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Sample records for 13-cis-retinoic acid ra

  1. Metabolic characteristics of 13-cis-retinoic acid (isotretinoin) and anti-tumour activity of the 13-cis-retinoic acid metabolite 4-oxo-13-cis-retinoic acid in neuroblastoma

    PubMed Central

    Sonawane, Poonam; Cho, Hwang Eui; Tagde, Ashujit; Verlekar, Dattesh; Yu, Alice L; Reynolds, C Patrick; Kang, Min H

    2014-01-01

    Background and Purpose Isotretinoin (13-cis-retinoic acid; 13-cRA) is a differentiation inducer used to treat minimal residual disease after myeloablative therapy for high-risk neuroblastoma. However, more than 40% of children develop recurrent disease during or after 13-cRA treatment. The plasma concentrations of 13-cRA in earlier studies were considered subtherapeutic while 4-oxo-13-cis-RA (4-oxo-13-cRA), a metabolite of 13-cRA considered by some investigators as inactive, were greater than threefold higher than 13-cRA. We sought to define the metabolic pathways of 13-cRA and investigated the anti-tumour activity of its major metabolite, 4-oxo-13-cRA. Experimental Approach Effects of 13-cRA and 4-oxo-13-cRA on human neuroblastoma cell lines were assessed by DIMSCAN and flow cytometry for cell proliferation, MYCN down-regulation by reverse transcription PCR and immunoblotting, and neurite outgrowth by confocal microscopy. 13-cRA metabolism was determined using tandem MS in human liver microsomes and in patient samples. Key Results Six major metabolites of 13-cRA were identified in patient samples. Of these, 4-oxo-13-cRA was the most abundant, and 4-oxo-13-cRA glucuronide was also detected at a higher level in patients. CYP3A4 was shown to play a major role in catalysing 13-cRA to 4-oxo-13-cRA. In human neuroblastoma cell lines, 4-oxo-13-cRA and 13-cRA were equi-effective at inducing neurite outgrowth, inhibiting proliferation, decreasing MYCN mRNA and protein, and increasing the expression of retinoic acid receptor-β mRNA and protein levels. Conclusions and Implications We showed that 4-oxo-13-cRA is as active as 13-cRA against neuroblastoma cell lines. Plasma levels of both 13-cRA and 4-oxo-13-cRA should be evaluated in pharmacokinetic studies of isotretinoin in neuroblastoma. PMID:25039756

  2. The Influence of 13-cis Retinoic Acid on Human Meibomian Gland Epithelial Cells

    PubMed Central

    Ding, Juan; Kam, Wendy R.; Dieckow, Julia; Sullivan, David A.

    2013-01-01

    Purpose. Meibomian gland dysfunction (MGD) is a primary cause of dry eye disease. One of the risk factors for MGD is exposure to 13-cis retinoic acid (13-cis RA), a metabolite of vitamin A. However, the mechanism is not well understood. We hypothesize that 13-cis RA inhibits cell proliferation, promotes cell death, alters gene and protein expressions, and attenuates cell survival pathways in human meibomian gland epithelial cells. Methods. To test our hypotheses, immortalized human meibomian gland epithelial cells were cultured with or without 13-cis RA for varying doses and time. Cell proliferation, cell death, gene expression, and proteins involved in proliferation/survival and inflammation were evaluated. Results. We found that 13-cis RA inhibited cell proliferation, induced cell death, and significantly altered the expression of 6726 genes, including those involved in cell proliferation, cell death, differentiation, keratinization, and inflammation, in human meibomian gland epithelial cells. Further, 13-cis RA also reduced the phosphorylation of Akt and increased the generation of interleukin-1β and matrix metallopeptidase 9. Conclusions. Exposure to 13-cis RA inhibits cell proliferation, increases cell death, alters gene expression, changes signaling pathways, and promotes inflammatory mediator and protease expression in meibomian gland epithelial cells. These effects may be responsible, at least in part, for the 13-cis RA–related induction of MGD. PMID:23722388

  3. Practical implications for the administration of 13-cis retinoic acid in pediatric oncology.

    PubMed

    Bauters, Tiene G M; Laureys, Geneviève; Van de Velde, Véronique; Benoit, Yves; Robays, Hugo

    2011-08-01

    Children with high-risk neuroblastoma are treated with polychemotherapy, surgery, radiotherapy and even autologous stem-cell transplantation. On top of this complex treatment, most children also receive 13-cis retinoic acid as differentiation agent. As no suitable pharmaceutical formulation is available so far, there are often problems with the administration of the product in children. The present report describes some practical recommendations for the administration of isotretinoin in children treated for high-risk neuroblastoma. PMID:21544558

  4. The effects of 13-cis retinoic acid and interferon-alpha in chronic myelogenous leukemia cells in vivo in patients.

    PubMed

    Handa, H; Hegde, U P; Kotelnikov, V M; Mundle, S D; Dong, L M; Burke, P; Rose, S; Hsu, W T; Gaskin, F; Raza, A; Preisler, H D

    1997-01-01

    The effects of the administration of a 3-day course of 13-cis retinoic acid in combination with interferon a [RA/IFN] on the leukemia cells was measured in vivo in 43 patients with chronic myelogenous leukemia. The administration of RA/IFN was associated with a significant fall in the white blood cell count of patients with chronic-phase disease and with a fall in the percentage S-phase cells in CML patients regardless of the stage of their leukemia. In two thirds of the patients studied the administration of RA/IFN was also associated with an increase in marrow apoptosis. The cytokine combination also suppressed bcl-2 and myc expression in a minority of patients and such expression appears to be associated with response to a treatment regimen which includes RA/IFN. These studies are the first to directly assess the effects of the combination of RA/IFN on chronic myelogenous leukemia cells in vivo in patients. These effects, if seen in other malignant diseases, could account for the therapeutic benefit which has been associated with the administration of this combination of biological agents to patients with malignant disease. PMID:9444943

  5. Recurrent asymptomatic demyelinating disease following 13-cis-retinoic acid exposure

    PubMed Central

    Okuda, Darin T; Prados, Michael D

    2009-01-01

    We report a case of multifocal demyelination within the central nervous system in a patient being treated for a left hemispheric gemnistocytic astrocytoma with radiation therapy and chemotherapy, comprising temozolomide (360 mg/day—days 1–5 every 28 days) and 13-cis-retinoic acid (100 mg/m2/day—separated into two doses administered every 12 h on days 1 through 21 every 28 days). Five months into her first round of chemotherapy, brain magnetic resonance imaging (MRI) demonstrated multifocal regions of T2 prolongation with associated gadolinium enhancement within the right cerebral hemisphere. Spectroscopic data were consistent with demyelination rather than neoplasia. Despite the incidentally identified radiological progression, new neurological symptoms were not described. Interval resolution of the demyelinating lesions was observed in the years following the discontinuance of her chemotherapy regimen with reactivation of the previously observed lesions and the development of new T2 foci 6 months into her second round of re-treatment for tumour progression 5 years later. PMID:21901115

  6. Chronic oral treatment with 13-cis-retinoic acid (isotretinoin) or all-trans-retinoic acid does not alter depression-like behaviors in rats.

    PubMed

    Ferguson, Sherry A; Cisneros, F Javier; Gough, B; Hanig, Joseph P; Berry, Kimberly J

    2005-10-01

    Oral treatment with the anti-acne drug Accutane (isotretinoin, 13-cis-retinoic acid) has been associated with suicide ideation and depression. Here, depression-like behaviors (i.e., behavioral despair and anhedonia) were quantified in adult Sprague-Dawley rats gavaged daily beginning at postnatal day (PND) 82 with 13-cis-RA (7.5 or 22.5 mg/kg) or all-trans-retinoic acid (10 or 15 mg/kg ). Tested at PND 130-131 in the Forced Swim Test, 7.5 mg/kg 13-cis-RA marginally decreased immobility and slightly increased climb/struggle durations whereas neither all-trans-retinoic acid group differed from controls. Voluntary saccharin solution (0.03%) intake at PND 102-104 and PND 151-153 was not different from controls in any treated group, although all RA-treated groups had lower intakes. Swim speed in a water maze at PND 180 was similar across groups, indicating no RA-induced differences in physical ability. Open field activity was mildly decreased at PND 91 in 7.5 mg/kg-treated males only, but it was within the control range at PND 119, 147, and 175. Thus, at serum levels similar to those in humans receiving the drug, chronic 13-cis-RA treatment did not severely affect depression-like behaviors in rats. These data do not substantiate the hypothesis of 13-cis-RA-induced depression. PMID:16033993

  7. Usefulness of 18F-Fluorodeoxyglucose Positron Emission Tomography for Follow-Up of 13-cis-Retinoic Acid Treatment for Residual Neuroblastoma After Myeloablative Chemotherapy

    PubMed Central

    Sato, Yuya; Kurosawa, Hidemitsu; Sakamoto, Setsu; Kuwashima, Shigeko; Hashimoto, Teisuke; Okamoto, Kentaro; Tsuchioka, Takashi; Fukushima, Keitaro; Arisaka, Osamu

    2015-01-01

    Abstract 13-cis-retinoic acid (13-cis-RA) treatment is used as a second-line treatment for residual or recurrent neuroblastoma. However, determining the duration of 13-cis-RA treatment for residual and recurrent neuroblastoma can be a problem because it is difficult to evaluate the effectiveness of the treatment. We performed 13-cis-RA treatment to remove residual active neuroblastoma cells in an 8-year-old boy with stage 4 neuroblastoma that developed from a left sympathetic ganglion and had been treated with chemotherapy, surgery, autologous peripheral blood stem-cell transplantation, and radiotherapy. 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) and iodine-123 metaiodobenzylguanidine (123I-MIBG) scintigraphy obtained immediately before 13-cis-RA treatment both showed positive findings in the area of the primary lesion. At 18 months after 13-cis-RA treatment, there was accumulation on 123I-MIBG scintigraphy but no uptake on 18F-FDG-PET, and 13-cis-RA treatment was suspended. The patient has been in complete remission for 3 years. In comparing the effectiveness of the 2 imaging modalities for monitoring the response to 13-cis-RA treatment, we considered that 18F-FDG-PET was superior to 123I-MIBG scintigraphy because 18F-FDG-PET images were not affected by the cell differentiation induced by 13-cis-RA treatment in our case. Thus, 18F-FDG-PET was useful for determining the treatment response and outcomes. We have reported a case of residual neuroblastoma treated with differentiation-inducing 13-cis-RA therapy. Different results were produced with 18F-FDG-PET and 123I-MIBG scintigraphy. The cessation of 13-cis-RA treatment was based on 18F-FDG-PET findings and there has been no relapse for 3 years. PMID:26252303

  8. Usefulness of 18F-Fluorodeoxyglucose Positron Emission Tomography for Follow-Up of 13-cis-Retinoic Acid Treatment for Residual Neuroblastoma After Myeloablative Chemotherapy.

    PubMed

    Sato, Yuya; Kurosawa, Hidemitsu; Sakamoto, Setsu; Kuwashima, Shigeko; Hashimoto, Teisuke; Okamoto, Kentaro; Tsuchioka, Takashi; Fukushima, Keitaro; Arisaka, Osamu

    2015-08-01

    13-cis-retinoic acid (13-cis-RA) treatment is used as a second-line treatment for residual or recurrent neuroblastoma. However, determining the duration of 13-cis-RA treatment for residual and recurrent neuroblastoma can be a problem because it is difficult to evaluate the effectiveness of the treatment.We performed 13-cis-RA treatment to remove residual active neuroblastoma cells in an 8-year-old boy with stage 4 neuroblastoma that developed from a left sympathetic ganglion and had been treated with chemotherapy, surgery, autologous peripheral blood stem-cell transplantation, and radiotherapy. F-fluorodeoxyglucose positron emission tomography (F-FDG-PET) and iodine-123 metaiodobenzylguanidine (I-MIBG) scintigraphy obtained immediately before 13-cis-RA treatment both showed positive findings in the area of the primary lesion. At 18 months after 13-cis-RA treatment, there was accumulation on I-MIBG scintigraphy but no uptake on F-FDG-PET, and 13-cis-RA treatment was suspended. The patient has been in complete remission for 3 years. In comparing the effectiveness of the 2 imaging modalities for monitoring the response to 13-cis-RA treatment, we considered that F-FDG-PET was superior to I-MIBG scintigraphy because F-FDG-PET images were not affected by the cell differentiation induced by 13-cis-RA treatment in our case. Thus, F-FDG-PET was useful for determining the treatment response and outcomes.We have reported a case of residual neuroblastoma treated with differentiation-inducing 13-cis-RA therapy. Different results were produced with F-FDG-PET and I-MIBG scintigraphy. The cessation of 13-cis-RA treatment was based on F-FDG-PET findings and there has been no relapse for 3 years. PMID:26252303

  9. Glutathione S-transferases act as isomerases in isomerization of 13-cis-retinoic acid to all-trans-retinoic acid in vitro.

    PubMed Central

    Chen, H; Juchau, M R

    1997-01-01

    A discovery that rapid enzymic isomerization of 13-cis-retinoic acid (13-cRA) to all-trans-retinoic acid (t-RA) can be catalysed by purified hepatic glutathione S-transferases (GSTs; EC 2.5.1.18) from rat is now reported. Rates of cis-trans isomerization were determined quantitatively by HPLC. GST-catalysed reactions reached equilibrium rapidly, in marked contrast with uncatalysed or GSH-catalysed isomerizations. The GST-catalysed reaction exhibited substrate saturation kinetics with a Km of approx. 8 microM. The maximal velocity of the reaction and the catalytic efficiency of GSTs were determined. The initial rate of the reaction increased linearly as a function of enzyme concentration. Catalysis by GSTs was independent of the presence of GSH, indicating that GSTs act as GSH-independent isomerases as well as transferases. Incubation with guanidine (7-8 M) or heat-inactivation of GSTs (100 degrees C for 3 min) decreased isomerase activities by approx. 50% and 75% respectively. The same heat treatment did not significantly inhibit isomerization catalysed by GSH and apoferritin, indicating that the observed decrease in isomerase activity by heat inactivation was not primarily due to oxidation of protein thiol groups in the GSTs. The specific activity of GSTs was approx. 23- and 340-fold those of GSH and apoferritin respectively when comparisons were made on the basis of free thiol concentrations, indicating that free thiol in GSTs cannot account for the majority of observed isomerase activities and suggesting that specific conformations of GSTs are important for such activities. Complete inhibition of the reaction by low concentrations of N-ethylmaleimide (10 microM) demonstrated that intact protein thiols are required for the isomerase activities of GSTs. PMID:9581548

  10. A Randomized Phase II Chemoprevention Trial of 13-CIS Retinoic Acid with Or without α Tocopherol or Observation in Subjects at High Risk for Lung Cancer

    PubMed Central

    Kelly, Karen; Kittelson, John; Franklin, Wilbur A.; Kennedy, Timothy C.; Klein, Catherine E.; Keith, Robert L.; Dempsey, Edward C.; Lewis, Marina; Jackson, Mary K.; Hirsch, Fred R.; Bunn, Paul A.; Miller, York E.

