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Search Results: 1 - 10 of 302008 matches for " Mary J. Emond? "
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A new mixture model approach to analyzing allelic-loss data using Bayes factors
Manisha Desai, Mary J Emond
BMC Bioinformatics , 2004, DOI: 10.1186/1471-2105-5-182
Abstract: We propose a large class of mixture models for describing the data, and we suggest using Bayes factors to select a reasonable model from the class in order to classify the chromosome arms. Bayes factors are especially useful in the case of testing that the number of components in a mixture model is n0 versus n1. In these cases, frequentist test statistics based on the likelihood ratio statistic have unknown distributions and are therefore not applicable. Our simulation study shows that Bayes factors favor the right model most of the time when tumor suppressor genes are present. When no tumor suppressor genes are present and background allelic-loss varies, the Bayes factors are often inconclusive, although this results in a markedly reduced false-positive rate compared to that of standard frequentist approaches. Application of our methods to three data sets of esophageal adenocarcinomas yields interesting differences from those results previously published.Our results indicate that Bayes factors are useful for analyzing allelic-loss data.The goal of studies of allelic loss is to determine those loci in tumor tissue where genetic material has been lost. A tumor suppressor gene (TSG) is much more likely to lie on a chromosome arm where there has been significant allelic loss than elsewhere [1,2]. The statistical challenge lies in distinguishing between "random" allelic loss that is expected in a tumor cell population and "nonrandom" loss that may be biologically meaningful. This corresponds to determining whether there is one group of arms with background allelic loss versus two groups of arms, one with background loss rates and one with elevated loss rates.Esophageal adenocarcinoma is a form of cancer involving the cells along the lining of the esophagus. The cause of esophageal adenocarcinoma is not well understood. The incidence of this cancer has been increasing rapidly. In fact, it is one of the fastest growing cancers in the United States over the past 20 years [
Information bounds for Cox regression models with missing data
Bin Nan,Mary J. Emond,Jon A. Wellner
Mathematics , 2004, DOI: 10.1214/009053604000000157
Abstract: We derive information bounds for the regression parameters in Cox models when data are missing at random. These calculations are of interest for understanding the behavior of efficient estimation in case-cohort designs, a type of two-phase design often used in cohort studies. The derivations make use of key lemmas appearing in Robins, Rotnitzky and Zhao [J. Amer. Statist. Assoc. 89 (1994) 846-866] and Robins, Hsieh and Newey [J. Roy. Statist. Soc. Ser. B 57 (1995) 409-424], but in a form suited for our purposes here. We begin by summarizing the results of Robins, Rotnitzky and Zhao in a form that leads directly to the projection method which will be of use for our model of interest. We then proceed to derive new information bounds for the regression parameters of the Cox model with data Missing At Random (MAR). In the final section we exemplify our calculations with several models of interest in cohort studies, including an i.i.d. version of the classical case-cohort design of Prentice [Biometrika 73 (1986) 1-11]
Mice lacking the Cβ subunit of PKA are resistant to angiotensin II-induced cardiac hypertrophy and dysfunction
Linda C Enns, Kenneth L Bible, Mary J Emond, Warren C Ladiges
BMC Research Notes , 2010, DOI: 10.1186/1756-0500-3-307
Abstract: Angiotensin II (ang II) induced hypertension in both PKA Cβ null mice and their WT littermates. However, PKA Cβ null mice were resistant to a number of ang II-induced, cardiopathological effects observed in the WT mice, including hypertrophy, decreased diastolic performance, and enlarged left atria.The Cβ subunit of PKA plays an important role in angiotensin-induced cardiac dysfunction. The Cβ null mouse highlights the potential of the PKA Cβ subunit as a pharmaceutical target for hypertrophic cardiac disease.PKA is a ubiquitous cellular kinase that is involved in regulating a vast number of different cellular processes. Several studies have implicated altered PKA signaling in cardiomyopathy [1,2]. For example, the onset of cardiac hypertrophy is influenced by alterations in muscle-specific A-kinase Anchoring Protein (mAKAP) signaling in myocytes. AKAPs subcellularly localize and modulate interactions between PKA and its downstream targets [3]. Deficiencies in the PKA pathway have also been linked both to cardiomyopathy in humans due to reduced phosphorylation of downstream targets such as cardiac troponin I [4], and to preservation of cardiac function against pressure overload in mice [5,6].PKA is a tetrameric protein, consisting of two regulatory subunits and two catalytic subunits. Binding of cAMP to the regulatory subunits releases the catalytic subunits, which are then free to interact with and phosphorylate downstream targets. There are four isoforms of the regulatory subunit (RIα, RIβ, RIIα, RIIβ) and three types of catalytic subunits (Cα, Cβ, Cγ) [7,8]. C57/BL6J male mice lacking the regulatory RIIβ subunit have been found to be resistant to a number of age-related pathologies, including cardiac hypertrophy and decline [9]. We are currently studying mice lacking the PKA catalytic C? subunit to establish whether they also enjoy age-delaying benefits. To date, we know that when challenged with a high fat, high calorie diet, these mice show robust obesity resis
