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Search Results: 1 - 10 of 163220 matches for " James F. Padbury "
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miR-16 and miR-21 Expression in the Placenta Is Associated with Fetal Growth
Matthew A. Maccani,James F. Padbury,Carmen J. Marsit
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0021210
Abstract: Novel research has suggested that altered miRNA expression in the placenta is associated with adverse pregnancy outcomes and with potentially harmful xenobiotic exposures. We hypothesized that aberrant expression of miRNA in the placenta is associated with fetal growth, a measurable phenotype resulting from a number of intrauterine factors, and one which is significantly predictive of later life outcomes.
Placental 11-Beta Hydroxysteroid Dehydrogenase Methylation Is Associated with Newborn Growth and a Measure of Neurobehavioral Outcome
Carmen J. Marsit, Matthew A. Maccani, James F. Padbury, Barry M. Lester
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0033794
Abstract: Background There is growing evidence that the intrauterine environment can impact the neurodevelopment of the fetus through alterations in the functional epigenome of the placenta. In the placenta, the HSD11B2 gene encoding the 11-beta hydroxysteroid dehydrogenase enzyme, which is responsible for the inactivation of maternal cortisol, is regulated by DNA methylation, and has been shown to be susceptible to stressors from the maternal environment. Methodology/Principal Findings We examined the association between DNA methylation of the HSD11B2 promoter region in the placenta of 185 healthy newborn infants and infant and maternal characteristics, as well as the association between this epigenetic variability and newborn neurobehavioral outcome assessed with the NICU Network Neurobehavioral Scales. Controlling for confounders, HSD11B2 methylation extent is greatest in infants with the lowest birthweights (P = 0.04), and this increasing methylation was associated with reduced scores of quality of movement (P = 0.04). Conclusions/Significance These results suggest that factors in the intrauterine environment which contribute to birth outcome may be associated with placental methylation of the HSD11B2 gene and that this epigenetic alteration is in turn associated with a prospectively predictive early neurobehavioral outcome, suggesting in some part a mechanism for the developmental origins of infant neurological health.
Forced expression of the cell cycle inhibitor p57Kip2 in cardiomyocytes attenuates ischemia-reperfusion injury in the mouse heart
Sheila A Haley, Ting Zhao, Lijun Zou, Jan E Klysik, James F Padbury, Lazaros K Kochilas
BMC Physiology , 2008, DOI: 10.1186/1472-6793-8-4
Abstract: Transgenic mice with cardiac specific overexpression of p57Kip2 are viable, fertile and normally active and their hearts are morphologically indistinguishable from the control hearts and have similar heart weight/body weight ratio. The baseline functional parameters, including left ventricular systolic pressure (LVSP), left ventricular end diastolic pressure (LVEDP), LVdp/dtmax, heart rate (HR) and rate pressure product (RPR) were not significantly different between the different groups as assessed by the Langendorff perfused heart preparation. However, after subjecting the heart ex vivo to 30 minutes of ischemia-reperfusion injury, the p57Kip2 overexpressing hearts demonstrated preserved cardiac function compared to control mice with higher left ventricular developed pressure (63 ± 15 vs 30 ± 6 mmHg, p = 0.05), rate pressure product (22.8 ± 4.86 vs 10.4 ± 2.1 × 103bpm × mmHg, p < 0.05) and coronary flow (3.5 ± 0.5 vs 2.38 ± 0.24 ml/min, p <0.05).These data suggest that forced cardiac expression of p57Kip2 does not affect myocardial growth, differentiation and baseline function but attenuates injury from ischemia-reperfusion in the adult mouse heart.Ischemic heart disease is the leading cause of morbidity and mortality in the industrialized world, but the development of effective therapy has been hampered by the lack of mechanistic insights into the physiological response of the heart to hypoxic stress. Adult cardiomyocytes respond to hypoxic stress by reverting to genetic programs associated with embryonic cardiac development, collectively referred to as "the fetal gene program" [1]. One of the most critical factors controlling heart growth and development is intrauterine oxygen availability [2,3]. Embryonic cardiac development occurs in an environment of low oxygen tension and hypoxia regulates several stress-related pathways affecting cellular proliferation, differentiation and death. While the low oxygen tension at this stage of development is "physiologic", the
