Phase Equilibria in Hydrocarbon Systems. I. Methods and Apparatus

No abstract

Phase Equilibria in Hydrocarbon Systems. II. Methane-Propane System

No abstract

The Halo Stars in NGC 5128. III: An Inner-Halo Field and the Metallicity Distribution

We present new HST/WFPC2 (V,I) photometry for the red-giant stars in NGC 5128 at a projected distance of 8 kpc from the galaxy center, which probe a mixture of its inner halo and outer bulge. The color-magnitude diagram shows an old red-giant branch which is even broader in color than our two previously studied outer-halo fields (at 21 and 31 kpc), with significant numbers of stars extending to Solar metallicity and higher. The peak frequency of the metallicity distribution function (MDF) is at [m/H] ~ -0.4, with even fewer metal-poor stars than in the outer-halo fields. We find that the main features of the halo MDF can be reproduced by a simple chemical evolution model in which early star formation goes on simultaneously with an initial stage of rapid infall of very metal-poor gas, after which the infall dies away exponentially. A comparison with the MDF for the NGC 5128 globular clusters indicates that there is a clear decrease of specific frequency $S_N$ (number of clusters per unit halo light) with increasing metallicity, from S_N ~ 4-8 at [Fe/H] < -1.6 down to S_N = 1.5 at [Fe/H] > -1. This trend may indicate that globular cluster formation efficiency is a strong function of the metallicity of the protocluster gas.Comment: 25 pages, LaTeX, plus 20 figures as .jpg files; Astronomical Journal vol.123, in press for May 2002. A complete postscript file with better quality figures is at http://physun.mcmaster.ca/~harris/WEHarris.htm

When Subterranean Termites Challenge the Rules of Fungal Epizootics

Over the past 50 years, repeated attempts have been made to develop biological control technologies for use against economically important species of subterranean termites, focusing primarily on the use of the entomopathogenic fungus Metarhizium anisopliae. However, no successful field implementation of biological control has been reported. Most previous work has been conducted under the assumption that environmental conditions within termite nests would favor the growth and dispersion of entomopathogenic agents, resulting in an epizootic. Epizootics rely on the ability of the pathogenic microorganism to self-replicate and disperse among the host population. However, our study shows that due to multilevel disease resistance mechanisms, the incidence of an epizootic within a group of termites is unlikely. By exposing groups of 50 termites in planar arenas containing sand particles treated with a range of densities of an entomopathogenic fungus, we were able to quantify behavioral patterns as a function of the death ratios resulting from the fungal exposure. The inability of the fungal pathogen M. anisopliae to complete its life cycle within a Coptotermes formosanus (Isoptera: Rhinotermitidae) group was mainly the result of cannibalism and the burial behavior of the nest mates, even when termite mortality reached up to 75%. Because a subterranean termite colony, as a superorganism, can prevent epizootics of M. anisopliae, the traditional concepts of epizootiology may not apply to this social insect when exposed to fungal pathogens, or other pathogen for which termites have evolved behavioral and physiological means of disrupting their life cycle

Equity in healthcare for coronary heart disease, Wales (UK) 2004–2010: A population-based electronic cohort study

Despite substantial falls in coronary heart disease (CHD) mortality in the United Kingdom (UK), marked socioeconomic inequalities in CHD risk factors and CHD mortality persist. We investigated whether inequity in CHD healthcare in Wales (UK) could contribute to the observed social gradient in CHD mortality. Linking data from primary and secondary care we constructed an electronic cohort of individuals (n = 1199342) with six year follow-up, 2004–2010. We identified indications for recommended CHD interventions, measured time to their delivery, and estimated risk of receiving the interventions for each of five ordered deprivation groups using a time-to-event approach with Cox regression frailty models. Interventions in primary and secondary prevention included risk-factor measurement, smoking management, statins and antihypertensive therapy, and in established CHD included medication and revascularization. For primary prevention, five of the 11 models favoured the more deprived and one favoured the less deprived. For medication in secondary prevention and established CHD, one of the 15 models favoured the more deprived and one the less deprived. In relation to revascularization, six of the 12 models favoured the less deprived and none favoured the more deprived–this evidence of inequity exemplified by a hazard ratio for revascularization in stable angina of 0.79 (95% confidence interval 0.68, 0.92). The main study limitation is the possibility of under-ascertainment or misclassification of clinical indications and treatment from variability in coding. Primary care components of CHD healthcare were equitably delivered. Evidence of inequity was found for revascularization procedures, although this inequity is likely to have only a modest effect on social gradients in CHD mortality. Policymakers should focus on reducing inequalities in CHD risk factors, particularly smoking, as these, rather than inequity in healthcare, are likely to be key drivers of inequalities in CHD mortality