Exome Sequencing of Phenotypic Extremes Identifies CAV2 and TMC6 as Interacting Modifiers of Chronic Pseudomonas aeruginosa Infection in Cystic Fibrosis
Mary J. Emond,Tin Louie?,Julia Emerson?,Jessica X. Chong?,Rasika A. Mathias?,Michael R. Knowles?,Mark J. Rieder?,Holly K. Tabor?,Debbie A. Nickerson?,Kathleen C. Barnes
PLOS Genetics , 2015, DOI: 10.1371/journal.pgen.1005273
Abstract: Discovery of rare or low frequency variants in exome or genome data that are associated with complex traits often will require use of very large sample sizes to achieve adequate statistical power. For a fixed sample size, sequencing of individuals sampled from the tails of a phenotype distribution (i.e., extreme phenotypes design) maximizes power and this approach was recently validated empirically with the discovery of variants in DCTN4 that influence the natural history of P. aeruginosa airway infection in persons with cystic fibrosis (CF; MIM219700). The increasing availability of large exome/genome sequence datasets that serve as proxies for population-based controls affords the opportunity to test an alternative, potentially more powerful and generalizable strategy, in which the frequency of rare variants in a single extreme phenotypic group is compared to a control group (i.e., extreme phenotype vs. control population design). As proof-of-principle, we applied this approach to search for variants associated with risk for age-of-onset of chronic P. aeruginosa airway infection among individuals with CF and identified variants in CAV2 and TMC6 that were significantly associated with group status. These results were validated using a large, prospective, longitudinal CF cohort and confirmed a significant association of a variant in CAV2 with increased age-of-onset of P. aeruginosa airway infection (hazard ratio = 0.48, 95% CI=[0.32, 0.88]) and variants in TMC6 with diminished age-of-onset of P. aeruginosa airway infection (HR = 5.4, 95% CI=[2.2, 13.5]) A strong interaction between CAV2 and TMC6 variants was observed (HR=12.1, 95% CI=[3.8, 39]) for children with the deleterious TMC6 variant and without the CAV2 protective variant. Neither gene showed a significant association using an extreme phenotypes design, and conditions for which the power of an extreme phenotype vs. control population design was greater than that for the extreme phenotypes design were explored.
Disruption of Protein Kinase A in Mice Enhances Healthy Aging
Linda C. Enns, John F. Morton, Piper R. Treuting, Mary J. Emond, Norman S. Wolf, G. S. McKnight, Peter S. Rabinovitch, Warren C. Ladiges
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0005963
Abstract: Mutations that cause a reduction in protein kinase A (PKA) activity have been shown to extend lifespan in yeast. Loss of function of mammalian RIIβ, a regulatory subunit of PKA expressed in brain and adipose tissue, results in mice that are lean and insulin sensitive. It was therefore hypothesized that RIIB null (RIIβ?/?) mice would express anti-aging phenotypes. We conducted lifespan studies using 40 mutant and 40 wild type (WT) littermates of equal gender numbers and found that both the median and maximum lifespans were significantly increased in mutant males compared to WT littermates. The median lifespan was increased from 884 days to 1005 days (p = 0.006 as determined by the log rank test) and the 80% lifespan (defined here as 80% deaths) was increased from 941 days to 1073 days (p = 0.004 as determined by the Wang-Allison test). There was no difference in either median or 80% lifespan in female genotypes. WT mice of both genders became increasingly obese with age, while mutant mice maintained their lean phenotype into old age. Adiposity was found to correlate with lifespan for males only. 50% of male mice between 30 and 35 g, corresponding to about 5% body fat, for either genotype lived over 1000 days. No male mouse outside of this weight range achieved this lifespan. During their last month of life, WT mice began losing weight (a total of 8% and 15% of body weight was lost for males and females, respectively), but RIIβ?/? male mice maintained their lean body mass to end of life. This attenuation of decline was not seen in female mutant mice. Old male mutant mice were insulin sensitive throughout their life. Both genders showed modestly lower blood glucose levels in old mutants compared to WT. Male mutants were also resistant to age-induced fatty liver. Pathological assessment of tissues from end of life male mutant mice showed a decrease in tumor incidence, decreased severity of renal lesions, and a trend towards a decrease in age-related cardiac pathology. These findings help establish the highly conserved nature of PKA and suggest that disruption of PKA affects physiological mechanisms known to be associated with healthy aging.