    2011-01-01

    No chemoprevention strategies have been proven effective for lung cancer. We evaluated the effect of 13-cis retinoic acid (13-cis RA), with or without α tocopherol, as a lung cancer chemoprevention agent in a phase II randomized controlled clinical trial of adult subjects at high risk for lung cancer as defined by the presence of sputum atypia, history of smoking, and airflow obstruction, or a prior surgically cured nonsmall cell lung cancer (disease free, >3 years). Subjects were randomly assigned to receive either 13-cis RA, 13-cis RA plus α tocopherol (13-cis RA/α toco) or observation for 12 months. Outcome measures are derived from histologic evaluation of bronchial biopsy specimens obtained by bronchoscopy at baseline and follow-up. The primary outcome measure is treatment “failure” defined as histologic progression (any increase in the maximum histologic score) or failure to return for follow-up bronchoscopy. Seventy-five subjects were randomized (27/22/26 to obervations/13-cis RA/13-cis RA/α toco); 59 completed the trial; 55 had both baseline and follow-up bronchoscopy. The risk of treatment failure was 55.6% (15 of 27) and 50% (24 of 48) in the observation and combined (13 cis RA plus 13 cis RA/α toco) treatment arms, respectively (odds ratio adjusted for baseline histology, 0.97; 95% confidence interval, 0.36–2.66; P = 0.95). Among subjects with complete histology data, maximum histology score in the observation arm increased by 0.37 units and by 0.03 units in the treated arms (difference adjusted for baseline, −0.18; 95% confidence interval, −1.16 to 0.81; P = 0.72). Similar (nonsignificant) results were observed for treatment effects on endobronchial proliferation as assessed by Ki-67 immunolabeling. Twelve-month treatment with 13-cis RA produced nonsignificant changes in bronchial histology, consistent with results in other trials. Agents advancing to phase III randomized trials should produce greater histologic changes. The addition of

  11. Combination of 13-Cis retinoic acid and lovastatin: marked antitumor potential in vivo in a pheochromocytoma allograft model in female athymic nude mice.

    PubMed

    Nölting, Svenja; Giubellino, Alessio; Tayem, Yasin; Young, Karen; Lauseker, Michael; Bullova, Petra; Schovanek, Jan; Anver, Miriam; Fliedner, Stephanie; Korbonits, Márta; Göke, Burkhard; Vlotides, George; Grossman, Ashley; Pacak, Karel

    2014-07-01

    Currently, there are no reliably effective therapeutic options for metastatic pheochromocytoma (PCC) and paraganglioma. Moreover, there are no therapies that may prevent the onset or progression of tumors in patients with succinate dehydrogenase type B mutations, which are associated with very aggressive tumors. Therefore, we tested the approved and well-tolerated drugs lovastatin and 13-cis-retinoic acid (13cRA) in vitro in an aggressive PCC mouse cell line, mouse tumor tissue-derived (MTT) cells, and in vivo in a PCC allograft nude mouse model, in therapeutically relevant doses. Treatment was started 24 hours before sc tumor cell injection and continued for 30 more days. Tumor sizes were measured from outside by caliper and sizes of viable tumor mass by bioluminescence imaging. Lovastatin showed antiproliferative effects in vitro and led to significantly smaller tumor sizes in vivo compared with vehicle treatment. 13cRA promoted tumor cell growth in vitro and led to significantly larger viable tumor mass and significantly faster increase of viable tumor mass in vivo over time compared with vehicle, lovastatin, and combination treatment. However, when combined with lovastatin, 13cRA enhanced the antiproliferative effect of lovastatin in vivo. The combination-treated mice showed slowest tumor growth of all groups with significantly slower tumor growth compared with the vehicle-treated mice and significantly smaller tumor sizes. Moreover, the combination-treated group displayed the smallest size of viable tumor mass and the slowest increase in viable tumor mass over time of all groups, with a significant difference compared with the vehicle- and 13cRA-treated group. The combination-treated tumors showed highest extent of necrosis, lowest median microvessel density and highest expression of α-smooth muscle actin. The combination of high microvessel density and low α-smooth muscle actin is a predictor of poor prognosis in other tumor entities. Therefore, this drug

  12. Inhibition of the visual cycle in vivo by 13-cis retinoic acid protects from light damage and provides a mechanism for night blindness in isotretinoin therapy.

    PubMed

    Sieving, P A; Chaudhry, P; Kondo, M; Provenzano, M; Wu, D; Carlson, T J; Bush, R A; Thompson, D A

    2001-02-13

    Isotretinoin (13-cis retinoic acid) is frequently prescribed for severe acne [Peck, G. L., Olsen, T. G., Yoder, F. W., Strauss, J. S., Downing, D. T., Pandya, M., Butkus, D. & Arnaud-Battandier, J. (1979) N. Engl. J. Med. 300, 329-333] but can impair night vision [Fraunfelder, F. T., LaBraico, J. M. & Meyer, S. M. (1985) Am. J. Ophthalmol. 100, 534-537] shortly after the beginning of therapy [Shulman, S. R. (1989) Am. J. Public Health 79, 1565-1568]. As rod photoreceptors are responsible for night vision, we administered isotretinoin to rats to learn whether night blindness resulted from rod cell death or from rod functional impairment. High-dose isotretinoin was given daily for 2 months and produced systemic toxicity, but this caused no histological loss of rod photoreceptors, and rod-driven electroretinogram amplitudes were normal after prolonged dark adaptation. Additional studies showed, however, that even a single dose of isotretinoin slowed the recovery of rod signaling after exposure to an intense bleaching light, and that rhodopsin regeneration was markedly slowed. When only a single dose was given, rod function recovered to normal within several days. Rods and cones both showed slow recovery from bleach after isotretinoin in rats and in mice. HPLC analysis of ocular retinoids after isotretinoin and an intense bleach showed decreased levels of rhodopsin chromophore, 11-cis retinal, and the accumulation of the biosynthetic intermediates, 11-cis and all-trans retinyl esters. Isotretinoin was also found to protect rat photoreceptors from light-induced damage, suggesting that strategies of altering retinoid cycling may have therapeutic implications for some forms of retinal and macular degeneration. PMID:11172037

  13. Long-term follow-up of myelodysplastic syndrome patients with moderate/severe anaemia receiving human recombinant erythropoietin + 13-cis-retinoic acid and dihydroxylated vitamin D3: independent positive impact of erythroid response on survival.

    PubMed

    Crisà, Elena; Foli, Cristina; Passera, Roberto; Darbesio, Antonella; Garvey, Kimberly B; Boccadoro, Mario; Ferrero, Dario

    2012-07-01

    We previously reported a 60% erythroid response rate with recombinant erythropoietin + 13-cis retinoic acid + dihydroxylated vitamin D3 in 63 elderly myelodysplastic patients (median age 75 years) with unfavourable features for response to erythropoietin alone [70% transfusion-dependent, 35% refractory anaemia with ring sideroblasts/refractory anaemia with excess of blasts type 1 (RAEB1), 70% with International Prognostic Scoring System (IPSS) Intermediate-1 or -2]. This report updates that case study at a 7-year follow-up, and compared the impact on overall survival of erythroid response to known prognostic factors. The erythroid response duration (median 17 months; 22 in non-RAEB patients, with 20% patients in response after 6 years of therapy) was longer than in most studies with erythropoietin alone. Overall survival (median 55 months in non-RAEB, 15 in RAEB1 patients) was negatively affected by RAEB1 diagnosis, IPSS and WPSS intermediate scores and transfusion-dependence. In the multivariate analysis, erythroid response maintained an independent positive impact on survival, particularly in non-RAEB patients in the first 3 years from diagnosis (90% survival compared to 50% of non-responders). In conclusion, the long-term follow-up confirmed the achievement, by our combined treatment, of fairly long-lasting erythroid response in the majority of MDS patients with unfavourable prognostic features for response to erythropoietin: this translated in a survival benefit that was independent from other prognostic features. PMID:22571649

  14. Murine Anti-GD2 Monoclonal Antibody 3F8 Combined With Granulocyte-Macrophage Colony-Stimulating Factor and 13-Cis-Retinoic Acid in High-Risk Patients With Stage 4 Neuroblastoma in First Remission

    PubMed Central

    Cheung, Nai-Kong V.; Cheung, Irene Y.; Kushner, Brian H.; Ostrovnaya, Irina; Chamberlain, Elizabeth; Kramer, Kim; Modak, Shakeel

    2012-01-01

    Purpose Anti-GD2 monoclonal antibody (MoAb) combined with granulocyte-macrophage colony-stimulating factor (GM-CSF) has shown efficacy against neuroblastoma (NB). Prognostic variables that could influence clinical outcome were explored. Patients and Methods One hundred sixty-nine children diagnosed with stage 4 NB (1988 to 2008) were enrolled onto consecutive anti-GD2 murine MoAb 3F8 ± GM-CSF ± 13-cis-retinoic acid (CRA) protocols after achieving first remission (complete remission/very good partial remission). Patients enrolled in regimen A (n = 43 high-risk [HR] patients) received 3F8 alone; regimen B (n = 41 HR patients), 3F8 + intravenous GM-CSF + CRA, after stem-cell transplantation (SCT); and regimen C (n = 85), 3F8 + subcutaneous GM-CSF + CRA, 46 of 85 after SCT, whereas 28 of 85 required additional induction therapy and were deemed ultra high risk (UHR). Marrow minimal residual disease (MRD) was measured by quantitative reverse transcription polymerase chain reaction. Survival probability was calculated by the Kaplan-Meier method, and prognostic variables were analyzed by multivariate Cox regression model. Results At 5 years from the start of immunotherapy, progression-free survival (PFS) improved from 44% for HR patients receiving regimen A to 56% and 62% for those receiving regimens B and C, respectively. Overall survival (OS) was 49%, 61%, and 81%, respectively. PFS and OS of UHR patients were 36% and 75%, respectively. Relapse was mostly at isolated sites. Independent adverse prognostic factors included UHR (PFS) and post–cycle two MRD (PFS and OS), whereas the prognostic factors for improved outcome were missing killer immunoglobulin-like receptor ligand (PFS and OS), human antimouse antibody response (OS), and regimen C (OS). Conclusion Retrospective analysis of consecutive trials from a single center demonstrated that MoAb 3F8 + GM-CSF + CRA is effective against chemotherapy-resistant marrow MRD. Its positive impact on long-term survival can only

  15. Oxidative and reductive metabolism of 9-cis-retinoic acid in the rat. Identification of 13,14-dihydro-9-cis-retinoic acid and its taurine conjugate.

    PubMed

    Shirley, M A; Bennani, Y L; Boehm, M F; Breau, A P; Pathirana, C; Ulm, E H

    1996-03-01

    9-cis-Retinoic acid (9-cis-RA), a hormone that binds and activates all known retinoid receptor subtypes, is structurally similar to all-trans-retinoic acid and may share common metabolic fates. Both oral and intravenous doses of 9-cis-RA to rats led to hydroxylation and ketone formation at carbon-4. 9-Cis-RA also isomerized in vivo to 13-cis-retinoic acid, 9-cis, 13-cis-retinoic acid, and all-trans-retinoic acid. After administration of [11-3H]9-cis-RA, the proportion of plasma radioactivity that was volatile increased over time, which suggested that beta-oxidative chain-shortening of 9-cis-RA might occur. An equimolar mixture of [1-13C2H3]9-cis-RA and 9-cis-RA was administered to rats for stable-isotope-labeled metabolite production. A chromatographic peak that had a lambdamax = 290 nm vs. 348 nm for the parent compound, had a retention time similar to the parent, and yielded a 1:1 positive-ion isotope cluster at m/z 303/307 in its mass spectrum. NMR analysis revealed 9-cis and 13,14-dihydro configurations, indicating that 9-cis-RA can be metabolized in rat by reduction to 13,14-dihydro-9-cis-RA. An earlier-eluting HPLC peak that exhibited a lambdamax at 290 nm, and a negative-ion-MS isotope cluster at m/z 408/412 was observed during separations of rat liver extracts. LC/MS/MS analysis revealed product ions for this peak diagnostic for carboxylic acid taurine conjugates. In rats, reduction of 9-cis-RA to 13,14-dihydro-9-cis-RA may represent an initial step leading to beta-oxidation, although available data demonstrate it is conjugated with taurine to form a novel metabolite. PMID:8820419

  16. The Retinoic Acid Receptor-α mediates human T-cell activation and Th2 cytokine and chemokine production

    PubMed Central

    Dawson, Harry D; Collins, Gary; Pyle, Robert; Key, Michael; Taub, Dennis D

    2008-01-01

    Background We have recently demonstrated that all-trans-retinoic acid (ATRA) and 9-cis-retinoic acid (9-cis RA) promote IL-4, IL-5 and IL-13 synthesis, while decreasing IFN-γ and TNF-α expression by activated human T cells and reduces the synthesis of IL-12p70 from accessory cells. Here, we have demonstrated that the observed effects using ATRA and 9-cis RA are shared with the clinically useful RAR ligand, 13-cis retinoic acid (13-cis RA), and the retinoic acid receptor-α (RAR-α)-selective agonist, AM580 but not with the RAR-β/γ ligand, 4-hydroxyphenylretinamide (4-HPR). Results The increase in type 2 cytokine production by these retinoids correlated with the expression of the T cell activation markers, CD69 and CD38. The RAR-α-selective agonist, AM580 recapitulated all of the T cell activation and type 2 cytokine-inducing effects of ATRA and 9-cis-RA, while the RAR-α-selective antagonist, RO 41–5253, inhibited these effects. Conclusion These results strongly support a role for RAR-α engagement in the regulation of genes and proteins involved with human T cell activation and type 2 cytokine production. PMID:18416830