In vitro silencing of the insulin receptor attenuates cellular accumulation of fibronectin in renal mesangial cells
Naohiro Yano, Daisuke Suzuki, Masayuki Endoh, Weizhi Zhang, Yan Xu, James F Padbury, Yi-Tang Tseng
Cell Communication and Signaling , 2012, DOI: 10.1186/1478-811x-10-29
Abstract: InsR silencing induced a unique phenotype of reduced fibronectin (FN) accumulation in renal glomerular MCs. Transcription level of FN was not significantly changed in the InsR silenced cells, suggesting the phenotype switching was caused by post-transcriptional modification. The decreased expression of InsR was associated with enhanced activity of insulin-like growth factor-1 receptor (IGF-1R)/PI3K/Akt signaling pathway which contributed in part to the attenuation of cellular FN accumulation. Formation of IGF-1R homodimer was increased in the InsR silenced cells. The InsR silenced cells also showed increased sensitivity to exogenous IGF-1, and increased PI3K activity was reversed significantly by incubating cells with IGF-1R specific antagonist, AG538. PI3K/Akt dependent activation of cAMP responsive element-binding protein (CREB)-1 induced expression of matrix metalloproteinase (MMP)-9 and suppressing MMP activity by doxycycline partially reversed FN accumulation in the InsR silenced cells.The effects of InsR silencing on cellular FN accumulation in vitro are, at least partially, mediated by increased degradation of FN by MMPs which is induced by enhanced signaling sequence of IGF-1R/PI3K/Akt/CREB-1.One of the common local pathologic changes of glomerulonephropathy is accumulation of extracellular matrix (ECM) components, including fibronectin (FN), which results in glomerulosclerosis. Although the mechanisms responsible for the ECM protein deposition are still inconclusive, the role of renal glomerular mesangial cells (MCs) in this sclerotic change has been gathering increasing attentions. Glomerular mesangium is an area which shows the most prominent ECM accumulations in diseased kidney. And the resulting glomerular fibrosis has been recognized as the major degenerative event in glomerulonephropathies regardless of their etiologies [1-3]. MCs are specialized pericytes located among the mesangium area within the renal corpuscle of the kidney [4]. ECM protein depos
Patterning in Placental 11-B Hydroxysteroid Dehydrogenase Methylation According to Prenatal Socioeconomic Adversity
Allison A. Appleton, David A. Armstrong, Corina Lesseur, Joyce Lee, James F. Padbury, Barry M. Lester, Carmen J. Marsit
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0074691
Abstract: Background Prenatal socioeconomic adversity as an intrauterine exposure is associated with a range of perinatal outcomes although the explanatory mechanisms are not well understood. The development of the fetus can be shaped by the intrauterine environment through alterations in the function of the placenta. In the placenta, the HSD11B2 gene encodes the 11-beta hydroxysteroid dehydrogenase enzyme, which is responsible for the inactivation of maternal cortisol thereby protecting the developing fetus from this exposure. This gene is regulated by DNA methylation, and this methylation and the expression it controls has been shown to be susceptible to a variety of stressors from the maternal environment. The association of prenatal socioeconomic adversity and placental HSD11B2 methylation has not been examined. Following a developmental origins of disease framework, prenatal socioeconomic adversity may alter fetal response to the postnatal environment through functional epigenetic alterations in the placenta. Therefore, we hypothesized that prenatal socioeconomic adversity would be associated with less HSD11B2 methylation. Methods and Findings We examined the association between DNA methylation of the HSD11B2 promoter region in the placenta of 444 healthy term newborn infants and several markers of prenatal socioeconomic adversity: maternal education, poverty, dwelling crowding, tobacco use and cumulative risk. We also examined whether such associations were sex-specific. We found that infants whose mothers experienced the greatest levels of socioeconomic adversity during pregnancy had the lowest extent of placental HSD11B2 methylation, particularly for males. Associations were maintained for maternal education when adjusting for confounders (p<0.05). Conclusions Patterns of HSD11B2 methylation suggest that environmental cues transmitted from the mother during gestation may program the developing fetus’s response to an adverse postnatal environment, potentially via less exposure to cortisol during development. Less methylation of placental HSD11B2 may therefore be adaptive and promote the effective management of stress associated with social adversity in a postnatal environment.