Survey of Innate Immune Responses to Burkholderia pseudomallei in Human Blood Identifies a Central Role for Lipopolysaccharide
Narisara Chantratita, Sarunporn Tandhavanant, Nicolle D. Myers, Sudeshna Seal, Arkhom Arayawichanont, Aroonsri Kliangsa-ad, Lauren E. Hittle, Robert K. Ernst, Mary J. Emond, Mark M. Wurfel, Nicholas P. J. Day, Sharon J. Peacock, T. Eoin West
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0081617
Abstract: B. pseudomallei is a gram-negative bacterium that causes the tropical infection melioidosis. In northeast Thailand, mortality from melioidosis approaches 40%. As exemplified by the lipopolysaccharide-Toll-like receptor 4 interaction, innate immune responses to invading bacteria are precipitated by activation of host pathogen recognition receptors by pathogen associated molecular patterns. Human melioidosis is characterized by up-regulation of pathogen recognition receptors and pro-inflammatory cytokine release. In contrast to many gram-negative pathogens, however, the lipopolysaccharide of B. pseudomallei is considered only weakly inflammatory. We conducted a study in 300 healthy Thai subjects to investigate the ex vivo human blood response to various bacterial pathogen associated molecular patterns, including lipopolysaccharide from several bacteria, and to two heat-killed B. pseudomallei isolates. We measured cytokine levels after stimulation of fresh whole blood with a panel of stimuli. We found that age, sex, and white blood cell count modulate the innate immune response to B. pseudomallei. We further observed that, in comparison to other stimuli, the innate immune response to B. pseudomallei is most highly correlated with the response to lipopolysaccharide. The magnitude of cytokine responses induced by B. pseudomallei lipopolysaccharide was significantly greater than those induced by lipopolysaccharide from Escherichia coli and comparable to many responses induced by lipopolysaccharide from Salmonella minnesota despite lower amounts of lipid A in the B. pseudomallei lipopolysaccharide preparation. In human monocytes stimulated with B. pseudomallei, addition of polymyxin B or a TLR4/MD-2 neutralizing antibody inhibited the majority of TNF-α production. Challenging existing views, our data indicate that the innate immune response to B. pseudomallei in human blood is largely driven by lipopolysaccharide, and that the response to B. pseudomallei lipopolysaccharide in blood is greater than the response to other lipopolysaccharide expressing isolates. Our findings suggest that B. pseudomallei lipopolysaccharide may play a central role in stimulating the host response in melioidosis.
Antimetastatic gene expression profiles mediated by retinoic acid receptor beta 2 in MDA-MB-435 breast cancer cells
Brett Wallden, Mary Emond, Mari E Swift, Mary L Disis, Karen Swisshelm
BMC Cancer , 2005, DOI: 10.1186/1471-2407-5-140
Abstract: RNA from MDA-MB-435 human breast cancer cells transduced with RARβ2 or empty retroviral vector (LXSN) was analyzed using Agilent Human 1A Oligo microarrays. The one hundred probes with the greatest differential intensity (p < 0.004, jointly) were determined by selecting the top median log ratios from eight-paired microarrays. Validation of differences in expression was done using Northern blot analysis and quantitative RT-PCR (qRT-PCR). We determined expression of selected genes in xenograft tumors.RARβ2 cells exhibit gene profiles with overrepresentation of genes from Xq28 (p = 2 × 10-8), a cytogenetic region that contains a large portion of the cancer/testis antigen gene family. Other functions or factors impacted by the presence of exogenous RARβ2 include mediators of the immune response and transcriptional regulatory mechanisms. Thirteen of fifteen (87%) of the genes evaluated in xenograft tumors were consistent with differences we found in the cell cultures (p = 0.007).Antimetastatic RARβ2 signalling, direct or indirect, results in an elevation of expression for genes such as tumor-cell antigens (CTAG1 and CTAG2), those involved in innate immune response (e.g., RIG-I/DDX58), and tumor suppressor functions (e.g., TYRP1). Genes whose expression is diminished by RARβ2 signalling include cell adhesion functions (e.g, CD164) nutritional or metabolic processes (e.g., FABP6), and the transcription factor, JUN.It is estimated that approximately 15–25% of women with node-negative breast cancer will eventually succumb to the disease due to distant metastases [1]. While important and promising anti-hormonal therapies – tamoxifen and aromatase inhibitors – exist for postmenopausal breast cancer patients with estrogen receptor positive tumors [2], chemo- and radiation-therapy remain the major options for all other women with progressive disease. Elucidating gene expression alterations in metastatic lesions compared to non-metastatic tumors is compelling, and orthotopic xeno