  17. Retinoic Acid and Affective Disorders: The Evidence for an Association

    PubMed Central

    Bremner, J Douglas; Shearer, Kirsty; McCaffery, Peter

    2011-01-01

    Objective Isotretinoin (13-cis-retinoic acid, or 13-cis-RA) (Accutane), approved by the FDA for the treatment of acne, carries a black box warning related to the risk of depression, suicide, and psychosis. Retinoic acid (RA), the active form of vitamin A, regulates gene expression in the brain, and isotretinoin is its 13-cis isomer. Retinoids represent a group of compounds derived from vitamin A that perform a large variety of functions in many systems, in particular the CNS, and abnormal retinoid levels can have neurological effects. Although infrequent, proper recognition and treatment of psychiatric side effects in acne patients is critical given the risk of death and disability. This paper reviews the evidence for a relationship between isotretinoin, depression and suicidality. Data Sources Evidence examined includes: 1) case reports; 2) temporal association between onset of depression and exposure to the drug; 3) challenge-rechallenge cases; 4) class effect (other compounds in the same class, like vitamin A, having similar neuropsychiatric effects); 5) dose response; and 6) biologically plausible mechanisms. Study Selection All papers in the literature related to isotretinoin, depression and suicide were reviewed, as well as papers related to class effect, dose response, and biological plausibility. Data Extraction Information from individual articles in the literature was extracted. Data Synthesis The literature reviewed is consistent with an association between isotretinoin administration, depression and suicide in some individuals. Conclusions The relationship between isotretinoin and depression may have implications for a greater understanding of the neurobiology of affective disorders. PMID:21903028

  18. Retinoic acid isomers up-regulate ATP binding cassette A1 and G1 and cholesterol efflux in rat astrocytes: implications for their therapeutic and teratogenic effects.

    PubMed

    Chen, Jing; Costa, Lucio G; Guizzetti, Marina

    2011-09-01

    Recent studies suggest that retinoids may be effective in the treatment of Alzheimer's disease, although exposure to an excess of retinoids during gestation causes teratogenesis. Cholesterol is essential for brain development, but high levels of cholesterol have been associated with Alzheimer's disease. We hypothesized that retinoic acid may affect cholesterol homeostasis in rat astrocytes, which regulate cholesterol distribution in the brain, through the up-regulation of cholesterol transporters ATP binding cassette (Abc)a1 and Abcg1. Tretinoin, 13-cis retinoic acid (13-cis-RA), 9-cis-RA, and the selective retinoid X receptor (RXR) agonist methoprene significantly increased cholesterol efflux induced by cholesterol acceptors and protein levels of Abca1 by 2.3- (± 0.25), 3.6- (± 0.42), 4.1- (± 0.5), and 1.75- (± 0.43) fold, respectively, and Abcg1 by 2.1- (± 0.26), 2.2- (± 0.33), 2.5- (± 0.23), and 2.2- (± 0.21) fold, respectively. 13-cis-RA and 9-cis-RA also significantly increased mRNA levels of Abca1 (maximal induction 7.3 ± 0.42 and 2.7 ± 0.17, respectively) and Abcg1 (maximal induction 2.0 ± 0.18 and 1.8 ± 0.09, respectively), and the levels of membrane-bound Abca1 (2.5 ± 0.3 and 2.5 ± 0.40-fold increase, respectively), whereas they significantly decreased intracellular cholesterol content without affecting cholesterol synthesis. The effect of 9-cis-RA on cholesterol homeostasis in astrocytes can be ascribed to the activation of RXR, whereas the effects of 13-cis-RA and tretinoin were independent of either RXRs or retinoic acid receptors. These findings suggest that retinoids affect cholesterol homeostasis in astrocytes and that this effect may be involved in both their therapeutic and teratogenic actions. PMID:21628419

  19. ZebRA: An overview of retinoic acid signaling during zebrafish development.

    PubMed

    Samarut, Eric; Fraher, Daniel; Laudet, Vincent; Gibert, Yann

    2015-02-01

    Retinoic acid (RA), the main active vitamin A derivative, is crucial for embryo development, regulating cellular processes, embryo patterning and organogenesis. Many studies performed in mammalian or avian models have successfully undertaken the investigation of the role played by RA during embryogenesis. Since the early 1980s, the zebrafish (Danio rerio) has emerged as a powerful developmental model to study the in vivo role of RA during embryogenesis. Unlike mammalian models, zebrafish embryogenesis is external, not only allowing the observation of the translucent embryo from the earliest steps but also providing an easily accessible system for pharmacological treatment or genetic approaches. Therefore, zebrafish research largely participates in deciphering the role of RA during development. This review aims at illustrating different concepts of RA signaling based on the research performed on zebrafish. Indeed, RA action relies on a multitude of cross-talk with other signaling pathways and requires a coordinated, dynamic and fine-regulation of its level and activity in both temporal and spatial dimensions. This review also highlights major advances that have been discovered using zebrafish such as the observation of the RA gradient in vivo for the first time, the effects of RA signaling in brain patterning, its role in establishing left-right asymmetry and its effects on the development of a variety of organs and tissues including the heart, blood, bone and fat. This review demonstrates that the zebrafish is a convenient and powerful model to study retinoic acid signaling during vertebrate embryogenesis. This article is part of a Special Issue entitled: Nuclear receptors in animal development. PMID:24928143

  20. Additive Effects of Retinoic Acid (RA) and Bone Morphogenetic Protein 4 (BMP-4) Apoptosis Signaling in Retinoblastoma Cell Lines

    PubMed Central

    Müller, Patrick; Doliva, Rebekka; Busch, Maike; Philippeit, Claudia; Stephan, Harald; Dünker, Nicole

    2015-01-01

    Retinoids have been shown to serve promising therapeutic agents for human cancers, e.g. the treatment of neuroblastoma. Synthetic retinoids, specific for particular retinoic acid (RA) receptors, are tested as new therapy strategies. In the present study, application of recombinant retinoic acid (RA) lowers retinoblastoma (RB) cell viability and induces apoptosis in RB cell lines. Combined treatment of RA and bone morphogenetic protein 4 (BMP-4) increases the pro-apoptotic effect of RA in the RB cells lines WERI-Rb1, Y-79, RB355, RBL-30 and RBL-15, indicating an additive effect. We could show that in WERI-Rb1 cells RA/BMP-4 mediated cell death is at least partially caspase-dependent, whereby RA and BMP-4 additively increased (i) Apaf-1 mRNA levels, (ii) caspase-9 cleavage activity and (iii) the number of activated, cleaved caspase-3 positive cells. Compared to single application of RA and BMP-4, combined RA/BMP-4 treatment significantly augments mRNA levels of the retinoic acid receptors (RARs) RARα and RARß and the retinoic X receptor (RXR) RXRγ suggesting an interaction in the induction of these RA receptor subtypes in WERI-Rb1 cells. Agonist studies revealed that both, RARs and RXRs are involved in RA/BMP-4 mediated apoptosis in WERI-Rb1 retinoblastoma cells. Employing specific RAR subtype antagonists and a RXRß and RXRγ knockdown, we proved that RA/BMP-4 apoptosis signaling in WERI-Rb1 cells requires the RA receptor subtypes RARα, RARß, RXRß and RXRγ. Deciphering signaling mechanisms underlying apoptosis induction of RA and BMP-4 in WERI-Rb1 cells, our study provides useful starting-points for future retinoid-based therapy strategies in retinoblastoma. PMID:26173116

  1. Effect of 9-cis retinoic acid (RA) on progesterone and estradiol secretion and RA receptor expression in the chicken ovarian follicles.

    PubMed

    Pawłowska, Katarzyna; Sechman, Andrzej; Suchanek, Iwona; Grzegorzewska, Agnieszka; Rzasa, Janusz

    2008-01-01

    Several lines of evidence indicate that retinoids, derivates of vitamin A, affect reproductive function in birds, however, the mechanism of their action in the ovary is still unknown. Therefore, the present study was designed (i) to show whether in the domestic hen 9-cis retinoic acid (9-cis RA), one of the retinoids, influences steroid secretion in vitro by white and yellow chicken ovarian follicles, and (ii) to detect expression of retinoic acid RXR receptor mRNA in these follicles. The white follicles (small: 1-4 mm, medium: 4-6 mm and large 6-8 mm in diameter) and the three largest yellow preovulatory follicles (F3-F1; 25-37 mm) were isolated from the ovary 3 h before ovulation. The granulosa layer was separated from the theca layer in the preovulatory follicles, which were subsequently divided into 4 equal pieces. The isolated whole white follicles or parts of the granulosa or theca layers were incubated for 24 h at 38 degrees C in Eagle's medium in the following 4 groups: control, ovine LH (oLH; 10 ng/ml), 9-cis RA (100 ng/ml) and 9-cis RA + oLH. After incubation, the medium was collected for estradiol (E2) and progesterone (P4) determination while tissues were saved for protein assay. It was found that 9-cis RA affects steroid secretion from chicken ovarian follicles. It decreased E2 secretion from white follicles and from the theca layer of the two largest (F2 and F1) preovulatory follicles. 9-cis RA had no effect on oLH-stimulated E2 secretion by the white follicles and yellow F2 and F1 follicles, but it diminished E2 secretion by F3 follicles. As regards P4, the effect of 9-cis RA was opposite; it increased P4 secretion from the granulosa layer of all preovulatory follicles. 9-cis RA did not change oLH-stimulated P4 secretion by granulosa layers ofF3 and F2 follicles, however, it inhibited oLH-enhanced P4 secretion from the F1 granulosa layer. In a separate experiment, the presence of mRNA encoding RXR was found in the stroma and all follicles of the

  2. Neutrophils are immune cells preferentially targeted by retinoic acid in elderly subjects

    PubMed Central

    2010-01-01

    Background The immune system gradually deteriorates with age and nutritional status is a major factor in immunosenescence. Of the many nutritional factors implicated in age-related immune dysfunction, vitamin A may be a good candidate, since vitamin A concentrations classically decrease during aging whereas it may possess important immunomodulatory properties via its active metabolites, the retinoic acids. This prompted us to investigate the immune response induced by retinoids in adults and elderly healthy subjects. Before and after oral supplementation with 13cis retinoic acid (0.5 mg/kg/day during 28 days), whole blood cells were phenotyped, and functions of peripheral blood mononuclear cells (PBMC) and polymorphonuclear cells (PMN) were investigated by flow cytometry and ELISA tests. Results In both young adults (n = 20, 25 ± 4 years) and older subjects (n = 20, 65 ± 4 years), retinoic acid supplementation had no effect on the distribution of leukocyte subpopulations or on the functions of PBMC (Il-2 and sIl-2R production, membrane expression of CD25). Concerning PMN, retinoic acid induced an increase in both spontaneous migration and cell surface expression of CD11b in the two different age populations, whereas bactericidal activity and phagocytosis remained unchanged. Conclusions We demonstrated that retinoic acid induces the same intensity of immune response between adult and older subjects, and more specifically affects PMN functions, i.e. adhesion and migration, than PBMC functions. PMID:20727130

  3. Retinoic acid signaling and mouse embryonic stem cell differentiation: Cross talk between genomic and non-genomic effects of RA.

    PubMed

    Rochette-Egly, Cécile

    2015-01-01

    Retinoic acid (RA), the active derivative of vitamin A, a fat-soluble vitamin, plays key roles in cell growth and differentiation by activating nuclear receptors, RARs (α, β and γ), which are ligand dependent regulators of transcription. The past years highlighted several novelties in the field that increased the complexity of RA effects. Indeed, in addition to its classical genomic effects, RA also has extranuclear and non-transcriptional effects. RA induces the rapid and transient activation of kinase cascades, which are integrated in the nucleus via the phosphorylation of RARs at a conserved serine residue located in the N-terminal domain and their coregulators. In order to investigate the relevance of RARs' phosphorylation in cell differentiation, mouse embryonic stem (mES) cells were used as a model. When treated with RA, these pluripotent cells give rise to neuronal cells. Cells invalidated for each RAR were generated as well as stable rescue lines expressing RARs mutated in phosphor acceptor sites. Such a strategy revealed that RA-induced neuronal differentiation involves the RARγ2 subtype and requires RARγ2 phosphorylation. Moreover, in gene expression profiling experiments, the phosphorylated form of RARγ2 was found to regulate a small subset of genes through binding a novel RA response element consisting of two direct repeats with a 7 base pair spacer. These new findings suggest an important role for RAR phosphorylation during cell differentiation, and pave the way for further investigations with other cell types and during embryonic development. This article is part of a Special Issue entitled Linking transcription to physiology in lipodomics. PMID:24768681

  4. Sulfuric acid vapor in the atmosphere of Venus as observed by the Venus Express Radio Science experiment VeRa

    NASA Astrophysics Data System (ADS)

    Oschlisniok, Janusz; Pätzold, Martin; Häusler, Bernd; Tellmann, Silvia; Bird, Mike; Andert, Tom

    2016-04-01

    The cloud deck within Venus' atmosphere, which covers the entire planet between approx. 50 and 70 km altitude, consists mostly of liquid and gaseous sulfuric acid. The gaseous part increases strongly just below the main clouds and builds an approx. 15 km thick haze layer of H2SO4. This region is responsible for a strong absorption of radio waves as seen in VeRa radio science observations. The amount of the absorption, which is used to derive the abundance of gaseous sulfuric acid, depends on the signal frequency. VeRa probed the atmosphere of Venus between 2006 and 2015 with radio signals at 13 cm (S-band) and 3.6 cm (X-band) wavelengths. We present H2SO4 profiles derived from S-band and X-band absorption during the first occultation season in 2006. The comparison of the H2SO4 profiles derived from both frequency bands provides a reliable picture of the H2SO4 abundance. Distinct differences in the S- and X-band profiles may give a clue to increased SO2 abundances. The derived VeRa results shall be compared with results provided by other experiments onboard Venus Express as well as with previous missions.