Efficacy of a Non-Hypercalcemic Vitamin-D2 Derived Anti-Cancer Agent (MT19c) and Inhibition of Fatty Acid Synthesis in an Ovarian Cancer Xenograft Model
Richard G. Moore, Thilo S. Lange, Katina Robinson, Kyu K. Kim, Alper Uzun, Timothy C. Horan, Nada Kawar, Naohiro Yano, Sharon R. Chu, Quanfu Mao, Laurent Brard, Monique E. DePaepe, James F. Padbury, Leggy A. Arnold, Alexander Brodsky, Tun-Li Shen, Rakesh K. Singh
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0034443
Abstract: Background Numerous vitamin-D analogs exhibited poor response rates, high systemic toxicities and hypercalcemia in human trials to treat cancer. We identified the first non-hypercalcemic anti-cancer vitamin D analog MT19c by altering the A-ring of ergocalciferol. This study describes the therapeutic efficacy and mechanism of action of MT19c in both in vitro and in vivo models. Methodology/Principal Finding Antitumor efficacy of MT19c was evaluated in ovarian cancer cell (SKOV-3) xenografts in nude mice and a syngenic rat ovarian cancer model. Serum calcium levels of MT19c or calcitriol treated animals were measured. In-silico molecular docking simulation and a cell based VDR reporter assay revealed MT19c–VDR interaction. Genomewide mRNA analysis of MT19c treated tumors identified drug targets which were verified by immunoblotting and microscopy. Quantification of cellular malonyl CoA was carried out by HPLC-MS. A binding study with PPAR-Y receptor was performed. MT19c reduced ovarian cancer growth in xenograft and syngeneic animal models without causing hypercalcemia or acute toxicity. MT19c is a weak vitamin-D receptor (VDR) antagonist that disrupted the interaction between VDR and coactivator SRC2-3. Genome-wide mRNA analysis and western blot and microscopy of MT19c treated xenograft tumors showed inhibition of fatty acid synthase (FASN) activity. MT19c reduced cellular levels of malonyl CoA in SKOV-3 cells and inhibited EGFR/phosphoinositol-3kinase (PI-3K) activity independently of PPAR-gamma protein. Significance Antitumor effects of non-hypercalcemic agent MT19c provide a new approach to the design of vitamin-D based anticancer molecules and a rationale for developing MT19c as a therapeutic agent for malignant ovarian tumors by targeting oncogenic de novo lipogenesis.
Aging and Environmental Exposures Alter Tissue-Specific DNA Methylation Dependent upon CpG Island Context
Brock C. Christensen,E. Andres Houseman,Carmen J. Marsit,Shichun Zheng,Margaret R. Wrensch,Joseph L. Wiemels,Heather H. Nelson,Margaret R. Karagas,James F. Padbury,Raphael Bueno,David J. Sugarbaker,Ru-Fang Yeh,John K. Wiencke,Karl T. Kelsey
PLOS Genetics , 2009, DOI: 10.1371/journal.pgen.1000602
Abstract: Epigenetic control of gene transcription is critical for normal human development and cellular differentiation. While alterations of epigenetic marks such as DNA methylation have been linked to cancers and many other human diseases, interindividual epigenetic variations in normal tissues due to aging, environmental factors, or innate susceptibility are poorly characterized. The plasticity, tissue-specific nature, and variability of gene expression are related to epigenomic states that vary across individuals. Thus, population-based investigations are needed to further our understanding of the fundamental dynamics of normal individual epigenomes. We analyzed 217 non-pathologic human tissues from 10 anatomic sites at 1,413 autosomal CpG loci associated with 773 genes to investigate tissue-specific differences in DNA methylation and to discern how aging and exposures contribute to normal variation in methylation. Methylation profile classes derived from unsupervised modeling were significantly associated with age (P<0.0001) and were significant predictors of tissue origin (P<0.0001). In solid tissues (n = 119) we found striking, highly significant CpG island–dependent correlations between age and methylation; loci in CpG islands gained methylation with age, loci not in CpG islands lost methylation with age (P<0.001), and this pattern was consistent across tissues and in an analysis of blood-derived DNA. Our data clearly demonstrate age- and exposure-related differences in tissue-specific methylation and significant age-associated methylation patterns which are CpG island context-dependent. This work provides novel insight into the role of aging and the environment in susceptibility to diseases such as cancer and critically informs the field of epigenomics by providing evidence of epigenetic dysregulation by age-related methylation alterations. Collectively we reveal key issues to consider both in the construction of reference and disease-related epigenomes and in the interpretation of potentially pathologically important alterations.