Human Amniotic Epithelial Cell Transplantation Induces Markers of Alternative Macrophage Activation and Reduces Established Hepatic Fibrosis

Chronic hepatic inflammation from multiple etiologies leads to a fibrogenic response that can progress to cirrhosis and liver failure. Transplantation of human amniotic epithelial cells (hAEC) from term delivered placenta has been shown to decrease mild to moderate hepatic fibrosis in a murine model. To model advanced human liver disease and assess the efficacy of hAEC therapy, we transplanted hAEC in mice with advanced hepatic fibrosis. Immunocompetent C57BL/6 mice were administered carbon tetrachloride (CCl4) twice weekly resulting in bridging fibrosis by 12 weeks. hAEC (2×106) were infused via the tail vein at week 8 or weeks 8 and 10 (single and double dose, respectively). Human cells were detected in mouse liver four weeks after transplantation showing hAEC engraftment. CCl4 treated mice receiving single or double hAEC doses showed a significant but similar decrease in liver fibrosis area associated with decreased activation of collagen-producing hepatic stellate cells and decreased hepatic protein levels of the pro-fibrogenic cytokine, transforming growth factor-beta1. CCl4 administration caused hepatic T cell infiltration that decreased significantly following hAEC transplantation. Hepatic macrophages play a crucial role in both fibrogenesis and fibrosis resolution. Mice exposed to CCl4 demonstrated increased numbers of hepatic macrophages compared to normal mice; the number of macrophages decreased significantly in CCl4 treated mice given hAEC. These mice had significantly lower hepatic protein levels of the chemokine monocyte chemoattractant protein-1 than mice given CCl4 alone. Alternatively activated M2 macrophages are associated with fibrosis resolution. CCl4 treated mice given hAEC showed increased expression of genes associated with M2 macrophages including YM-1, IL-10 and CD206. We provide novel data showing that hAEC transplantation induces a wound healing M2 macrophage phenotype associated with reduction of established hepatic fibrosis that justifies further investigation of this potential cell-based therapy for advanced hepatic fibrosis

Dopamine acting at D1-like, D2-like and α1-adrenergic receptors differentially modulates theta and gamma oscillatory activity in primary motor cortex

The loss of dopamine (DA) in Parkinson’s is accompanied by the emergence of exaggerated theta and beta frequency neuronal oscillatory activity in the primary motor cortex (M1) and basal ganglia. DA replacement therapy or deep brain stimulation reduces the power of these oscillations and this is coincident with an improvement in motor performance implying a causal relationship. Here we provide in vitro evidence for the differential modulation of theta and gamma activity in M1 by DA acting at receptors exhibiting conventional and non-conventional DA pharmacology. Recording local field potentials in deep layer V of rat M1, co-application of carbachol (CCh, 5 μM) and kainic acid (KA, 150 nM) elicited simultaneous oscillations at a frequency of 6.49 ± 0.18 Hz (theta, n = 84) and 34.97 ± 0.39 Hz (gamma, n = 84). Bath application of DA resulted in a decrease in gamma power with no change in theta power. However, application of either the D1-like receptor agonist SKF38393 or the D2-like agonist quinpirole increased the power of both theta and gamma suggesting that the DA-mediated inhibition of oscillatory power is by action at other sites other than classical DA receptors. Application of amphetamine, which promotes endogenous amine neurotransmitter release, or the adrenergic α1-selective agonist phenylephrine mimicked the action of DA and reduced gamma power, a result unaffected by prior co-application of D1 and D2 receptor antagonists SCH23390 and sulpiride. Finally, application of the α1-adrenergic receptor antagonist prazosin blocked the action of DA on gamma power suggestive of interaction between α1 and DA receptors. These results show that DA mediates complex actions acting at dopamine D1-like and D2-like receptors, α1 adrenergic receptors and possibly DA/α1 heteromultimeric receptors to differentially modulate theta and gamma activity in M1

A Cross-Species Analysis of a Mouse Model of Breast Cancer-Specific Osteolysis and Human Bone Metastases Using Gene Expression Profiling