  5. Synthesis and characterization of a new retinoic acid ECPIRM as potential chemotherapeutic agent for human cutaneous squamous carcinoma.

    PubMed

    Zhang, Mengli; Tao, Yue; Ma, Pengcheng; Wang, Dechuan; He, Chundi; Cao, Yuping; Wei, Jun; Li, Lingjun; Tao, Lei

    2015-01-01

    Cutaneous squamous cell carcinoma (CSCC) is one of the most common cancers worldwide, requiring effective therapeutic interventions. Retinoids are important chemopreventive and therapeutic agents for a variety of human cancers including CSCC. In this study we synthesized a novel retinoic derivative N-(4-ethoxycarbonylphenyl) isoretinamide (ECPIRM) and evaluated its biological activities and possible mechanisms in human cutaneous squamous cell lines. ECPIRM had better inhibitory effect on the proliferation of squamous carcinoma cells SCL-1 and colo-16, compared with All-trans retinoic acid and 13-cis retinoic acid. ECPIRM had less toxicity to normal keratinocyte cell line HaCaT. Mechanistically, ECPIRM induced G1 cell cycle arrest in SCL-1 cells, via the downregulation of CDK2, CDK4, cycling D1 and cyclin E expression and upregulation of p21. In addition, these effects were at least partially due to the inhibition of JNK/ ERK-AP-1 signaling pathway by ECPIRM. Importantly, these effects of ECPIRM are independent of the classical retinoid receptor pathway, suggesting that the novel compound will have less side-effects in chemotherapy. These findings demonstrate that ECPIRM is a potential inhibitor of MPAK-AP-1 pathway, and is a potential therapeutic agent against CSCC. PMID:25991427

  6. The Neurobiology of Retinoic Acid in Affective Disorders

    PubMed Central

    Bremner, J Douglas; McCaffery, Peter

    2009-01-01

    Current models of affective disorders implicate alterations in norepinephrine, serotonin, dopamine, and CRF/cortisol; however treatments targeted at these neurotransmitters or hormones have led to imperfect resolution of symptoms, suggesting that the neurobiology of affective disorders is incompletely understood. Until now retinoids have not been considered as possible contributors to affective disorders. Retinoids represent a family of compounds derived from Vitamin A that perform a large number of functions, many via the vitamin A product, retinoic acid. This signaling molecule binds to specific retinoic acid receptors in the brain which, like the glucocorticoid and thyroid hormone receptors, are part of the nuclear receptor superfamily and regulate gene transcription. Research in the field of retinoic acid in the CNS has focused on the developing brain, in part stimulated by the observation that isotretinoin (13-cis retinoic acid), an isomer of retinoic acid used in the treatment of acne, is highly teratogenic for the CNS. More recent work has suggested that retinoic acid may influence the adult brain; animal studies indicated that the administration of isotretinoin is associated with alterations in behavior as well as inhibition of neurogenesis in the hippocampus. Clinical evidence for an association between retinoids and depression includes case reports in the literature, studies of health care databases, and other sources. A preliminary PET study in human subjects showed that isotretinoin was associated with a decrease in orbitofrontal metabolism. Several studies have shown that the molecular components required for retinoic acid signaling are expressed in the adult brain ; the overlap of brain areas implicated in retinoic acid function and stress and depression suggest that retinoids could play a role in affective disorders. This report reviews the evidence in this area and describes several systems that may be targets of retinoic acid and which contribute

  7. 40 CFR 721.6120 - Phosphoric acid, 1,2-eth-a-ne-diyl tet-ra-kis(2-chloro-1-meth-yl-ethyl) ester.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 31 2014-07-01 2014-07-01 false Phosphoric acid, 1,2-eth-a-ne-diyl tet-ra-kis(2-chloro-1-meth-yl-ethyl) ester. 721.6120 Section 721.6120 Protection of Environment...-diyl tet-ra-kis(2-chloro-1-meth-yl-ethyl) ester. (a) Chemical substances and significant new...

  8. 40 CFR 721.6120 - Phosphoric acid, 1,2-eth-a-ne-diyl tet-ra-kis(2-chloro-1-meth-yl-ethyl) ester.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 31 2011-07-01 2011-07-01 false Phosphoric acid, 1,2-eth-a-ne-diyl tet-ra-kis(2-chloro-1-meth-yl-ethyl) ester. 721.6120 Section 721.6120 Protection of Environment...-diyl tet-ra-kis(2-chloro-1-meth-yl-ethyl) ester. (a) Chemical substances and significant new...

  9. 40 CFR 721.6120 - Phosphoric acid, 1,2-eth-a-ne-diyl tet-ra-kis(2-chloro-1-meth-yl-ethyl) ester.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Phosphoric acid, 1,2-eth-a-ne-diyl tet-ra-kis(2-chloro-1-meth-yl-ethyl) ester. 721.6120 Section 721.6120 Protection of Environment...-diyl tet-ra-kis(2-chloro-1-meth-yl-ethyl) ester. (a) Chemical substances and significant new...

  10. 40 CFR 721.6120 - Phosphoric acid, 1,2-eth-a-ne-diyl tet-ra-kis(2-chloro-1-meth-yl-ethyl) ester.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 32 2012-07-01 2012-07-01 false Phosphoric acid, 1,2-eth-a-ne-diyl tet-ra-kis(2-chloro-1-meth-yl-ethyl) ester. 721.6120 Section 721.6120 Protection of Environment...-diyl tet-ra-kis(2-chloro-1-meth-yl-ethyl) ester. (a) Chemical substances and significant new...

  11. Okadaic acid: An additional non-phorbol-12-tetradecanoate-13-acetate-type tumor promoter

    SciTech Connect

    Suganuma, Masami; Fujiki, Hirota; Suguri, Hiroko; Yoshizawa, Shigeru; Hirota, Mitsuru; Nakayasu, Michie ); Ojika, Makoto; Wakamatsu, Kazumasa; Yamada, Kiyoyuki ); Sugimura, Takashi )

    1988-03-01

    Okadaic acid is a polyether compound of a C{sub 38} fatty acid, isolated from a black sponge, Halichondria okadai. Previous studies showed that okadaic acid is a skin irritant and induces ornithine decarboxylase in mouse skin 4 hr after its application to the skin. This induction was strongly inhibited by pretreatment of the skin with 13-cis-retinoic acid. A two-stage carcinogenesis experiment in mouse skin initiated by a single application of 100 {mu}g of 7,12-dimethylbenz(a)anthracene (DMBA) and followed by application of 10 {mu}g of okadaic acid twice a week revealed that okadaic acid is a potent additional tumor promoter: tumors developed in 93% of the mice treated with DMBA and okadaic acid by week 16. In contrast, tumors were found in only one mouse each in the groups treated with DMBA alone or okadaic acid alone. An average of 2.6 tumors per mouse was found in week 30 in the group treated with DMBA and okadaic acid. Unlike phorbol 12-tetradecanoate 13-acetate (TPA), teleocidin, and aplysiatoxin, okadaic acid did not inhibit the specific binding of ({sup 3}H)TPA to a mouse skin particulate fraction when added up to 100 {mu}M or activate calcium-activated, phospholipid-dependent protein kinase (protein kinase C) in vitro when added up to 1.2 {mu}M. Therefore, the actions of okadaic acid and phorbol ester may be mediated in different ways. These results show that okadaic acid is a non-TPA-type tumor promoter in mouse skin carcinogenesis.

  12. All-trans retinoic acid (RA) stimulates events in organ-cultured human skin that underlie repair. Adult skin from sun-protected and sun-exposed sites responds in an identical manner to RA while neonatal foreskin responds differently.

    PubMed Central

    Varani, J; Perone, P; Griffiths, C E; Inman, D R; Fligiel, S E; Voorhees, J J

    1994-01-01

    Adult human skin from a sun-protected site (hip) and from a sun-exposed site (forearm) was maintained in organ culture for 12 d in the presence of a serum-free, growth factor-free basal medium. Cultures were incubated under conditions optimized for keratinocyte growth (i.e., in 0.15 mM extracellular Ca2+) or for fibroblast growth (i.e., in 1.4 mM extracellular Ca2+). Treatment with all-trans retinoic acid (RA) induced histological changes in the organ-cultured skin under both conditions which were similar to the changes seen in intact skin after topical application. These included expansion of the viable portion of the epidermis and activation of cells in the dermis. In sun-damaged skin samples, which were characterized by destruction of normal connective tissue elements and presence of thick, dark-staining elastotic fibers, a zone of healthy connective tissue could be seen immediately below the dermo-epidermal junction. This zone was more prominent in RA-treated organ cultures than in matched controls. Associated with these histological changes was an increase in overall protein and extracellular matrix synthesis. In concomitant studies, it was found that RA treatment enhanced survival and proliferation of adult keratinocytes and adult dermal fibroblasts under both low- and high-Ca2+ conditions. In all of these assays, responses of sun-protected and sun-exposed skin were identical. In contrast, responses of neonatal foreskin to RA were similar to those of adult skin in the presence of low-Ca2+ culture medium, but under conditions of high extracellular Ca2+ RA provided little or no additional stimulus. Together these studies suggest that the ability of RA to enhance repair of sun-damaged skin (documented in previous studies) may reflect its ability to influence the behavior of skin in a manner that is age dependent but independent of sun-exposure status. Images PMID:7962521

  13. The all-trans retinoic acid (atRA)-regulated gene Calmin (Clmn) regulates cell cycle exit and neurite outgrowth in murine neuroblastoma (Neuro2a) cells

    SciTech Connect

    Marzinke, Mark A.; Clagett-Dame, Margaret

    2012-01-01

    The vitamin A metabolite all-trans retinoic acid (atRA) functions in nervous system development and regulates cell proliferation and differentiation. Neuroblastoma cells (SH-SY5Y and Neuro2a or N2A) exposed to atRA undergo growth inhibition and neuronal differentiation, both of which are preceded by an increase in Clmn mRNA. Treatment of N2A cells with atRA produces a reduction in phosphohistone 3 immunostaining and BrdU incorporation, both indicators of a reduction in cell proliferation. These effects are nearly eliminated in atRA-treated shClmn knockdown cells. Loss of Clmn in the mouse N2A cell line also results in a significant reduction of atRA-mediated neurite outgrowth, a response that can be rescued by reintroduction of the Clmn sequence. In contrast, ectopic overexpression of Clmn produces an increase in the cyclin dependent kinase inhibitor, p21{sup Cip1}, a decrease in cyclin D1 protein and an increase in hypophosphorylated Rb, showing that Clmn participates in G{sub 1}/S arrest. Clmn overexpression alone is sufficient to inhibit N2A cell proliferation, whereas both Clmn and atRA must be present to induce neurite outgrowth. This study shows that the atRA-responsive gene Clmn promotes exit from the cell cycle, a requisite event for neuronal differentiation. -- Highlights: Black-Right-Pointing-Pointer Calmin is a retinoic acid-responsive gene. Black-Right-Pointing-Pointer Calmin promotes cell cycle exit in N2A cells. Black-Right-Pointing-Pointer Calmin overexpression increases p21Cip1 and decreases cyclin D1. Black-Right-Pointing-Pointer Calmin is required for RA-induced growth inhibition and neurite outgrowth.

  14. MicroRNA Mediates DNA De-methylation Events Triggered By Retinoic Acid During Neuroblastoma Cell Differentiation

    PubMed Central

    Das, Sudipto; Foley, Niamh; Bryan, Kenneth; Watters, Karen M; Bray, Isabella; Murphy, Derek M; Buckley, Patrick G; Stallings, Raymond L

    2010-01-01

    Neuroblastoma is an often fatal pediatric cancer arising from precursor cells of the sympathetic nervous system. 13-Cis retinoic acid is included in the treatment regime for patients with high-risk disease, and a similar derivative, all-trans retinoic acid (ATRA) causes neuroblastoma cell lines to undergo differentiation. The molecular signaling pathways involved with ATRA induced differentiation are complex, and the role that DNA methylation changes might play are unknown. The purpose of this study was to evaluate the genome-wide effects of ATRA on DNA methylation using methylated DNA immunoprecipitation applied to microarrays representing all known promoter and CpG islands. 402 gene promoters became demethylated, while 88 were hypermethylated post-ATRA. mRNA expression microarrays revealed that 82 of the demethylated genes were over-expressed by >2 fold, while 13 of the hyper methylated genes were under-expressed. Gene ontology analysis indicated that de-methylated and re-expressed genes were enriched for signal transduction pathways, including NOS1, which is required for neural cell differentiation. As a potential mechanism for the DNA methylation changes, we demonstrate the down-regulation of methyltransferases, DNMT1 and DNMT3B, along with the up-regulation of endogenous microRNAs targeting them. Ectopic over-expression of miR-152, targeting DNMT1, also negatively impacted cell invasiveness and anchorage independent growth, contributing in part to the differentiated phenotype. We conclude that functionally important, miRNA-mediated DNA de-methylation changes contribute to the process of ATRA induced differentiation resulting in the activation of NOS1, a critical determinant of neural cell differentiation. Our findings illustrate the plasticity and dynamic nature of the epigenome during cancer cell differentiation. PMID:20841484

  15. Plasma retinoids concentration in Leptodactylus chaquensis (Amphibia: Leptodactylidae) from rice agroecosystems, Santa Fe province, Argentina.

