Primary pulmonary hypertension is associated with reduced pulmonary vascular expression of type II bone morphogenetic protein receptor

BACKGROUND: Mutations in the type II receptor for bone morphogenetic protein (BMPR-II), a receptor member of the transforming growth factor-beta (TGF-beta) superfamily, underlie many familial and sporadic cases of primary pulmonary hypertension (PPH). METHODS AND RESULTS: Because the sites of expression of BMPR-II in the normal and hypertensive lung are unknown, we studied the cellular localization of BMPR-II and the related type I and II receptors for TGF-beta by immunohistochemistry in lung sections from patients undergoing heart-lung transplantation for PPH (n=11, including 3 familial cases) or secondary pulmonary hypertension (n=6) and from unused donor lungs (n=4). In situ hybridization was performed for BMPR-II mRNA. Patients were screened for the presence of mutations in BMPR2. In normal lungs, BMPR-II expression was prominent on vascular endothelium, with minimal expression in airway and arterial smooth muscle. In pulmonary hypertension cases, the intensity of BMPR-II immunostaining varied between lesions but involved endothelial and myofibroblast components. Image analysis confirmed that expression of BMPR-II was markedly reduced in the peripheral lung of PPH patients, especially in those harboring heterozygous BMPR2 mutations. A less marked reduction was also observed in patients with secondary pulmonary hypertension. In contrast, there was no difference in level of staining for TGF-betaRII or the endothelial marker CD31. CONCLUSIONS: The cellular localization of BMPR-II is consistent with a role in the formation of pulmonary vascular lesions in PPH, and reduced BMPR-II expression may contribute to the process of vascular obliteration in severe pulmonary hypertension

Low-fluence Electron Yields of Highly Insulating Materials

Electron-induced electron yields of high-resistivity high-yield materials - ceramic polycrystalline aluminum oxide and polymer polyimide (Kapton HN) - were made by using a low-fluence pulsed incident electron beam and charge neutralization electron source to minimize charge accumulation. Large changes in the energy-dependent total yield curves and yield decay curves were observed, even for incident electron fluences of \u3c 3 fC/mm2. The evolution of the electron yield as charge accumulates in the material is modeled in terms of electron recapture based on an extended Chung-Everhart model of the electron emission spectrum. This model is used to explain the anomalies measured in highly insulating high-yield materials and to provide a method for determining the limiting yield spectra of uncharged dielectrics. The relevance of these results to spacecraft charging is also discussed

Kate Loves Topshop: Celebrity Endorsements and the Lovemarks Concept in a Fashion Retail Context

Fashion designers and retailers often employ celebrities as endorsers due to celebrities’ power to influence consumer attitudes, drive sales and command loyalty. This power may be predicated on the transfer of a celebrity’s perceived personality to the promoted brand, thus enhancing consumer attitudes toward it. Celebrity endorsement is regarded as one component of contemporary brand management, the practice of which has two consequences: first, consumers increasingly expect ‘good’ brand performance from ALL brands; second, brands correspondingly find it difficult to continually distinguish themselves. One response has been the Lovemarks concept (Roberts 2005). A Lovemark is distinguished from conventional brands by inspiring deep, long-lasting relationships based on emotional responses invoked by the characteristics and personality it represents. While the Lovemark model is considered useful to practitioners (Bain 2004; Cooper & Pawle 2006), its academic study is limited, especially in its application to established marketing concepts. Here, a qualitative case-study explores the Lovemark concept in context of celebrity endorsement by examining the congruency between emotions felt for UK fashion retailer Topshop, and its associated celebrity, Kate Moss. Findings suggest that emotional responses to a celebrity have resonance on attitudes toward a brand; these and implications for practice and theory will be presented

Using Nuclear Magnetic Resonance Spectroscopy to Develop Physiological Profiles for Bighorn Sheep (Poster)

This study employs new techniques using nuclear magnetic resonance (NMR) to assess the relative health, physiological condition, and reproductive function of wild bighorn sheep (Ovis canadensis) in Montana and Wyoming. Ongoing bighorn studies in Montana and the Greater Yellowstone Ecosystem are focused on herd attributes and the population dynamics which are affected by disease, climate, habitat and physiology. Indices of herd health and physiological status are typically obtained through expensive and time consuming lab assays and field measurements. Recently, NMR spectroscopy has been used to revolutionize the assessment of human metabolic health, and we expect that there is similar potential for studies of wildlife populations. Using NMR spectroscopy to assess metabolites associated with disease, nutrition and stress may eliminate the need for many traditional assays and techniques used today. NMR can be used to evaluate a large suite of metabolites associated with a variety of physiological functions from as little as 500 uL of serum or plasma. Blood samples from 242 sheep from 13 different herds were collected during the winters of 2013-14 and 2014-15 to develop a comprehensive metabolite panel for bighorn sheep. We have used a recently developed statistical program known as MetaboAnalyst™ to begin to analyze and evaluate differences in NMR metabolic profiles among herds and across the fall-winter season when nutritional and physiological stress is expected to be acute. We will be presenting the results of this preliminary study and discussing the potential for application in wildlife management

Nuclear Magnetic Resonance Spectroscopy Metabolic Profiles to Distinguish Geographically Isolated Populations of Mountain Goats

