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Search Results: 1 - 10 of 185192 matches for " James E. Loyd "
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EGR1 is essential for transcriptional regulation of BMPR2  [PDF]
Radhika Gaddipati, James D. West, James E. Loyd, Thomas Blackwell, Kirsten A. Lane, Nicole M. Lane, Kirk B. Lane
American Journal of Molecular Biology (AJMB) , 2011, DOI: 10.4236/ajmb.2011.13014
Abstract: In this study, RLM-RACE was used to identify the transcriptional start site 387 bp upstream of the translational start. Evolutionarily conserved transcription factor binding sites were identified, and a series of luciferase reporter constructs driven by BMPR2 promoter elements used to determine their functional relevance. We found the promoter area from 983 bp to 90 bp upstream of the transcriptional start gave maximal activity, greater than longer constructs, with an area between 570 bp and 290 bp upstream of the transcriptional start containing an important repressor element. To characterize this repressor, we used a combination of EMSA, mutation of the EGR1 binding site, transfection with EGR1 and NAB1 constructs, and mutation of the NAB1 binding site within the EGR1 protein. From this we conclude that EGR1 is essential to BMPR2 transcription, but that NAB1 binding to EGR1 causes it to act as a repressor.
Copy-number variation in BMPR2 is not associated with the pathogenesis of pulmonary arterial hypertension
Jennifer A Johnson, Cindy L Vnencak-Jones, Joy D Cogan, James E Loyd, James West
BMC Medical Genetics , 2009, DOI: 10.1186/1471-2350-10-58
Abstract: 97 human DNA samples were obtained which included 24 patients with familial PAH, 18 obligate carriers (BMPR2 mutation positive), 20 sporadic PAH patients, and 35 controls. Two sets of primers were designed within the CNV, and two sets of control primers were designed outside the CNV. Quantitative PCR was performed to quantify genomic copies of CNV and control sequences.A CNV in BMPR2 was present in one African American negative control subject.We conclude that the CNV in intron 1 in BMPR2 is unlikely to play a role in the pathogenesis of either familial or sporadic PAH.NIH NCT00091546.Pulmonary arterial hypertension is a progressive disease characterized by obstruction of pre-capillary pulmonary arteries. Symptoms of PAH include fatigue and shortness of breath. Sustained pulmonary arterial hypertension eventually leads to right-sided heart failure and death. In 2000, mutations in BMPR2 (bone morphogenic protein receptor type 2) located on chromosome 2 were shown to cause familial PAH[1]. The BMPR2 gene spans 190 kb but encodes only a 4 kb transcript. It contains 13 exons and a large first intron composed of over 90 kb with frequent repetitive sequences. BMPR2 mutations are present in over 80% of patients diagnosed with familial PAH and are responsible for some cases of idiopathic PAH. Although the discovery of the BMPR2 mutation has enhanced our understanding of PAH, there are several important characteristics of the disease which remain unexplained. For example, the lifetime risk of developing PAH with the BMPR2 mutation is less than 20%, anticipation is observed, and there are both familial and sporadic patients without the BMPR2 mutation who develop PAH[2]. Recently, penetrance has been linked to levels of BMPR2; unaffected carriers (patients with a BMPR2 mutation who do not have PAH) have higher levels of wild-type BMPR2 allele transcript than patients with BMPR2 mutations and PAH[3]. This finding suggests that alterations of gene expression may be relevant to P
Gene expression profiling: can we identify the right target genes?
J. E. Loyd
European Respiratory Review , 2008,
Abstract: Gene expression profiling allows the simultaneous monitoring of the transcriptional behaviour of thousands of genes, which may potentially be involved in disease development. Several studies have been performed in idiopathic pulmonary fibrosis (IPF), which aim to define genetic links to the disease in an attempt to improve the current understanding of the underlying pathogenesis of the disease and target pathways for intervention. Expression profiling has shown a clear difference in gene expression between IPF and normal lung tissue, and has identified a wide range of candidate genes, including those known to encode for proteins involved in extracellular matrix formation and degradation, growth factors and chemokines. Recently, familial pulmonary fibrosis cohorts have been examined in an attempt to detect specific genetic mutations associated with IPF. To date, these studies have identified families in which IPF is associated with mutations in the gene encoding surfactant protein C, or with mutations in genes encoding components of telomerase. Although rare and clearly not responsible for the disease in all individuals, the nature of these mutations highlight the importance of the alveolar epithelium in disease pathogenesis and demonstrate the potential for gene expression profiling in helping to advance the current understanding of idiopathic pulmonary fibrosis.