    PubMed

    Teglia, Carla M; Attademo, Andrés M; Peltzer, Paola M; Goicoechea, Héctor C; Lajmanovich, Rafael C

    2015-09-01

    Retinoids are known to regulate important processes such as differentiation, development, and embryogenesis of vertebrates: Alteration in endogenous retinoids concentration is linked with teratogenic effects. Retinol (ROH), retinoid acid (RA), and isoform 13-Cis-retinoic acid (13-Cis-RA), in plasma of a native adults frog, Leptodactylus chaquensis from a rice field (RF) and a forest (reference site; RS) were measured. ROH did not vary between treatment sites. RA and 13-Cis-RA activities were higher (93.7±8.6 μg mL(-1) and 131.7±11.4 μg mL(-1), respectively) in individuals collected from RF than in those from RS (65.5±8.6 μg mL(-1) and 92.2±10.2 μg mL(-1), respectively). The ratios retinoic acid-retinol (RA/ROH) and 13-Cis-RA/ROH revealed significantly higher values in RF than in RS. RA and 13-Cis-RA concentrations in plasma on wild amphibian's species such as L. chaquensis would be suitable biomarkers of pesticide exposure in field monitoring. Finally, the mechanism of alteration in retinoid metabolites alteration should be further explored both in larvae and adult, considering that the potential exposition and uptake contaminants vary between the double lives of these vertebrates. PMID:25880706

  16. Fasting Induces IL-1 Resistance and Free-Fatty Acid-Mediated Up-Regulation of IL-1R2 and IL-1RA

    PubMed Central

    Joesting, Jennifer J.; Moon, Morgan L.; Gainey, Stephen J.; Tisza, Brittany L.; Blevins, Neil A.; Freund, Gregory G.

    2014-01-01

    Objective: Weight-loss is a near societal obsession and many diet programs use significant calorie restriction including fasting/short term starvation to generate rapid effects. Fasting is also a well-recognized cause of immunosuppression especially within the innate immune system. In this study, we sought to determine if the IL-1 arm of the neuroimmune system was down-regulated by a 24 h fast and how fasting might generate this effect. Design: Mice were allowed ad libitum access to food or had food withheld for 24 h. Expression of the endogenous IL-1 antagonists, IL-1 receptor type 2 (IL-1R2), and IL-1 receptor antagonist (IL-1RA) was determined as were sickness behaviors before and after IL-1β administration. Results: Fasting markedly increased gene expression of IL-1R2 (83-fold in adipose tissue, 9.5-fold in liver) and IL-1RA (68-fold in liver). Fasted mice were protected from IL-1β-induced weight-loss, hypoglycemia, loss of locomotor, and social anxiety. These protections were coupled to a large positive interaction of fasting and IL-1β on IL-1R2 gene expression in adipose tissue and liver (2.6- and 1.6-fold, respectively). Fasting not only increased IL-1RA and IL-1R2 protein 2.5- and 3.2-fold, respectively, in liver but also increased IL-1R2 1.8-fold in adipose tissue. Fasting, in turn, triggered a 2.4-fold increase in plasma free-fatty acids (FFAs) and a 2.1-fold increase in plasma corticosterone. Inhibition, of glucocorticoid action with mifepristone did not impact fasting-dependent IL-1R2 or IL-1RA gene expression. Administration of the FFA, palmitate, to mice increased liver IL-1R2 and IL-1RA gene expression by 14- and 11-fold, respectively. Conclusion: These findings indicate that fasting augments expression of endogenous IL-1 antagonists inducing IL-1 resistance. Fasting-induced increases in plasma FFAs appears to be a signal that drives immunosuppression during fasting/short term starvation. PMID:25071776

  17. Synergistic activation of retinoic acid (RA)-responsive genes and induction of embryonal carcinoma cell differentiation by an RA receptor {alpha} (RAR{alpha})-, RAR{beta}-, or RAR{gamma}-selective ligand in combination with retinoid Z receptor-specific ligand

    SciTech Connect

    Roy, B.; Taneja, R.; Chambon, P.

    1995-12-01

    This research indicates thatn retinoic acid receptor (RAR)-retinoid X receptor (RXR) heterodimers activate transcription of RA-responsive genes and induce cell differentiation of P19 and F9 cells in a ligand-dependent manner. 43 refs., 4 figs., 2 tabs.

  18. Biological activity of all-trans retinol requires metabolic conversion to all-trans retinoic acid and is mediated through activation of nuclear retinoid receptors in human keratinocytes.

    PubMed

    Kurlandsky, S B; Xiao, J H; Duell, E A; Voorhees, J J; Fisher, G J

    1994-12-30

    The biological activity of all-trans retinol, in human keratinocytes, was investigated through metabolic and functional analyses that assessed the capacity for retinol uptake and metabolism and the mechanism of retinol-induced activation of gene transcription. Human keratinocytes converted all-trans retinol predominantly to retinyl esters, which accounted for 60 and 90% of cell-associated radiolabel after a 90-min pulse and a 48-h chase, respectively. Human keratinocytes also metabolized all-trans retinol to low levels of all-trans retinoic acid (11.47-131.3 ng/mg of protein) in a dose-dependent manner, between 0.3 and 10 microM added retinol. Small amounts of 13-cis retinoic acid (5.47-8.62 ng/mg of protein) were detected, but 9-cis retinoic acid was detected only when keratinocytes were incubated with radiolabeled retinol. There was no accumulation of the oxidized catabolic metabolites 4-hydroxy- or 4-oxoretinoic acid; however, 5,6-epoxy retinoic acid was detected at pharmacological levels (10 and 30 microM) of added retinol. Biological activity of retinol was assessed through analysis of two known retinoic acid-mediated responses: 1) reduction of type I epidermal transglutaminase and 2) activation of a retinoic acid receptor-dependent reporter gene, beta RARE3-tk-CAT. Both all-trans retinol and all-trans retinoic acid reduced type I epidermal transglutaminase in a dose-dependent manner; however, the ED50 for all-trans retinol (10 nM) was 10 times greater than for all-trans retinoic acid (1 nM). All-trans retinol also stimulated beta RARE3-tk-CAT reporter gene activity in a dose-dependent manner. Half-maximal induction was observed at 30 nM retinol, which was again 10-fold greater than observed with all-trans retinoic acid. Cotransfection of human keratinocytes with expression vectors for dominant negative mutant retinoic acid and retinoid X receptors reduced retinol-induced beta RARE3-tk-CAT reporter gene activation by 80%. Inhibition of conversion of all

  19. Phosphoproteome and Transcriptome of RA-Responsive and RA-Resistant Breast Cancer Cell Lines

    PubMed Central

    Carrier, Marilyn; Joint, Mathilde; Lutzing, Régis; Page, Adeline; Rochette-Egly, Cécile

    2016-01-01

    Retinoic acid (RA), the main active vitamin A metabolite, controls multiple biological processes such as cell proliferation and differentiation through genomic programs and kinase cascades activation. Due to these properties, RA has proven anti-cancer capacity. Several breast cancer cells respond to the antiproliferative effects of RA, while others are RA-resistant. However, the overall signaling and transcriptional pathways that are altered in such cells have not been elucidated. Here, in a large-scale analysis of the phosphoproteins and in a genome-wide analysis of the RA-regulated genes, we compared two human breast cancer cell lines, a RA-responsive one, the MCF7 cell line, and a RA-resistant one, the BT474 cell line, which depicts several alterations of the “kinome”. Using high-resolution nano-LC-LTQ-Orbitrap mass spectrometry associated to phosphopeptide enrichment, we found that several proteins involved in signaling and in transcription, are differentially phosphorylated before and after RA addition. The paradigm of these proteins is the RA receptor α (RARα), which was phosphorylated in MCF7 cells but not in BT474 cells after RA addition. The panel of the RA-regulated genes was also different. Overall our results indicate that RA resistance might correlate with the deregulation of the phosphoproteome with consequences on gene expression. PMID:27362937

  20. Preparation of (228)Ra standard solution.

    PubMed

    Havelka, Miroslav

    2016-03-01

    For the preparation of a standard solution of (228)Ra, (228)Ra was isolated from (232)Th salt. Two simple methods were developed for Th-Ra separation. Both are based on a very good solubility of thorium nitrate in organic solvents. The first one used Ra co-precipitation with Pb in the form of Pb(NO3)2 from acetic acid solution. The second method was based on solvent extraction, remaining Th in the organic phase, while Ra was concentrated in the aqueous phase. The activity of (228)Ra (up to 20kBq) in the standard solution was related to the (232)Th standard by means of gamma ray spectrometry measurement. The obtained uncertainty was less than 0.7% (k=1). The standard solution was free of (232)Th and contained the carrier in the usual concentration (1gL(-1) BaCl2, 10gL(-1) HCl). PMID:26651171

  1. Distribution of sulphuric acid aerosols in the clouds and upper haze of Venus using Venus Express VAST and VeRa temperature profiles

    NASA Astrophysics Data System (ADS)

    Parkinson, Christopher D.; Gao, Peter; Schulte, Rick; Bougher, Stephen W.; Yung, Yuk L.; Bardeen, Charles G.; Wilquet, Valérie; Vandaele, Ann Carine; Mahieux, Arnaud; Tellmann, Silvia; Pätzold, Martin

    2015-08-01

    Observations from Pioneer Venus and from SPICAV/SOIR aboard Venus Express (VEx) have shown the upper haze (UH) of Venus to be highly spatially and temporally variable, and populated by multiple particle size modes. Previous models of this system (e.g., Gao et al., 2014. Icarus 231, 83-98), using a typical temperature profile representative of the atmosphere (viz., equatorial VIRA profile), did not investigate the effect of temperature on the UH particle distributions. We show that the inclusion of latitude-dependent temperature profiles for both the morning and evening terminators of Venus helps to explain how the atmospheric aerosol distributions vary spatially. In this work we use temperature profiles obtained by two instruments onboard VEx, VeRa and SPICAV/SOIR, to represent the latitudinal temperature dependence. We find that there are no significant differences between results for the morning and evening terminators at any latitude and that the cloud base moves downwards as the latitude increases due to decreasing temperatures. The UH is not affected much by varying the temperature profiles; however, the haze does show some periodic differences, and is slightly thicker at the poles than at the equator. We also find that the sulphuric acid "rain" seen in previous models may be restricted to the equatorial regions of Venus, such that the particle size distribution is relatively stable at higher latitudes and at the poles.

  2. "Redefining RA": The RA Tool Kit

    ERIC Educational Resources Information Center

    Wyatt, Neal

    2008-01-01

    No one likes being two steps behind, and the fastest way to fall off the pace is by not keeping up with major titles and hot authors. Fortunately, there are numerous resources, both prepublication and postpublication, that can help. It is best when readers' advisory (RA) librarians know what is coming out months ahead of time--in order to think…

  3. Martin RA-30 Baltimore

    NASA Technical Reports Server (NTRS)

    1943-01-01

    Martin RA-30 Baltimore: The Martin RA-30 Baltimore was a light bomber ordered by the Royal Air Force. Some examples were retained in the United States as part of a 'Reverse Lend-Lease.' This example was flown by the NACA from June 1943 until March 1944.

  4. 228Ra and 226Ra Profiles from the Northern South China Sea

    NASA Astrophysics Data System (ADS)

    Lin, H.; Chung, Y.; Lin, C.

    2005-05-01

    We previously reported the distributions of 228Ra and 226Ra in the northern South China Sea (SCS) which showed that both nuclides in surface waters were much higher than those in the open oceans because the SCS was enclosed mostly by landmasses which are known as sources of these nuclides. Large temporal and spectial variations were also observed probably due to the monsoons and intrusion of the Kuroshio Current. During a recent cruise conducted in the northern SCS in February, 2004, three vertical 228Ra profiles were measured by gamma spectrometry on the Ra isotopes which were concentrated first by the MnO2-impregnated acrylic fiber and then acid-washed as sample solution for counting. The two deep water 228Ra profiles are remarkably similar, showing high values in the surface layer and fairly uniform at about 10 to 13 dpm/100L below 200m depth but with a clear increase toward the bottom due to input from the underlying sediments. The shallow water profile on the shelf shows higher 228Ra values due to both vertical and horizontal mixing of the shelf water with additional source from the shore zone. Additional 228Ra profiles measured on samples from earlier cruises show that the deep water values may differ significantly (up to 5 dpm/100L) at the same location in different seasons or cruises. The associated 226Ra profiles are also variable but quite comparable to those in the northwest Pacific in deep water. 226Ra activities in the shallow water (less than 1000m depth) are higher in the SCS than in the open oceans. The 228Ra/226Ra activity ratios vary mostly from about 0.3 to 0.5 in the deep water. These values are much higher than those in the open oceans which are generally less than 0.1.

  5. Measuring the radium quartet (228Ra, 226Ra, 224Ra, 223Ra) in seawater samples using gamma spectrometry.

    PubMed

    van Beek, P; Souhaut, M; Reyss, J-L

    2010-07-01

    Radium isotopes are widely used in marine studies (eg. to trace water masses, to quantify mixing processes or to study submarine groundwater discharge). While 228Ra and 226Ra are usually measured using gamma spectrometry, short-lived Ra isotopes (224Ra and 223Ra) are usually measured using a Radium Delayed Coincidence Counter (RaDeCC). Here we show that the four radium isotopes can be analyzed using gamma spectrometry. We report 226Ra, 228Ra, 224Ra, 223Ra activities measured using low-background gamma spectrometry in standard samples, in water samples collected in the vicinity of our laboratory (La Palme and Vaccarès lagoons, France) but also in seawater samples collected in the plume of the Amazon river, off French Guyana (AMANDES project). The 223Ra and 224Ra activities determined in these samples using gamma spectrometry were compared to the activities determined using RaDeCC. Activities determined using the two techniques are in good agreement. Uncertainties associated with the 224Ra activities are similar for the two techniques. RaDeCC is more sensitive for the detection of low 223Ra activities. Gamma spectrometry thus constitutes an alternate method for the determination of short-lived Ra isotopes. PMID:20106569

  6. 40 CFR 721.6120 - Phosphoric acid, 1,2-eth-a-ne-diyl tet-ra-kis(2-chloro-1-meth-yl-ethyl) ester.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Phosphoric acid, 1,2-eth-a-ne-diyl tet... SUBSTANCES Significant New Uses for Specific Chemical Substances § 721.6120 Phosphoric acid, 1,2-eth-a-ne... subject to reporting. (1) The chemical substance identified as phosphoric acid, 1,2-ethanediyl...