Basic physiological studies on mountain goats (Oreamnos americanus) are conspicuously lacking in the literature, and the physiology of this species is perhaps the least known of the high mountain ungulates. The objective of this study was to evaluate metabolic profiles of female mountain goats from five geographically distinct populations using Nuclear Magnetic Resonance (NMR) spectroscopy. Serum samples were collected from nannies located in Alaska in September (AK) from Glacier in August (GMT), from the Grand Tetons in November-December (GT), from NE Yellowstone in December (NEY) and from Absaroka in March (AB). Serum was extracted with acetone, dried and re-suspended in a standard NMR buffer. NMR spectra were analyzed with Chenomix™ software. Metabolites were identified and concentrations determined using the Chenomix™ database and the Human Metabolome Database. We identified 55 metabolites in the serum of mountain goats using this emerging technology. Of these 42 metabolites differed among the herds (P < 0.05). Of these 42 metabolites; creatinine, lactate and pyruvate distinguished (P < 0.05) each herd from another. Furthermore, using Principal Component Analyses of these metabolites allowed us to clearly differentiate metabolic profiles in carbohydrate, protein and lipid metabolism in nannies from these five populations. This study has the potential to enhance our understanding of how changes in nutrition, reproduction, susceptibility to disease, and survival rates drive population dynamics

Dynamic changes in 5-hydroxymethylation signatures underpin early and late events in drug exposed liver

Aberrant DNA methylation is a common feature of neoplastic lesions, and early detection of such changes may provide powerful mechanistic insights and biomarkers for carcinogenesis. Here, we investigate dynamic changes in the mouse liver DNA methylome associated with short (1 day) and prolonged (7, 28 and 91 days) exposure to the rodent liver non-genotoxic carcinogen, phenobarbital (PB). We find that the distribution of 5mC/5hmC is highly consistent between untreated individuals of a similar age; yet, changes during liver maturation in a transcriptionally dependent manner. Following drug treatment, we identify and validate a series of differentially methylated or hydroxymethylated regions: exposure results in staged transcriptional responses with distinct kinetic profiles that strongly correlate with promoter proximal region 5hmC levels. Furthermore, reciprocal changes for both 5mC and 5hmC in response to PB suggest that active demethylation may be taking place at each set of these loci via a 5hmC intermediate. Finally, we identify potential early biomarkers for non-genotoxic carcinogenesis, including several genes aberrantly expressed in liver cancer. Our work suggests that 5hmC profiling can be used as an indicator of cell states during organ maturation and drug-induced responses and provides novel epigenetic signatures for non-genotoxic carcinogen exposur

Comparative analysis of affinity-based 5-hydroxymethylation enrichment techniques

The epigenetic modification of 5-hydroxymethylcytosine (5hmC) is receiving great attention due to its potential role in DNA methylation reprogramming and as a cell state identifier. Given this interest, it is important to identify reliable and cost-effective methods for the enrichment of 5hmC marked DNA for downstream analysis. We tested three commonly used affinity-based enrichment techniques; (i) antibody, (ii) chemical capture and (iii) protein affinity enrichment and assessed their ability to accurately and reproducibly report 5hmC profiles in mouse tissues containing high (brain) and lower (liver) levels of 5hmC. The protein-affinity technique is a poor reporter of 5hmC profiles, delivering 5hmC patterns that are incompatible with other methods. Both antibody and chemical capture-based techniques generate highly similar genome-wide patterns for 5hmC, which are independently validated by standard quantitative PCR (qPCR) and glucosyl-sensitive restriction enzyme digestion (gRES-qPCR). Both antibody and chemical capture generated profiles reproducibly link to unique chromatin modification profiles associated with 5hmC. However, there appears to be a slight bias of the antibody to bind to regions of DNA rich in simple repeats. Ultimately, the increased specificity observed with chemical capture-based approaches makes this an attractive method for the analysis of locus-specific or genome-wide patterns of 5hm

Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia

BACKGROUND: Most patients with familial primary pulmonary hypertension have defects in the gene for bone morphogenetic protein receptor II (BMPR2), a member of the transforming growth factor beta (TGF-beta) superfamily of receptors. Because patients with hereditary hemorrhagic telangiectasia may have lung disease that is indistinguishable from primary pulmonary hypertension, we investigated the genetic basis of lung disease in these patients. METHODS: We evaluated members of five kindreds plus one individual patient with hereditary hemorrhagic telangiectasia and identified 10 cases of pulmonary hypertension. In the two largest families, we used microsatellite markers to test for linkage to genes encoding TGF-beta-receptor proteins, including endoglin and activin-receptor-like kinase 1 (ALK1), and BMPR2. In subjects with hereditary hemorrhagic telangiectasia and pulmonary hypertension, we also scanned ALK1 and BMPR2 for mutations. RESULTS: We identified suggestive linkage of pulmonary hypertension with hereditary hemorrhagic telangiectasia on chromosome 12q13, a region that includes ALK1. We identified amino acid changes in activin-receptor-like kinase 1 that were inherited in subjects who had a disorder with clinical and histologic features indistinguishable from those of primary pulmonary hypertension. Immunohistochemical analysis in four subjects and one control showed pulmonary vascular endothelial expression of activin-receptor-like kinase 1 in normal and diseased pulmonary arteries. CONCLUSIONS: Pulmonary hypertension in association with hereditary hemorrhagic telangiectasia can involve mutations in ALK1. These mutations are associated with diverse effects, including the vascular dilatation characteristic of hereditary hemorrhagic telangiectasia and the occlusion of small pulmonary arteries that is typical of primary pulmonary hypertension