Altered prostanoid production by fibroblasts cultured from the lungs of human subjects with idiopathic pulmonary fibrosis
Roberto Cruz-Gervis, Arlene A Stecenko, Ryszard Dworski, Kirk B Lane, James E Loyd, Richard Pierson, Gayle King, Kenneth L Brigham
Respiratory Research , 2002, DOI: 10.1186/rr166
Abstract: We measured inducible cyclooxygenase (COX)-2 gene and protein expression, and a profile of prostanoids at baseline and after IL-1β stimulation.In both HF-IPF and HF-NL COX-2 expression was undetectable at baseline, but was significantly upregulated by IL-1β. PGE2 was the predominant COX product in IL-1β-stimulated cells with no significant difference between HF-IPF and HF-NL (28.35 [9.09–89.09] vs. 17.12 [8.58–29.33] ng/106 cells/30 min, respectively; P = 0.25). TXB2 (the stable metabolite of TXA2) production was significantly higher in IL-1β-stimulated HF-IPF compared to HF-NL (1.92 [1.27–2.57] vs. 0.61 [0.21–1.64] ng/106 cells/30 min, respectively; P = 0.007) and the ratio of PGI2 (as measured by its stable metabolite 6-keto-PGF1α) to TXB2 was significantly lower at baseline in HF-IPF (0.08 [0.04–0.52] vs. 0.12 [0.11–0.89] in HF-NL; P = 0.028) and with IL-1β stimulation (0.24 [0.05–1.53] vs. 1.08 [0.51–3.79] in HF-NL; P = 0.09).An alteration in the balance of profibrotic and antifibrotic PGs in HF-IPF may play a role in the pathogeneses of IPF.The concept of lung fibroblasts as effector cells in the pathogenesis of idiopathic pulmonary fibrosis (IPF) has recently evolved [1,2]. Lung fibroblasts respond, in vitro, to inflammatory cytokines by producing growth factors and collagen, resulting in fibroblast proliferation and extracellular matrix deposition [2-4]. In addition, activated lung fibroblasts have been shown to produce large amounts of inflammatory cytokines and chemokines, in vitro, and hence, these cells may also have a role as effector–inflammatory cells [1,2]. This capacity to produce both inflammatory and fibrotic factors could mean that phenotypically altered lung fibroblasts act simultaneously as effector and target cells, via paracrine and autocrine mechanisms, perpetuating the fibrotic process [2].Prostanoids are important regulators of fibroblast function [5-9]. Prostaglandin (PG)E2 is thought to have antifibrotic properties in vitro, but also can
BMPR2 expression is suppressed by signaling through the estrogen receptor
Eric D Austin, Rizwan Hamid, Anna R Hemnes, James E Loyd, Tom Blackwell, Chang Yu, John A Phillips III, Radhika Gaddipati, Santhi Gladson, Everett Gu, James West, Kirk B Lane
Biology of Sex Differences , 2012, DOI: 10.1186/2042-6410-3-6
Abstract: A variety of techniques were utilized across several model platforms to evaluate the relationship between estrogens and BMPR2 gene expression. We used quantitative RT-PCR, gel mobility shift, and luciferase activity assays in human samples, live mice, and cell culture.BMPR2 expression is reduced in lymphocytes from female patients compared with male patients, and in whole lungs from female mice compared with male mice. There is an evolutionarily conserved estrogen receptor binding site in the BMPR2 promoter, which binds estrogen receptor by gel-shift assay. Increased exogenous estrogen decreases BMPR2 expression in cell culture, particularly when induced to proliferate. Transfection of increasing quantities of estrogen receptor alpha correlates strongly with decreasing expression of BMPR2.BMPR2 gene expression is reduced in females compared to males in live humans and in mice, likely through direct estrogen receptor alpha binding to the BMPR2 promoter. This reduced BMPR2 expression may contribute to the increased prevalence of PAH in females.Bone morphogenetic protein receptor type 2 (BMPR2) is essential for development; mice lacking the gene fail to progress to gastrulation [1]. BMP signaling is essential in almost all tubular organogenesis. In lung, kidney and lacrimal gland formation BMP signaling is central to development [2-4]. The BMP pathway also plays a central role in Müllerian duct regression and Sertoli cell maturation regression [5,6].Beyond its developmental role, signaling through BMPR2 is associated with several adult diseases, including arthritis, pulmonary hypertension, atherosclerosis, diabetic nephropathy, renal fibrosis, and osteoporosis [7-10]. The common role for the BMP pathway in all of these seems to be an inappropriate response to damage to the respective organ. Many of these diseases show a marked gender imbalance in prevalence, and cross-talk between estrogen and BMP signaling has been noted in systems throughout the body [11-13].For inst
Physiologic and molecular consequences of endothelial Bmpr2 mutation
Susan Majka, Moira Hagen, Thomas Blackwell, Julie Harral, Jennifer A Johnson, Robert Gendron, Helene Paradis, Daniel Crona, James E Loyd, Eva Nozik-Grayck, Kurt R Stenmark, James West
Respiratory Research , 2011, DOI: 10.1186/1465-9921-12-84