<p>Abstract</p> <p>Background</p> <p>Breast cancer is the second leading cause of cancer-related death in women in the United States. During the advanced stages of disease, many breast cancer patients suffer from bone metastasis. These metastases are predominantly osteolytic and develop when tumor cells interact with bone. <it>In vivo </it>models that mimic the breast cancer-specific osteolytic bone microenvironment are limited. Previously, we developed a mouse model of tumor-bone interaction in which three mouse breast cancer cell lines were implanted onto the calvaria. Analysis of tumors from this model revealed that they exhibited strong bone resorption, induction of osteoclasts and intracranial penetration at the tumor bone (TB)-interface.</p> <p>Methods</p> <p>In this study, we identified and used a TB microenvironment-specific gene expression signature from this model to extend our understanding of the metastatic bone microenvironment in human disease and to predict potential therapeutic targets.</p> <p>Results</p> <p>We identified a TB signature consisting of 934 genes that were commonly (among our 3 cell lines) and specifically (as compared to tumor-alone area within the bone microenvironment) up- and down-regulated >2-fold at the TB interface in our mouse osteolytic model. By comparing the TB signature with gene expression profiles from human breast metastases and an <it>in vitro </it>osteoclast model, we demonstrate that our model mimics both the human breast cancer bone microenvironment and osteoclastogenesis. Furthermore, we observed enrichment in various signaling pathways specific to the TB interface; that is, TGF-β and myeloid self-renewal pathways were activated and the Wnt pathway was inactivated. Lastly, we used the TB-signature to predict cyclopenthiazide as a potential inhibitor of the TB interface.</p> <p>Conclusion</p> <p>Our mouse breast cancer model morphologically and genetically resembles the osteoclastic bone microenvironment observed in human disease. Characterization of the gene expression signature specific to the TB interface in our model revealed signaling mechanisms operative in human breast cancer metastases and predicted a therapeutic inhibitor of cancer-mediated osteolysis.</p

Identification and Characterization of Nucleolin as a COUP-TFII Coactivator of Retinoic Acid Receptor β Transcription in Breast Cancer Cells

The orphan nuclear receptor COUP-TFII plays an undefined role in breast cancer. Previously we reported lower COUP-TFII expression in tamoxifen/endocrine-resistant versus sensitive breast cancer cell lines. The identification of COUP-TFII-interacting proteins will help to elucidate its mechanism of action as a transcriptional regulator in breast cancer.FLAG-affinity purification and multidimensional protein identification technology (MudPIT) identified nucleolin among the proteins interacting with COUP-TFII in MCF-7 tamoxifen-sensitive breast cancer cells. Interaction of COUP-TFII and nucleolin was confirmed by coimmunoprecipitation of endogenous proteins in MCF-7 and T47D breast cancer cells. In vitro studies revealed that COUP-TFII interacts with the C-terminal arginine-glycine repeat (RGG) domain of nucleolin. Functional interaction between COUP-TFII and nucleolin was indicated by studies showing that siRNA knockdown of nucleolin and an oligonucleotide aptamer that targets nucleolin, AS1411, inhibited endogenous COUP-TFII-stimulated RARB2 expression in MCF-7 and T47D cells. Chromatin immunoprecipitation revealed COUP-TFII occupancy of the RARB2 promoter was increased by all-trans retinoic acid (atRA). RARβ2 regulated gene RRIG1 was increased by atRA and COUP-TFII transfection and inhibited by siCOUP-TFII. Immunohistochemical staining of breast tumor microarrays showed nuclear COUP-TFII and nucleolin staining was correlated in invasive ductal carcinomas. COUP-TFII staining correlated with ERα, SRC-1, AIB1, Pea3, MMP2, and phospho-Src and was reduced with increased tumor grade.Our data indicate that nucleolin plays a coregulatory role in transcriptional regulation of the tumor suppressor RARB2 by COUP-TFII

A likelihood ratio approach for utilizing case-control data in the clinical classification of rare sequence variants:Application to BRCA1 and BRCA2

A large number of variants identified through clinical genetic testing in disease susceptibility genes are of uncertain significance (VUS). Following the recommendations of the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP), the frequency in case-control datasets (PS4 criterion) can inform their interpretation. We present a novel case-control likelihood ratio-based method that incorporates gene-specific age-related penetrance. We demonstrate the utility of this method in the analysis of simulated and real datasets. In the analysis of simulated data, the likelihood ratio method was more powerful compared to other methods. Likelihood ratios were calculated for a case-control dataset of BRCA1 and BRCA2 variants from the Breast Cancer Association Consortium (BCAC) and compared with logistic regression results. A larger number of variants reached evidence in favor of pathogenicity, and a substantial number of variants had evidence against pathogenicity findings that would not have been reached using other case-control analysis methods. Our novel method provides greater power to classify rare variants compared with classical case-control methods. As an initiative from the ENIGMA Analytical Working Group, we provide user-friendly scripts and preformatted Excel calculators for implementation of the method for rare variants in BRCA1, BRCA2, and other high-risk genes with known penetrance.</p