  7. Rapid Method for Ra-226 and Ra-228 in Water Samples

    SciTech Connect

    Maxwell, Sherrod, L. III

    2006-02-10

    The measurement of radium isotopes in natural waters is important for oceanographic studies and for public health reasons. Ra-226 (1620 year half-life) is one of the most toxic of the long-lived alpha emitters present in the environment due to its long life and its tendency to concentrate in bones, which increases the internal radiation dose of individuals. The analysis of radium-226 and radium-228 in natural waters can be tedious and time-consuming. Different sample preparation methods are often required to prepare Ra-226 and Ra-228 for separate analyses. A rapid method has been developed at the Savannah River Environmental Laboratory that effectively separates both Ra-226 and Ra-228 (via Ac-228) for assay. This method uses MnO{sub 2} Resin from Eichrom Technologies (Darien, IL, USA) to preconcentrate Ra-226 and Ra-228 rapidly from water samples, along with Ba-133 tracer. DGA Resin{reg_sign} (Eichrom) and Ln-Resin{reg_sign} (Eichrom) are employed in tandem to prepare Ra-226 for assay by alpha spectrometry and to determine Ra-228 via the measurement of Ac-228 by gas proportional counting. After preconcentration, the manganese dioxide is dissolved from the resin and passed through stacked Ln-Resin-DGA Resin cartridges that remove uranium and thorium interferences and retain Ac-228 on DGA Resin. The eluate that passed through this column is evaporated, redissolved in a lower acidity and passed through Ln-Resin again to further remove interferences before performing a barium sulfate microprecipitation. The Ac-228 is stripped from the resin, collected using cerium fluoride microprecipitation and counted by gas proportional counting. By using vacuum box cartridge technology with rapid flow rates, sample preparation time is minimized.

  8. Effects of topical retinoids on cytoskeletal proteins: implications for retinoid effects on epidermal differentiation.

    PubMed

    Eichner, R; Kahn, M; Capetola, R J; Gendimenico, G J; Mezick, J A

    1992-02-01

    In vivo effects of retinoids on epidermal differentiation were investigated by analyzing cytoskeletal proteins in rhino mice treated topically with all-trans-retinoic acid (RA) and other retinoids (13-cis-retinoic acid, etretinate, TTNPB). Non-disulfide-linked cytoskeletal proteins, including keratins from the epidermal "living layers," were first selectively extracted using 9.5 M urea; subsequently, keratins of the stratum corneum were isolated using 9.5 M urea plus a reducing agent. Gel electrophoresis and immunoblot analysis showed that urea extracts of epidermis from vehicle-treated skin were composed predominantly of four major keratins (analogous to human epidermal keratins K1, K5, K10, and K14), and the keratin filament-associated protein filaggrin. In contrast, extracts of epidermis from retinoid-treated skin contained additional keratins (K6, K16, and K17) and almost no detectable filaggrin. Furthermore, similar analysis of stratum corneum keratins demonstrated that extracts from RA-treated skin did not contain the partially proteolyzed keratins typically observed in stratum corneum extracts of control animals. Hyperplasia-inducing agents (salicylic acid, croton oil) caused an increase in keratins K6, K16, and K17, but they did not effect filaggrin or alter proteolysis of stratum corneum keratins. The result that RA induced expression of keratins K6, K16, and K17, as commonly expressed in hyperproliferative epidermis, is consistent with the notion that retinoids increase epidermal cell proliferation in the basal and/or lower spinous layers. The findings that topical RA decreased filaggrin expression and reduced proteolysis of stratum corneum keratins, despite increased size and number of granular cells and the presence of an anucleate stratum corneum, suggest that topical RA may also modulate a later stage of epidermal differentiation involved in stratum corneum formation. PMID:1370674

  9. Leaching of 226Ra from components of uranium mill tailings

    USGS Publications Warehouse

    Landa, E.R.

    1991-01-01

    A sequential extraction procedure was used to characterize the geochemical forms of 226Ra retained by mixtures of quartz sand and a variety of fine-grained rock and mineral species. These mixtures had previously been exposed to the sulfuric acid milling liquor of a simulated acid-leach uranium milling circuit. For most test cases, the major fraction of the 226Ra was extracted with 1 mol/1 NH4Cl and was deemed to be exchangeable. However, 226Ra retained by the barite-containing mixture was resistant to both 1 mol/1 NH4Cl and 1 mol/HCHCl extraction. ?? 1991.

  10. Retinoid- and sodium-butyrate-induced decrease in heat shock protein 70 membrane-positive tumor cells is associated with reduced sensitivity to natural killer cell lysis, growth delay, and altered growth morphology.

    PubMed

    Gehrmann, Mathias; Schönberger, Johann; Zilch, Tanja; Rossbacher, Lydia; Thonigs, Gerald; Eilles, Christoph; Multhoff, Gabriele

    2005-01-01

    Human tumors frequently present heat shock protein 70 (Hsp70) on their cell membranes, whereas corresponding normal tissues fail to do so. Therefore, an Hsp70 membrane-positive phenotype provided a tumor-specific marker. Moreover, membrane-bound Hsp70 provides a target structure for the cytolytic attack mediated by natural killer (NK) cells. Vitamin A derivatives 13-cis retinoic acid (13-RA) and all-trans retinoic acid (ATRA) and sodium-butyrate (SBU) are known for their redifferentiating capacity. Therefore, we asked the question whether loss in tumorigenicity might be associated with a reduced Hsp70 membrane expression. For our studies we used epithelial colon (CX+/CX-) and thyroid (ML-1) cancer cells, with initially different Hsp70 cell surface expression pattern. After treatment up to 7 weeks with freshly prepared 13-RA, ATRA, and SBU at nonlethal concentrations of 10 microM, 1 microM, and 0.5 mM, respectively, growth morphology, Hsp70 levels, and sensitivity toward Hsp70-specific NK cells were compared with that of untreated tumor cells. Significant growth delay was determined in CX+ tumor cells after 6 weeks treatment with 13-RA. Concomitantly, growth morphology changed from spheroid cell clusters to monolayers. Despite a weak increase in cytosolic Hsp70, the percentage of Hsp70 membrane-positive cells dropped significantly after repeated treatments with 13-RA and ATRA in CX+ and ML-1 but not in CX- tumor cells. Similar results were observed with SBU. Functionally, the decrease in Hsp70 membrane-positive CX+ and ML-1 cells correlated with a reduced sensitivity to lysis mediated by NK cells. In summary, redifferentiating agents predominantly affected Hsp70 membrane-positive tumors. The decrease in Hsp70 membrane positivity correlated with a lower sensitivity to NK lysis, growth delay, and altered growth morphology. PMID:16038410

  11. Retinoid- and sodium-butyrate– induced decrease in heat shock protein 70 membrane-positive tumor cells is associated with reduced sensitivity to natural killer cell lysis, growth delay, and altered growth morphology

    PubMed Central

    Gehrmann, Mathias; Schönberger, Johann; Zilch, Tanja; Rossbacher, Lydia; Thonigs, Gerald; Eilles, Christoph; Multhoff, Gabriele

    2005-01-01

    Human tumors frequently present heat shock protein 70 (Hsp70) on their cell membranes, whereas corresponding normal tissues fail to do so. Therefore, an Hsp70 membrane-positive phenotype provided a tumor-specific marker. Moreover, membrane-bound Hsp70 provides a target structure for the cytolytic attack mediated by natural killer (NK) cells. Vitamin A derivatives 13-cis retinoic acid (13-RA) and all-trans retinoic acid (ATRA) and sodium-butyrate (SBU) are known for their redifferentiating capacity. Therefore, we asked the question whether loss in tumorigenicity might be associated with a reduced Hsp70 membrane expression. For our studies we used epithelial colon (CX+/CX−) and thyroid (ML-1) cancer cells, with initially different Hsp70 cell surface expression pattern. After treatment up to 7 weeks with freshly prepared 13-RA, ATRA, and SBU at nonlethal concentrations of 10 μM, 1 μM, and 0.5 mM, respectively, growth morphology, Hsp70 levels, and sensitivity toward Hsp70-specific NK cells were compared with that of untreated tumor cells. Significant growth delay was determined in CX+ tumor cells after 6 weeks treatment with 13-RA. Concomitantly, growth morphology changed from spheroid cell clusters to monolayers. Despite a weak increase in cytosolic Hsp70, the percentage of Hsp70 membrane-positive cells dropped significantly after repeated treatments with 13-RA and ATRA in CX+ and ML-1 but not in CX− tumor cells. Similar results were observed with SBU. Functionally, the decrease in Hsp70 membrane-positive CX+ and ML-1 cells correlated with a reduced sensitivity to lysis mediated by NK cells. In summary, redifferentiating agents predominantly affected Hsp70 membrane-positive tumors. The decrease in Hsp70 membrane positivity correlated with a lower sensitivity to NK lysis, growth delay, and altered growth morphology. PMID:16038410

  12. Inhibition of proliferation and induction of apoptosis in soft tissue sarcoma cells by interferon-α and retinoids

    PubMed Central

    Brodowicz, T; Wiltschke, C; Kandioler-Eckersberger, D; Grunt, T W; Rudas, M; Schneider, S M; Hejna, M; Budinsky, A; Zielinski, C C

    1999-01-01

    Uncontrolled proliferation and a defect of apoptosis constitute crucial elements in the development and progression of tumours. Among many other biological response modifiers known to influence these mechanisms, the efficacy of retinoids and interferons in the treatment of various malignant entities is currently matter of discussion. In the present study, we have investigated the effects of 9-cis-retinoic acid (9cRA), 13-cis-retinoic acid (13cRA), all-trans-retinoic acid (tRA) and interferon-α on proliferation and apoptosis of human soft tissue sarcoma (STS) cell lines HTB-82 (rhabdomyosarcoma), HTB-91 (fibrosarcoma), HTB-92 (liposarcoma), HTB-93 (synovial sarcoma) and HTB-94 (chondrosarcoma) in relation to p53 genotype as well as p53 expression. HTB-91, HTB-92 and HTB-94 STS cells exhibited mutant p53, whereas wild-type p53 was found in HTB-93 STS cells, and a normal p53 status in HTB-82 STS cells, carrying a silent point mutation only. Interferon-α, irrespective of p53 status, inhibited the proliferation of all five cell lines dose- and time-dependently. Similarly, 9cRA, 13cRA and tRA decreased the proliferation of HTB-82 and HTB-93 STS cells, whereas the proliferation of p53-mutated HTB-91, HTB-92 and HTB-94 STS cells remained unchanged. Furthermore, only 9cRA and tRA were capable of inducing apoptosis in HTB-82 and HTB-93 STS cells, whereas HTB-91, HTB-92 and HTB-94 STS cells did not undergo apoptosis under the influence of 9cRA or tRA. Retinoic acid receptor (RAR)-α and RAR-β mRNA were not detectable by Northern blot analysis in the five STS cell lines, whereas mRNA for the universal retinoic acid receptor, RAR-γ, was expressed in all STS cell lines indicating that retinoid resistance was not associated with a lack of RAR expression. Apoptosis was not induced by interferon-α or 13cRA in any of the five STS cell lines tested. Our results indicate that within the panel of tested STS cell lines, inhibition of proliferation and induction of apoptosis result

  13. Z-scan measurements of the nonlinear refraction in retinal derivatives

    NASA Astrophysics Data System (ADS)

    Bezerra, Arandi G.; Gomes, A. S. L.; de Melo, Celso P.; de Araújo, Cid B.

    1997-09-01

    The nonlinear refractive index, n2, of 13-cis retinal aldehyde, 13-cis retinoic acid and all-trans retinoic acid were determined. For 13-cis retinal aldehyde solutions which were left to age for a few days, an increase of over one order of magnitude for n2 was observed. With basis on the comparison of infrared spectra of freshly prepared and aged solutions, we suggest that the enhancement of the nonlinear response is associated to a spontaneous cis to trans isomerization of the retinal molecule. The second order hyperpolarizabities of all the retinal derivatives were also inferred from the measurements.

  14. Radium content and the 226Ra /228Ra activity ratio in groundwater from bedrock

    NASA Astrophysics Data System (ADS)

    Asikainen, Matti

    1981-08-01

    The relative abundance of 226Ra and 228Ra were determined in the groundwater from 125 drilled wells containing from < 0.1 to 51.3 pCi/l of 226Ra. The determination of 228Ra was carried out with a liquid scintillation counter by measuring only the weakly energetic β particles emitted from 228Ra. Thus the interference from the daughter nuclides of 226Ra was avoided, without specific separation of 228Ac. The direct measurement of 228Ra made the method decisively simpler and faster in terms of the chemistry involved. The concentration of 228Ra was found to be independent of the amount of 226Ra present in the samples. The concentrations of 228Ra were nearly the same over the whole range of 226Ra concentrations and the average sol 226Ra /228Ra ratio sharply increased as the 226Ra content of water increased. The 226Ra /228Ra ratio in the drilled wells varied from 0.3 to 26. Abnormally high 226Ra /228Ra ratios were found in areas with known uranium deposits as well as in several drilled wells at other locations. The abnormally high 226Ra /228Ra ratios present in groundwater suggest that the radioactivity anomaly is caused by uranium deposits and not by common rocks. In samples with a low radioactivity level the average 226Ra /228Ra ratio was slightly below unity, corresponding to the typical U/ Th ratio of granite, the most common kind of rock in the study area. The samples from the rapakivi area proved to be exceptional in that they had a low 226Ra /228Ra ratio independent of the concentration of 226Ra.

  15. Pneumocystis carinii pneumonia: a late presentation following treatment for stage IV neuroblastoma.

    PubMed

    Clarke, Edward; Glaser, Adam W; Picton, Susan V

    2003-09-01

    This report describes a child who develops Pneumocystis carinii pneumonia 7 months after high-dose chemotherapy for stage IV neuroblastoma. In addition to chemotherapy the child had also been treated with abdominal radiotherapy and 13-cis-retinoic acid. Standard practice has been to treat patients with prophylactic co-trimoxazole for 3 months after high-dose therapy, but this report highlights the intensity and complexity of current treatment for stage IV neuroblastoma and the need to be aware of prolonged lymphopenia after such treatment. PMID:14631621

  16. Revealed: The spy who regulates neuroblastoma stem cells.

    PubMed

    Vora, Parvez; Venugopal, Chitra; Singh, Sheila K

    2014-11-30

    Neuroblastoma (NB), an embryonal tumour of the sympathetic nervous system, is thought to originate from undifferentiated neural crest cells and is known to exhibit extremely heterogeneous biological and clinical behaviors. Occurring in very young children, the median age at diagnosis is 17 months and it accounts for 10% of all pediatric cancer mortalities. The standard treatment regimen for patients with high-risk NB includes induction and surgery followed by isotretinoin or Accutane (13-cis retinoic acid) treatment, which is shown to induce terminal differentiation of NB cells. However, molecular regulators that maintain an undifferentiated phenotype in NB cells are still poorly understood. PMID:25483101

  17. Thymosin-β4 is a determinant of drug sensitivity for Fenretinide and Vorinostat combination therapy in neuroblastoma.

