RhoA/ROCK effector Lim kinase is overactive and phosphorylates and in activates the actin depolymerizing factor cofilin. Importantly, in vitro CCM phenotypes are rescued with knock down of Lim kinase in CCM protein deficient cells. We further show that a potential molecular mechanism governing the elevated RhoA levels and activity is through the E3 ubiquitin ligase Smurf1, which associates with CCM2 but not CCM1 or CCM3 and is responsible for ubiquitinating GTP bound RhoA. Current cell culture and animal models of CCM have given insight into CCM phenotypes, but the study of patient cells are needed to validate these models and to test potential therapeutics. Thus, we provide proof of principle studies demonstrating the utility of both endothelial progenitor derived endothelial cells and pluripotent stem cells in CCM disease modeling for the ultimate goal of producing a library of patient induced pluripotent stem cells. Overall, our findings elaborate on and provide insight into the complex molecular pathways involved in CCM phenotypes while also making the first steps towards in vitro patient specific CCM disease modeling.Doctor of Philosoph

Multiple Signaling Pathways of Human Interleukin-8 Receptor A: Independent Regulation by Phosphorylation

Interleukin-8 (IL-8) receptor A (CXCR1) couples to a pertussis toxin- sensitive G protein to mediate phospholipase Cβ (PLCβ) activation and cellular responses. Responses to CXCR1 are attenuated by prior exposure of neutrophils to either IL-8, a cleavage product of the fifth component of complement (C5a) or n-formylated peptides (formylmethionylleucylphenylalanine, fMLP). To characterize the role of receptor phosphorylation in the regulation of the CXCR1, a phosphorylation- deficient mutant, M2CXCR1, was constructed. This receptor, stably expressed in RBL-2H3 cells, coupled more efficiently to G protein and stimulated enhanced phosphoinositide hydrolysis, cAMP production, exocytosis, and phospholipase D activation, and was resistant to IL-8-induced receptor internalization. The rate and total amount of ligand stimulated actin polymerization remained unchanged, but interestingly, chemotaxis was decreased by ~30% compared with the wild type receptor. To study the role of receptor phosphorylation in cross-desensitization of chemoattractant receptors, M2CXCR1 was coexpressed with cDNAs encoding receptors for either fMLP (FR), C5a (C5aR), or platelet-activating factor (PAFR). Both C5aR and PAFR were cross-phosphorylated upon M2CXCR1 activation, resulting in attenuated guanosine 5\u27-3\u27-O-(thio)triphosphate (GTPγS) binding in membranes. In contrast, FR and M2CXCR1 were resistant to cross- phosphorylation and cross-inhibition of GTPγS binding by other receptors. Despite the resistance of M2CXCR1 to cross-phosphorylation and receptor/G protein uncoupling, its susceptibility to cross-desensitization of its Ca2+ response by fMLP and C5a, was equivalent to CXCR1. Regardless of the enhancement in certain receptor functions in M2CXCR1 compared with the wild type CXCR1, the mutated receptors mediated equivalent PLCβ3 phosphorylation and cross-desensitization of Ca2+ mobilization by FR, C5aR, and PAFR. The results herein indicate that phosphorylation of CXCR1 regulates some, but not all of the receptors functions. While receptor phosphorylation inhibits G protein turnover, PLC activation, Ca2+ mobilization and secretion, it is required for normal chemotaxis and receptor internalization. Since phosphorylation of CXCR1 had no effect on its ability to induce phosphorylation of PLCβ3 or to mediate class-desensitization, these activities may be mediated by independently regulated pathways

The m-connecting imset and factorization for ADMG models

Directed acyclic graph (DAG) models have become widely studied and applied in statistics and machine learning -- indeed, their simplicity facilitates efficient procedures for learning and inference. Unfortunately, these models are not closed under marginalization, making them poorly equipped to handle systems with latent confounding. Acyclic directed mixed graph (ADMG) models characterize margins of DAG models, making them far better suited to handle such systems. However, ADMG models have not seen wide-spread use due to their complexity and a shortage of statistical tools for their analysis. In this paper, we introduce the m-connecting imset which provides an alternative representation for the independence models induced by ADMGs. Furthermore, we define the m-connecting factorization criterion for ADMG models, characterized by a single equation, and prove its equivalence to the global Markov property. The m-connecting imset and factorization criterion provide two new statistical tools for learning and inference with ADMG models. We demonstrate the usefulness of these tools by formulating and evaluating a consistent scoring criterion with a closed form solution

Are Nested Case-Control Studies Biased?