Abstract: In vivo experiments were performed on adult mice with conditional endothelial-specific expression of the truncation mutation Bmpr2delx4+, with age-matched transactivator-only mice as controls. Phenotype was assessed by RVSP, counts of muscularized vessels and proliferating cells, and staining for thromboses, inflammatory cells, and apoptotic cells. The effects of BMPR2 knockdown in PMVEC by siRNA on rates of apoptosis were assessed. Affymetrix expression arrays were performed on PMVEC isolated and cultured from triple transgenic mice carrying the immortomouse gene, a transactivator, and either control, Bmpr2delx4+ or Bmpr2R899X mutation.Transgenic mice showed increased RVSP and corresponding muscularization of small vessels, with histologic alterations including thrombosis, increased inflammatory cells, increased proliferating cells, and a moderate increase in apoptotic cells. Expression arrays showed alterations in specific pathways consistent with the histologic changes. Bmpr2delx4+ and Bmpr2R899X mutations resulted in very similar alterations in proliferation, apoptosis, metabolism, and adhesion; Bmpr2delx4+ cells showed upregulation of platelet adhesion genes and cytokines not seen in Bmpr2R899X PMVEC. Bmpr2 mutation in PMVEC does not cause a loss of differentiation markers as was seen with Bmpr2 mutation in smooth muscle cells.Bmpr2 mutation in PMVEC in vivo may drive PAH through multiple, potentially independent, downstream mechanisms, including proliferation, apoptosis, inflammation, and thrombosis.Pulmonary arterial hypertension (PAH) is a lethal disorder characterized by pulmonary vasoconstriction and vascular remodeling, leading to progressively worsening right ventricular strain, and eventual right heart failure[1]. Early molecular and physiologic events in the development of the idiopathic form of PAH (IPAH) are not known. However, in most theories of etiology, the pulmonary microvascular endothelial cell (PMVEC) plays a central role, either because of a
Bronchoscopic Cryobiopsy for the Diagnosis of Diffuse Parenchymal Lung Disease
Jonathan A. Kropski, Jason M. Pritchett, Wendi R. Mason, Lakshmi Sivarajan, Linda A. Gleaves, Joyce E. Johnson, Lisa H. Lancaster, William E. Lawson, Timothy S. Blackwell, Mark P. Steele, James E. Loyd, Otis B. Rickman
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0078674
Abstract: Background Although in some cases clinical and radiographic features may be sufficient to establish a diagnosis of diffuse parenchymal lung disease (DPLD), surgical lung biopsy is frequently required. Recently a new technique for bronchoscopic lung biopsy has been developed using flexible cryo-probes. In this study we describe our clinical experience using bronchoscopic cryobiopsy for diagnosis of diffuse lung disease. Methods A retrospective study of subjects who had undergone bronchoscopic cryobiopsy for evaluation of DPLD at an academic tertiary care center from January 1, 2012 through January 15, 2013 was performed. The procedure was performed using a flexible bronchoscope to acquire biopsies of lung parenchyma. H&E stained biopsies were reviewed by an expert lung pathologist. Results Twenty-five eligible subjects were identified. With a mean area of 64.2 mm2, cryobiopsies were larger than that typically encountered with traditional transbronchial forceps biopsy. In 19 of the 25 subjects, a specific diagnosis was obtained. In one additional subject, biopsies demonstrating normal parenchyma were felt sufficient to exclude diffuse lung disease as a cause of dyspnea. The overall diagnostic yield of bronchoscopic cryobiopsy was 80% (20/25). The most frequent diagnosis was usual interstitial pneumonia (UIP) (n = 7). Three of the 25 subjects ultimately required surgical lung biopsy. There were no significant complications. Conclusion In patients with suspected diffuse parenchymal lung disease, bronchoscopic cryobiopsy is a promising and minimally invasive approach to obtain lung tissue with high diagnostic yield.
Ancestral Mutation in Telomerase Causes Defects in Repeat Addition Processivity and Manifests As Familial Pulmonary Fibrosis
Jonathan K. Alder,Joy D. Cogan,Andrew F. Brown,Collin J. Anderson,William E. Lawson,Peter M. Lansdorp,John A. Phillips III,James E. Loyd,Julian J.-L. Chen,Mary Armanios
PLOS Genetics , 2011, DOI: 10.1371/journal.pgen.1001352
Abstract: The telomerase reverse transcriptase synthesizes new telomeres onto chromosome ends by copying from a short template within its integral RNA component. During telomere synthesis, telomerase adds multiple short DNA repeats successively, a property known as repeat addition processivity. However, the consequences of defects in processivity on telomere length maintenance are not fully known. Germline mutations in telomerase cause haploinsufficiency in syndromes of telomere shortening, which most commonly manifest in the age-related disease idiopathic pulmonary fibrosis. We identified two pulmonary fibrosis families that share two non-synonymous substitutions in the catalytic domain of the telomerase reverse transcriptase gene hTERT: V791I and V867M. The two variants fell on the same hTERT allele and were associated with telomere shortening. Genealogy suggested that the pedigrees shared a single ancestor from the nineteenth century, and genetic studies confirmed the two families had a common founder. Functional studies indicated that, although the double mutant did not dramatically affect first repeat addition, hTERT V791I-V867M showed severe defects in telomere repeat addition processivity in vitro. Our data identify an ancestral mutation in telomerase with a novel loss-of-function mechanism. They indicate that telomere repeat addition processivity is a critical determinant of telomere length and telomere-mediated disease.