Host Genetic Risk Factors for West Nile Virus Infection and Disease Progression
Abigail W. Bigham, Kati J. Buckingham, Sofia Husain, Mary J. Emond, Kathryn M. Bofferding, Heidi Gildersleeve, Ann Rutherford, Natalia M. Astakhova, Andrey A. Perelygin, Michael P. Busch, Kristy O. Murray, James J. Sejvar, Sharone Green, John Kriesel, Margo A. Brinton, Michael Bamshad
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0024745
Abstract: West Nile virus (WNV), a category B pathogen endemic in parts of Africa, Asia and Europe, emerged in North America in 1999, and spread rapidly across the continental U.S. Outcomes of infection with WNV range from asymptomatic to severe neuroinvasive disease manifested as encephalitis, paralysis, and/or death. Neuroinvasive WNV disease occurs in less than one percent of cases, and although host genetic factors are thought to influence risk for symptomatic disease, the identity of these factors remains largely unknown. We tested 360 common haplotype tagging and/or functional SNPs in 86 genes that encode key regulators of immune function in 753 individuals infected with WNV including: 422 symptomatic WNV cases and 331 cases with asymptomatic infections. After applying a Bonferroni correction for multiple tests and controlling for population stratification, SNPs in IRF3 (OR 0.54, p = 0.035) and MX1, (OR 0.19, p = 0.014) were associated with symptomatic WNV infection and a single SNP in OAS1 (OR 9.79, p = 0.003) was associated with increased risk for West Nile encephalitis and paralysis (WNE/P). Together, these results suggest that genetic variation in the interferon response pathway is associated with both risk for symptomatic WNV infection and WNV disease progression.
A Photo-Based Environmental History of the Use of Climbing Plants in Central Oxford, UK  [PDF]
Mary J. Thornbush
International Journal of Geosciences (IJG) , 2013, DOI: 10.4236/ijg.2013.47102
Abstract:

This paper examines environmental change associated with climbing plants (ivy/creeper) on several historical buildings in central Oxford using archival photographs. ViewFinder from English Heritage was used to access the photo archives in an advanced search of the area of “Oxford” and in the county of “Oxfordshire”. The study includes a variety of buildings, including colleges, churches, chapels, asylums, inns/hotels, factories, a brewery, pubs, a castle as well as architectural elements, such as doorways, cloisters, gates, and walls. The findings reveal that a majority of photographs denoted ivy-/creeper-clad buildings (in nearly 53% of photographs found mostly in the Taunt collection). The greatest abundance of climbing plants was found in the 1880s followed by the 1900s. A further examination of University colleges is warranted due to the earlier and more frequent appearance of ivy/creeper on these buildings.

Measuring Surface Roughness through the Use of Digital Photography and Image Processing  [PDF]
Mary J. Thornbush
International Journal of Geosciences (IJG) , 2014, DOI: 10.4236/ijg.2014.55050
Abstract:

This paper aims to provide a quantitative method that employs image processing in the assessment of surface roughness based on digital photograph field surveys, as in previous studies employing the outdoor integrated digital photography and image processing (O-IDIP) method. Digital photographs were taken on two different days under contrasting outdoor lighting conditions (overcast versus clear sky). Images were captured mounted on a tripod close up to the surface of a 380-year-old wall located at the University of Oxford Botanic Garden in the City of Oxford, UK. Sampling points were established at regular intervals along the border wall and encompassed sections facing west, north, and east, respectively along the survey. Two photographs were taken with a digital camera at each sampling point, one containing a color chart used to calibrate outdoor lighting conditions across images, which was excluded from the other photographic pair. Histogram-based quantification was performed based on images converted to Lab Color mode. The 10-step calibration procedure presented in this paper required more adjustments of contrast. However, more adjustments were not required under a clear sky. Std Dev L measurements were used to establish categories in a simple 3-point roughness index, namely the surface roughness index (SRI). The results denote that pitting did not affect surface roughness measurements. The study shows that it is possible to use Std Dev L measurements to quantify surface roughness on a comparative basis.

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