It has been recently asserted that the nested case-control study design, in which case-control sets are sampled from cohort risk sets, can introduce bias (“study design bias”) when there are lagged exposures. The bases for this claim include a theoretic and an “empirical evaluation” argument. Both of these arguments are examined and found to be incorrect. Appropriate methods to explore the performance of nested case-control study designs, analysis methods, and compute power and sample size from an existing cohort are described. This empirical evaluation approach relies on simulating case-control outcomes from risk sets in the cohort from which the case-control study is to be performed. Because it is based on the underlying cohort structure, the empirical evaluation can provide an assessment that is tailored to the specific characteristics of the study under consideration. The methods are illustrated using samples from the Colorado Plateau uranium miners cohort

Chronic intrauterine hypoxia interferes with aortic development in the late gestation ovine fetus

This study explored arterial remodelling in fetuses growth restricted by hypoxia. Chronically catheterized fetal sheep were made moderately or severely hypoxic by placental embolization for 15 days starting at gestational age 116-118 (term ∼147 days). Cross-sections of the aorta were analysed for collagen and elastin content using histological procedures, while immunofluorescence was applied to measure markers of vascular smooth muscle cell (VSMC) type. In frozen aortae quantitative PCR was used to measure mRNA levels of extracellular matrix (ECM) precursor proteins as well as molecular regulators of developmental and pathological remodelling. Relative to Control (n= 6), aortic wall thickness was increased by 23% in the Moderate group (n= 5) and 33% (P \u3c 0.01) in the Severe group (n= 5). Relative to Control, the Severe group exhibited a 5-fold increase in total collagen content (P \u3c 0.01) that paralleled increases in mRNA levels of procollagen I (P \u3c 0.05) and III and transforming growth factor β (TGF-β 1) (P \u3c 0.05). The percentage area stained for α-actin was inversely related to fetal arterial oxygen saturation (P \u3c 0.05) and total α-actin content was 45% higher in the Moderate group and 65% (P \u3c 0.05) higher in the Severe group, compared to Control. A 12% and 39% (P \u3c 0.05) reduction in relative elastic fibre content was observed in Moderate and Severe fetuses, respectively. mRNA levels of the elastolytic enzyme, matrix metalloproteinase-2 (MMP-2) were inversely correlated with fetal arterial oxygen saturation (P \u3c 0.05) (Fig. 7) and mRNA levels of its activator, membrane-type MMP (MTI-MMP), were elevated in the Severe group (P \u3c 0.05). Marked neointima formation was apparent in Severe fetuses (P \u3c 0.05) concomitant with an increase in E-selectin mRNA expression (P \u3c 0.05). Thus, aberrant aortic formation in utero mediated by molecular regulators of arterial growth occurs in response to chronic hypoxaemia. © 2011 The Authors. Journal compilation © 2011 The Physiological Society

Background stratified Poisson regression analysis of cohort data

Background stratified Poisson regression is an approach that has been used in the analysis of data derived from a variety of epidemiologically important studies of radiation-exposed populations, including uranium miners, nuclear industry workers, and atomic bomb survivors. We describe a novel approach to fit Poisson regression models that adjust for a set of covariates through background stratification while directly estimating the radiation-disease association of primary interest. The approach makes use of an expression for the Poisson likelihood that treats the coefficients for stratum-specific indicator variables as ‘nuisance’ variables and avoids the need to explicitly estimate the coefficients for these stratum-specific parameters. Log-linear models, as well as other general relative rate models, are accommodated. This approach is illustrated using data from the Life Span Study of Japanese atomic bomb survivors and data from a study of underground uranium miners. The point estimate and confidence interval obtained from this ‘conditional’ regression approach are identical to the values obtained using unconditional Poisson regression with model terms for each background stratum. Moreover, it is shown that the proposed approach allows estimation of background stratified Poisson regression models of non-standard form, such as models that parameterize latency effects, as well as regression models in which the number of strata is large, thereby overcoming the limitations of previously available statistical software for fitting background stratified Poisson regression models