    PubMed

    Cheung, Belamy B; Tan, Owen; Koach, Jessica; Liu, Bing; Shum, Michael S Y; Carter, Daniel R; Sutton, Selina; Po'uha, Sela T; Chesler, Louis; Haber, Michelle; Norris, Murray D; Kavallaris, Maria; Liu, Tao; O'Neill, Geraldine M; Marshall, Glenn M

    2015-08-01

    Retinoids are an important component of neuroblastoma therapy at the stage of minimal residual disease, yet 40-50% of patients treated with 13-cis-retinoic acid (13-cis-RA) still relapse, indicating the need for more effective retinoid therapy. Vorinostat, or Suberoylanilide hydroxamic acid (SAHA), is a potent inhibitor of histone deacetylase (HDAC) classes I & II and has antitumor activity in vitro and in vivo. Fenretinide (4-HPR) is a synthetic retinoid which acts on cancer cells through both nuclear retinoid receptor and non-receptor mechanisms. In this study, we found that the combination of 4-HPR + SAHA exhibited potent cytotoxic effects on neuroblastoma cells, much more effective than 13-cis-RA + SAHA. The 4-HPR + SAHA combination induced caspase-dependent apoptosis through activation of caspase 3, reduced colony formation and cell migration in vitro, and tumorigenicity in vivo. The 4-HPR and SAHA combination significantly increased mRNA expression of thymosin-beta-4 (Tβ4) and decreased mRNA expression of retinoic acid receptor α (RARα). Importantly, the up-regulation of Tβ4 and down-regulation of RARα were both necessary for the 4-HPR + SAHA cytotoxic effect on neuroblastoma cells. Moreover, Tβ4 knockdown in neuroblastoma cells increased cell migration and blocked the effect of 4-HPR + SAHA on cell migration and focal adhesion formation. In primary human neuroblastoma tumor tissues, low expression of Tβ4 was associated with metastatic disease and predicted poor patient prognosis. Our findings demonstrate that Tβ4 is a novel therapeutic target in neuroblastoma, and that 4-HPR + SAHA is a potential therapy for the disease. PMID:25963741

  18. Compilation of Spectroscopic Data of Radium (Ra I and Ra II)

    NASA Astrophysics Data System (ADS)

    Dammalapati, U.; Jungmann, K.; Willmann, L.

    2016-03-01

    Energy levels, wavelengths, lifetimes, and hyperfine structure constants for the isotopes of the first and second spectra of radium, Ra I and Ra II, have been compiled. Wavelengths and wavenumbers are tabulated for 226Ra and for other Ra isotopes. Isotope shifts and hyperfine structure constants of even and odd-A isotopes of neutral radium atom and singly ionized radium are included. Experimental lifetimes of the states for both neutral and ionic Ra are also added, where available. The information is beneficial for present and future experiments aimed at different physics motivations using neutral Ra and singly ionized Ra.

  19. Non-destructive determination of 224Ra, 226Ra and 228Ra concentrations in drinking water by gamma spectroscopy.

    PubMed

    Parekh, Pravin; Haines, Douglas; Bari, Abdul; Torres, Miguel

    2003-11-01

    The U.S. Environmental Protection Agency mandates that drinking water showing gross alpha-activity greater than 0.19 Bq L(-1) should be analyzed for radium, a known human carcinogen. The recommended testing methods are intricate and laborious. The method reported in this paper is a direct, non-destructive gamma-spectroscopic method for the determination of 224Ra, 226Ra, and 228Ra, the three radium isotopes of environmental concern in drinking water. Large-volume Marinelli beakers (4.1-L capacity), especially designed for measuring radioactive gases, in conjunction with a low-background, high-efficiency (131%) germanium detector were used in this work. It was first established that radon, the gaseous decay product of radium, and its progeny are quantitatively retained in this Marinelli beaker. The 224Ra, 226Ra, and 228Ra activity concentrations are determined from the equilibrium activities of their progeny: 212Pb, 214Pb (214Bi), and 228Ac; and the gamma-lines used in the analysis are 238.6, 351.9 (and 609.2), and 911.2 keV, respectively. The 224Ra activity is determined from the first 1,000-min measurement performed after expulsion of radon from the sample. The 226Ra activity is determined from the second, 2,400-min measurement, made 3 to 5 d later, and the 228Ra activity is determined from either the first or the second measurement, depending on its concentration level. The method's minimum detectable activities are 0.017 Bq L(-1), 0.020 Bq L(-1), and 0.027 Bq L(-1) for 224Ra, 226Ra, and 228Ra, respectively, when measured under radioactive equilibrium. These limits are well within the National Primary Drinking Water Regulations required limit of 0.037 Bq L(-1) for 226Ra and for 228Ra. The precision and accuracy of the method, evaluated using the U.S. Environmental Protection Agency and the Environmental Resource Associates' quality control samples, were found to be within acceptable limits. PMID:14571995

  20. All-trans retinoic acid regulates hepatic bile acid homeostasis

    PubMed Central

    Yang, Fan; He, Yuqi; Liu, Hui-Xin; Tsuei, Jessica; Jiang, Xiaoyue; Yang, Li; Wang, Zheng-Tao; Wan, Yu-Jui Yvonne

    2014-01-01

    Retinoic acid (RA) and bile acids share common roles in regulating lipid homeostasis and insulin sensitivity. In addition, the receptor for RA (retinoid x receptor) is a permissive partner of the receptor for bile acids, farnesoid x receptor (FXR/NR1H4). Thus, RA can activate the FXR-mediated pathway as well. The current study was designed to understand the effect of all-trans RA on bile acid homeostasis. Mice were fed an all-trans RA-supplemented diet and the expression of 46 genes that participate in regulating bile acid homeostasis was studied. The data showed that all-trans RA has a profound effect in regulating genes involved in synthesis and transport of bile acids. All-trans RA treatment reduced the gene expression levels of Cyp7a1, Cyp8b1, and Akr1d1, which are involved in bile acid synthesis. All-trans RA also decreased the hepatic mRNA levels of Lrh-1 (Nr5a2) and Hnf4α (Nr2a1), which positively regulate the gene expression of Cyp7a1 and Cyp8b1. Moreover, all-trans RA induced the gene expression levels of negative regulators of bile acid synthesis including hepatic Fgfr4, Fxr, and Shp (Nr0b2) as well as ileal Fgf15. All-trans RA also decreased the expression of Abcb11 and Slc51b, which have a role in bile acid transport. Consistently, all-trans RA reduced hepatic bile acid levels and the ratio of CA/CDCA, as demonstrated by liquid chromatography-mass spectrometry. The data suggest that all-trans RA-induced SHP may contribute to the inhibition of CYP7A1 and CYP8B1, which in turn reduces bile acid synthesis and affects lipid absorption in the gastrointestinal tract. PMID:25175738

  1. Cardiovascular risk factor management in patients with RA compared to matched non-RA patients

    PubMed Central

    Cawston, Helene; Bourhis, Francois; Al, Maiwenn; Rutten-van Mölken, Maureen P. M. H.; Liao, Katherine P.; Solomon, Daniel H.

    2016-01-01

    Objective. RA is associated with a 50–60% increase in risk of cardiovascular (CV) death. This study aimed to compare management of CV risk factors in RA and matched non-RA patients. Methods. A retrospective cohort study was conducted using UK clinical practice data. Patients presenting with an incident RA diagnosis were matched 1:4 to non-RA patients based on a propensity score for RA, entry year, CV risk category and treatment received at index date (date of RA diagnosis). Patients tested and treated for CV risk factors as well as those attaining CV risk factor management goals were evaluated in both groups. Results. Between 1987 and 2010, 24 859 RA patients were identified and matched to 87 304 non-RA patients. At index date, groups had similar baseline characteristics. Annual blood pressure, lipids and diabetes-related testing were similar in both groups, although CRP and ESR were higher in RA patients at diagnosis and decreased over time. RA patients prescribed antihypertensives increased from 38.2% at diagnosis to 45.7% at 5 years, from 14.0 to 20.6% for lipid-lowering treatments and from 5.1 to 6.4% for antidiabetics. Similar treatment percentages were observed in non-RA patients, although slightly lower for antihypertensives. Modest (2%) but significantly lower attainment of lipid and diabetes goals at 1 year was observed in RA patients. Conclusion. There were no differences between groups in the frequency of testing and treatment of CV risk factors. Higher CV risk in RA patients seems unlikely to be driven by differences in traditional CV risk factor management. PMID:26705329

  2. Modulation of proliferating cell nuclear antigen in the bronchial epithelium of smokers.

    PubMed

    Khuri, F R; Lee, J S; Lippman, S M; Lee, J J; Kalapurakal, S; Yu, R; Ro, J Y; Morice, R C; Hong, W K; Hittelman, W N

    2001-04-01

    Clinical chemoprevention trials seek to intervene in the carcinogenic process to suppress, reverse, or delay the development of invasive cancer. Dysregulated cell growth is a hallmark of epithelial carcinogenesis, and proliferating cell nuclear antigen (PCNA) is a marker of dysregulated proliferation that is highly expressed in non-small cell lung cancers. Squamous metaplasia of the bronchial epithelium is found in chronic smokers and has been considered an early premalignant change. To evaluate the effect of 13-cis-retinoic acid (13-cRA) on PCNA modulation, we evaluated PCNA expression in a total of 706 bronchial biopsy specimens from histologically normal, hyperplastic, metaplastic, and dysplastic bronchial tissues obtained from 86 healthy smokers at baseline, of whom 69 subjects had completed 6 months of treatment on a randomized placebo-controlled chemoprevention trial of 13-cRA and had repeat bronchoscopic biopsies. PCNA expression was evaluated with respect to bronchial metaplasia and as an intermediate end point for response in the trial. In the bronchial biopsies obtained from six standardized pretreatment and posttreatment sites, high PCNA expression correlated significantly with more advanced histological grade (P < 0.001). Furthermore, smoking cessation during therapy correlated well with reduced PCNA expression (P = 0.006), although multivariate analysis indicated that this reduction in PCNA expression was associated with the reversal of squamous metaplasia. The level of PCNA expression appeared to correlate with the level of epidermal growth factor receptor expression both at baseline and at 6 months. In those patients who ceased smoking during the intervention, the 13-cRA also appeared to be more effective than placebo in reducing PCNA expression (P = 0.034 in all of the layers; P = 0.026 in basal layers). The efficacy of 13-cRA in the down-regulation of PCNA in quitters was independent of baseline PCNA expression levels. Our study demonstrated that

  3. Nuclear structure of {sup 231}Ra

    SciTech Connect

    Boutami, R.; Fraile, L. M.; Borge, M. J. G.; Lopez-Jimenez, M. J.; Teijeiro, A. G.; Aas, A. J.; Hageboe, E.; Fogelberg, B.; Mach, H.; Garcia-Raffi, L. M.; Martinez, T.; Rubio, B.; Tain, J. L.; Grant, I. S.; Gulda, K.; Kurcewicz, W.; Loevhoeiden, G.; Tengblad, O.; Thorsteinsen, T. F.

    1999-11-16

    The study of the upper border of the octupole deformation region near A=225, where the octupole deformation vanishes in the presence of a well developed quadrupole field, is of great relevance in order to understand the interplay of octupole and quadrupole collectivities. Within the IS322 collaboration at CERN we carry out a systematic investigation of the heavy Fr-Th nuclei that presently includes {sup 227}Fr, {sup 227,228,229}Ra, {sup 229}Ac and {sup 229,231}Th. The heaviest Ra isotope we have studied so far and in which the fast timing {beta}{gamma}{gamma}(t) method has been applied is {sup 231}Ra.

  4. Nuclear Structure of {sup 231}Ra

    SciTech Connect

    Boutami, R.; Fraile, L.M.; Borge, M.J.G.; Aas, A.J.; Fogelberg, B.; Garcia-Raffi, L.M.; Grant, I.S.; Gulda, K.; Hagebo, E.; Kurcewicz, W.; Lopez-Jimenez, M.J.; Lovhoiden, G.; Mach, H.; Martinez, T.; Rubio, B.; Tain, J.L.; Teijeiro, A.G.; Tengblad, O.; Thorsteinsen, T.F.

    1999-12-31

    The study of the upper border of the octupole deformation region near A=225, where the octupole deformation vanishes in the presence of a well developed quadrupole field, is of great relevance in order to understand the interplay of octupole and quadrupole collectivities. Within the IS322 collaboration at CERN we carry out a systematic investigation of the heavy Fr - Th nuclei that presently includes {sup 227}Fr, {sup 227,228,229}Ra, {sup 229}Ac and {sup 229,231}Th. The heaviest Ra isotope we have studied so far and in which the fast timing {beta}{gamma}{gamma}(t) method has been applied is {sup 231}Ra.

  5. Measuring 226Ra/228Ra in Oceanic Lavas by MC-ICPMS

    NASA Astrophysics Data System (ADS)

    Standish, J. J.; Sims, K.; Ball, L.; Blusztajn, J.