Truncating and missense BMPR2 mutations differentially affect the severity of heritable pulmonary arterial hypertension
Eric D Austin, John A Phillips, Joy D Cogan, Rizwan Hamid, Chang Yu, Krista C Stanton, Charles A Phillips, Lisa A Wheeler, Ivan M Robbins, John H Newman, James E Loyd
Respiratory Research , 2009, DOI: 10.1186/1465-9921-10-87
Abstract: Testing for BMPR2 mutations was performed in 169 patients with PAH (125 with a family history of PAH and 44 with sporadic disease). Of the 106 patients with a detectable BMPR2 mutation, lymphocytes were available in 96 to functionally assess the nonsense-mediated decay pathway of RNA surveillance. Phenotypic characteristics were compared between BMPR2 mutation carriers and noncarriers, as well as between those carriers with a missense versus truncating mutation.While there was a statistically significant difference in age at diagnosis between carriers and noncarriers, subgroup analysis revealed this to be the case only for females. Among carriers, there was no difference in age at diagnosis, death, or survival according to exonic location of the BMPR2 mutation. However, patients with missense mutations had statistically significant younger ages at diagnosis and death, as well as shorter survival from diagnosis to death or lung transplantation than those with truncating mutations. Consistent with this data, the majority of missense mutations were penetrant prior to age 36 years, while the majority of truncating mutations were penetrant after age 36 years.In this cohort, BMPR2 mutation carriers have more severe PAH disease than noncarriers, but this is only the case for females. Among carriers, patients with missense mutations that escape nonsense-mediated decay have more severe disease than those with truncating mutations. These findings suggest that treatment and prevention strategies directed specifically at BMPR2 pathway defects may need to vary according to the type of mutation.Pulmonary arterial hypertension (PAH) is a devastating disease that affects people of all ages. The small pulmonary arteries are primarily affected, resulting in progressive pulmonary vascular remodeling that leads to increased pulmonary vascular resistance and right heart failure [1]. PAH may occur in a variety of clinical contexts, including as a sporadic disease known as idiopathic PAH
The Habitat Structure of Lukanga Ramsar Site in Central Zambia: An Understanding of Wetland Ecological Condition  [PDF]
Harry Chabwela, Chansa Chomba, Loyd Thole
Open Journal of Ecology (OJE) , 2017, DOI: 10.4236/oje.2017.76029
Abstract: A field survey was carried out to determine the vegetation structure of the Lukanga Swamp Ramsar site in central Zambia. The aim of the study was to identify the different vegetation communities, species composition and distribution patterns for improved habitat management. Sampling was conducted in all recognizable vegetation communities. The results of the survey showed that the swamp was a littoral palustrine wetland predominantly characterized by the dominance of Leersia hexandria Swartz (42.02%), Typha capensis Rohrb (62.43%), Phragmites australis (Cav.) Trin. ex Steud (33.61%), Aeschynomeme fluitans Peter (31.58%) and Polygonum senegalense Meisn (48.8%). The occurrence of Vossia cuspidata Griff and Cyperus papyrusL was restricted to small and isolated locations. Short Termitaria was generally covered by Acrocerus macrum Stapf (35.25%) while tall Termitaria was dominated by Panicum maximum Jacq. (26.00%). The most important woody plant species included Combretum ghasalense Engl. et Diels (I. V = 62.88), Pseudolachnostylis maprouneifolia Pax ((I. V = 90.48), Albizia adianthifolia (Schmacher) W.F. Wight (I. V = 135.63) Isoberlinia angolensis Hyle and Brenan (I. V = 87.25). The current structure of the hydrophytes composition observed in this study was an indication of a generally silting wetland, while the dominant occurrence of understorey woody plants in the surrounding vegetation signified degraded miombo vegetation. It was concluded that the ecological status of wetland habitat was potentially threatened by mainly anthropogenic activities such as; wildfires, and unsustainable exploitation of surrounding vegetation. Further research is required to examine water flows, eutrophication and the long-term effects of deforestation on the ecological functioning of the wetland.
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