Alternative Methods for Analysis of Cyanobacterial Populations in Drinking Water Supplies: Fluorometric and Toxicological Applications Using Phycocyanin  [PDF]
Nancy J. Leland, James F. Haney
Journal of Water Resource and Protection (JWARP) , 2018, DOI: 10.4236/jwarp.2018.108042
Abstract: The management of cyanobacteria and potential exposure to associated biotoxins requires the allocation of scarce resources across a range of freshwater resources within various jurisdictions. Cost effective and reliable methods for sample processing and analysis form the foundation of the protocol yielding reliable data from which to derive important decisions. In this study the utilization of new methods to collect, process and analyze samples enhanced our ability to evaluate cyanobacterial populations. Extraction of phycocyanin using the single freeze thaw method provided more accurate and precise measurements (CV 4.7% and 6.4%), offering a simple and cost-effective means to overcome the influence of morphological variability. In-vacuo concentration of samples prior to ELISA analysis provided a detection limit of 0.001 μg·L?1 MC. Fractionation of samples (<0.2 μm, <2.0 μm, <50 μm, WLW and BFC) influenced our interpretations and improved our ability to establish a causative relationship between phycocyanin and microcystin levels in two aquatic systems with distinctly different cyanobacterial populations. In a Microcystis spp. dominant system Log MC (ng·L?1) = ?0.279 + (1.368 ? Log PC (μg·L?1) while in an Aphanizomemon spp. dominant system Log MC (ng·L?1) = 0.385 + (0.449 ? Log PC (μg·L?1). These methods and sampling protocol could be used in other aquatic systems across a broader regional landscape to estimate the levels of microcystins.
The Theory and Practice of Active Aging
James F. Fries
Current Gerontology and Geriatrics Research , 2012, DOI: 10.1155/2012/420637
Abstract: “Active aging” connotes a radically nontraditional paradigm of aging which posits possible improvement in health despite increasing longevity. The new paradigm is based upon postponing functional declines more than mortality declines and compressing morbidity into a shorter period later in life. This paradigm (Compression of Morbidity) contrasts with the old, where increasing longevity inevitably leads to increasing morbidity. We have focused our research on controlled longitudinal studies of aging. The Runners and Community Controls study began at age 58 in 1984 and the Health Risk Cohorts study at age 70 in 1986. We noted that disability was postponed by 14 to 16 years in vigorous exercisers compared with controls and postponed by 10 years in low-risk cohorts compared with higher risk. Mortality was also postponed, but too few persons had died for valid comparison of mortality and morbidity. With the new data presented here, age at death at 30% mortality is postponed by 7 years in Runners and age at death at 50% (median) mortality by 3.3 years compared to controls. Postponement of disability is more than double that of mortality in both studies. These differences increase over time, occur in all subgroups, and persist after statistical adjustment. 1. Introduction “Active aging” and the related terms “healthy aging,” “successful aging,” “productive aging,” “aging well,” “living well,” “senior wellness,” and “compression of morbidity” endorse a radically nontraditional paradigm of human aging, which includes gains as well as losses and which posits possible improvement in future human health despite increasing longevity. Each of these terms, discussed briefly below, foresees a new paradigm for gerontology, based upon postponing functional declines into older ages with a goal of postponement of morbidity more than mortality, compressing morbidity into a shorter period later in life, and decreasing cumulative lifetime morbidity [1]. The new paradigm contrasts strikingly with the old “Failures of Success” paradigm, where improvements in longevity would inevitably lead to ever larger numbers of persons in ever poorer health [2]. There are differences in nuance between these terms and in the metrics by which they might be measured, and confusion might be reduced by greater agreement on terminology. We are most comfortable with “Compression of Morbidity” since it implies a strategy for improving health, the theory behind the strategy, and the means of testing progress, albeit a more technical term than alternatives. Of alternative terms, we prefer the term
Upsetting the Dogma: Germline Selection in Human Males
James F. Crow ?
PLOS Genetics , 2012, DOI: 10.1371/journal.pgen.1002535
Abstract:
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