    2007-12-01

    238U-230Th-226Ra disequilibrium in volcanic rocks provides an important and unique tool to evaluate timescales of recent magmatic processes. Determination of 230Th-226Ra disequilibria requires measurement of U and Th isotopes and concentrations as well as measurement of 226Ra. While measurement of U and Th by ICPMS is now well established, few published studies documenting 226Ra measurement via ICPMS exist. Using 228Ra as an isotope spike we have investigated two ion-counting methods; a 'peak-hopping' routine, where 226Ra and 228Ra are measured in sequence on the central discrete dynode ETP secondary electron multiplier (SEM), and simultaneous measurement of 226Ra and 228Ra on two multiple ion-counter system (MICS) channeltron type detectors mounted on the low end of the collector block. Here we present 226Ra measurement by isotope dilution using the Thermo Fisher NEPTUNE MC-ICPMS. Analysis of external rock standards TML and AThO along with mid-ocean ridge basalt (MORB) and ocean island basalt (OIB) samples show three issues that need to be considered when making precise and accurate Ra measurements: 1) mass bias, 2) background, and 3) relative efficiencies of the detectors when measuring in MICS mode. Due to the absence of an established 226Ra/228Ra standard, we have used U reference material NBL-112A to monitor mass bias. Although Ball et. al., (in press) have shown that U does not serve as an adequate proxy for Th (and thus not likely for Ra either), measurements of rock standards TML and AThO are repeatedly in equilibrium within the uncertainty of the measurements (where total uncertainty includes propagation of the uncertainty in the 226Ra standard used for calibrating the 228Ra spike). For this application, U is an adequate proxy for Ra mass bias at the 1% uncertainly level. The more important issue is the background correction. Because of the extensive chemistry required to separate and purify Ra (typically fg/g level in volcanic rocks), we observe large

  6. The Mycobacterium tuberculosis H37Ra gene MRA_1916 causes growth defects upon down-regulation.

    PubMed

    Singh, Kumar Sachin; Singh, Sudheer Kumar

    2015-01-01

    D-amino acid oxidases play an important role in converting D-amino acids to their corresponding α-keto acids. MRA_1916 of Mycobacterium tuberculosis H37Ra (Mtb-Ra) is annotated to be a D-amino acid oxidase (DAO). However, not much information is available about its physiological role during Mtb-Ra growth and survival. The present study was taken-up to understand the role of DAO during different stages of growth and effect of its down-regulation on growth. Recombinant Mtb-Ra strains with DAO and GlcB (malate synthase: MRA_1848) gene knockdown were developed and their growth was studied using Microtiter Alamar Blue Assay (MABA) with glycerol, acetate and glycine as a carbon source. Ethyl bromopyruvate (BrP) was used as an inhibitor of GlcB. MABA study showed inhibition of wild-type (WT) and knockdowns in the presence of BrP (2.5mM). However, growth inhibition of WT was less noticeable at lower concentrations of BrP. Mtb-Ra with DAO knockdown showed poor utilization of glycine in the presence of BrP. The DAO localization study showed its prominent distribution in cytosolic fraction and to some extent in cell wall and membrane fractions. Growth profile of WT under oxygen and nutritional stress showed changes in expression of DAO, GlcB, PckA (phosphoenolpyruvate carboxykinase: MRA_0219) and GlyA1 (serine hydroxymethyltransferase: MRA_1104). PMID:26531045

  7. The Mycobacterium tuberculosis H37Ra gene MRA_1916 causes growth defects upon down-regulation

    PubMed Central

    Singh, Kumar Sachin; Singh, Sudheer Kumar

    2015-01-01

    D-amino acid oxidases play an important role in converting D-amino acids to their corresponding α-keto acids. MRA_1916 of Mycobacterium tuberculosis H37Ra (Mtb-Ra) is annotated to be a D-amino acid oxidase (DAO). However, not much information is available about its physiological role during Mtb-Ra growth and survival. The present study was taken-up to understand the role of DAO during different stages of growth and effect of its down-regulation on growth. Recombinant Mtb-Ra strains with DAO and GlcB (malate synthase: MRA_1848) gene knockdown were developed and their growth was studied using Microtiter Alamar Blue Assay (MABA) with glycerol, acetate and glycine as a carbon source. Ethyl bromopyruvate (BrP) was used as an inhibitor of GlcB. MABA study showed inhibition of wild-type (WT) and knockdowns in the presence of BrP (2.5mM). However, growth inhibition of WT was less noticeable at lower concentrations of BrP. Mtb-Ra with DAO knockdown showed poor utilization of glycine in the presence of BrP. The DAO localization study showed its prominent distribution in cytosolic fraction and to some extent in cell wall and membrane fractions. Growth profile of WT under oxygen and nutritional stress showed changes in expression of DAO, GlcB, PckA (phosphoenolpyruvate carboxykinase: MRA_0219) and GlyA1 (serine hydroxymethyltransferase: MRA_1104). PMID:26531045

  8. Understanding Rheumatoid Arthritis (RA): Treatment and Causes

    MedlinePlus

    ... this page please turn JavaScript on. Feature: Understanding Rheumatoid Arthritis (RA) Treatment and Causes Past Issues / Summer 2014 Table of Contents How Is Rheumatoid Arthritis Treated? Doctors have many ways to treat this ...

  9. SoRa first flight. Summer 2009

    NASA Astrophysics Data System (ADS)

    Pirrotta, S.; Flamini, E.

    The SoRa (Sounding Radar) experiment was successfully launched from Longyearbyen (Svalbard, Norway) during the summer 2009 campaign managed by the Italian/Norwegian "Nobile Amundsen / Stratospheric Balloon Centre" (NA/SBC). SoRa is part of the Italian Space Agency (ASI) programs for Long Duration Balloon Flights. Carried by the biggest balloon (800.000 m3) ever launched in polar regions, SoRa main experiment and its three piggyback payloads (DUSTER, ISA and SIDERALE) performed a nominal flight of almost 4 days over the North Sea and Greenland, until the separation, landing and recovery in Baffin Island (Canada). Despite the final destructive event that compromise the scientific main goal of SoRa, the 2009 ASI balloon campaign can be considered an important milestone, because of the obtained scientific and technical results but also for the lesson learned by the science, engineering and managerial teams looking at the future ASI scientific balloon-born activities.

  10. Distribution and flux of /sup 226/Ra and /sup 228/Ra in the Amazon River estuary

    SciTech Connect

    Key, R.M.; Sarmiento, J.L.; Stallard, R.F.; Moore, W.S.

    1985-07-20

    Measurements of /sup 226/Ra and /sup 228/Ra in the Amazon River estuary show that desorption from riverborne suspended particulate matter in the estuary increases the riverine flux of both isotopes to the ocean by a factor of approximately 5 over the flux attributable to radium dissolved in the river water alone. The total Amazon flux supplies approximately 0.20% of the /sup 226/Ra and approximately 2.6% of the /sup 228/Ra standing crops in the near-surface Atlantic (0-200 m). Diffusive flux from estuarine and shelf sediments and desorption from resuspended sediments in the region of the estuary approximately double the estuarine /sup 226/Ra concentration and quadruple the estuarine /sup 228/Ra concentration above that caused by the dissolved and desorbed river components alone.

  11. Determination of 226Ra and 224Ra in drinking waters by liquid scintillation counting.

    PubMed

    Manjón, G; Vioque, I; Moreno, H; García-Tenorio, R; García-León, M

    1997-04-01

    A method for the determination of Ra-isotopes in water samples has been developed. Ra is coprecipitated with Ba as sulphate. The precipitate is then dissolved with EDTA and counted with a liquid scintillation system after mixing with a scintillation cocktail. The study of the temporal evolution of the separated activity gives the isotopic composition of the sample, i.e. the 224Ra and 226Ra contribution to the total activity. The method has been applied to some Spanish drinking waters. PMID:9106993

  12. Integrating Retinoic Acid Signaling with Brain Function

    ERIC Educational Resources Information Center

    Luo, Tuanlian; Wagner, Elisabeth; Drager, Ursula C.

    2009-01-01

    The vitamin A derivative retinoic acid (RA) regulates the transcription of about a 6th of the human genome. Compelling evidence indicates a role of RA in cognitive activities, but its integration with the molecular mechanisms of higher brain functions is not known. Here we describe the properties of RA signaling in the mouse, which point to…

  13. Leaching of 226Ra from U mill tailings by sulfate-reducing bacteria.

    PubMed

    Landa, E R; Miller, C L; Updegraff, D M

    1986-10-01

    Relatively insoluble sulfate precipitates appear to be a major host for Ra in sulfuric acid-treated, U mill tailings. The dissolution of such precipitates by natural processes, such as metabolism by sulfate-reducing bacteria (SRB), creates the potential for release of Ra to contacting waters. Significant leaching of Ra by SRB was achieved in the laboratory during the anaerobic incubation (1 to 119 days) of U mill tailings with pure cultures of Desulfovibrio desulfuricans and mixed cultures containing SRB isolated from the tailings, all grown on a lactate medium at room temperature. While the maximum 226Ra concentration reached in a sterile media control was 0.44 Bq/L (12 pCi/L), that in the SRB systems was 61 Bq/L (1640 pCi/L) or about 20% of the total Ra inventory in the original tailings sample. The leaching of Ra in SRB systems was accompanied by a decrease in soluble sulfate concentration, an increase in total sulfide concentration, and an increase in the number of SRB. The observed leaching effect does not appear to be due to the action of microbial chelates or to binding to cell walls. Potential implications of these findings to the management of U mill tailings and other radioactive wastes are discussed. PMID:3759464

  14. Leaching of /sup 226/Ra from U mill tailings by sulfate-reducing bacteria

    SciTech Connect

    Landa, E.R.; Miller, C.L.; Updegraff, D.M.

    1986-10-01

    Relatively insoluble sulfate precipitates appear to be a major host for Ra in sulfuric acid-treated, U mill tailings. The dissolution of such precipitates by natural processes, such as metabolism by sulfate-reducing bacteria (SRB), creates the potential for release of Ra to contacting waters. Significant leaching of Ra by SRB was achieved in the laboratory during the anaerobic incubation (1 to 119 days) of U mill tailings with pure cultures of Desulfovibrio desulfuricans and mixed cultures containing SRB isolated from the tailings, all grown on a lactate medium at room temperature. While the maximum /sup 226/Ra concentration reached in a sterile media control was 0.44 Bq/L (12 pCi/L), that in the SRB systems was 61 Bq/L (1640 pCi/L) or about 20% of the total Ra inventory in the original tailings sample. The leaching of Ra in SRB systems was accompanied by a decrease in soluble sulfate concentration, an increase in total sulfide concentration, and an increase in the number of SRB. The observed leaching effect does not appear to be due to the action of microbial chelates or to binding to cell walls. Potential implications of these findings to the management of U mill tailings and other radioactive wastes are discussed.

  15. 226Ra in the western Indian Ocean

    NASA Astrophysics Data System (ADS)

    Chung, Y.

    1987-09-01

    226Ra profiles have been measured in the western Indian Ocean as part of the 1977-1978 Indian Ocean GEOSECS program. These profiles show a general increase in deep and bottom water Ra concentration from the Circumpolar region to the Arabian Sea. A deep Ra maximum which originates in the Arabian Sea and in the Somali basin at about 3000 m depth spreads southward into the Mascarene basin and remains discernible in the Madagascar and Crozet basins. In the western Indian Ocean, the cold Antarctic Bottom Water spreads northward under the possibly southward-flowing deep water, forming a clear benthic front along the Crozet basin across the Southwest Indian Ridge into the Madagascar and Mascarene basins. The Antarctic Bottom Water continues to spread farther north to the Somali basin through the Amirante Passage at 10°S as a western boundary current. The benthic front and other characteristic features in the western Indian Ocean are quite similar to those observed in the western Pacific where the benthic front as a distinctive feature was first described by Craig et al. [15]. Across the Mid-Indian Ridge toward the Ceylon abyssal plain near the triple junction, Ra profiles display a layered structure, reflecting the topographic effect of the mid-ocean ridge system on the mixing and circulation of the deep and bottom waters. Both Ra and Si show a deep maximum north of the Madagascar basin. Linear relationships between these two elements are observed in the deep and bottom water with slopes increasing northward. This suggests a preferential input of Ra over Si from the bottom sediments of the Arabian Sea and also from the flank sediments of the Somali basin.

  16. Discovery of radioactive decay of /sup 222/Ra and /sup 224/Ra by /sup 14/C emission

    SciTech Connect

    Price, P.B.; Stevenson, J.D.; Barwick, S.W.; Ravn, H.L.

    1985-01-28

    Using the ISOLDE on-line isotope separator at CERN to produce sources of /sup 221/Fr, /sup 221/Ra, /sup 222/Ra, /sup 223/Ra, and /sup 224/Ra, and using polycarbonate track-recording films sensitive to energetic carbon nuclei but not to alpha particles, we have discovered two new cases of the rare /sup 14/C decay mode: in /sup 222/Ra and /sup 224/Ra. Our results for branching ratios, B, relative to alpha decay are for /sup 221/Fr and /sup 221/Ra, B<4.4 x 10/sup -12/; for /sup 222/Ra, B = (3.7 +- 0.6) x 10/sup -10/; for /sup 223/Ra, B = (6.1 +- 1.0) x 10/sup -10/; for /sup 224/Ra, B = (4.3 +- 1.2) x 10/sup -11/. .AE

  17. Extensive polymorphism of Ra86 genes in field populations of Rhipicephalus appendiculatus from Kenya.

    PubMed

    Kamau, L M; Skilton, R A; Githaka, N; Kiara, H; Kabiru, E; Shah, T; Musoke, Aj; Bishop, R P

    2016-07-01

    Commercial vaccines based on recombinant forms of the Bm86 tick gut antigen are used to control the southern cattle tick, Rhipicephalus microplus, a 1-host species, in Australia and Latin America. We describe herein sequence polymorphism in genes encoding Ra86 homologues of Bm86 in the brown ear tick, Rhipicephalus appendiculatus, isolated from four Kenyan field populations and one laboratory colony. Sequencing of 19 Ra86 sequences defined two alleles differentiated by indels, encoding 693 amino acids (aa) and 654 aa respectively, from the Muguga laboratory reference strain. Ra86 sequences were also determined from gut cDNA from four field populations of R. appendiculatus collected in different livestock production systems in Kenya. Analysis of approximately 20 Ra86 sequences from each of the four field sites in central and Western Kenya; Makuyu, Kiambu, Kakamega and Uasin Gishu, revealed three additional size types differentiated by 39-49 amino acid indels resulting in a total of 5 indel-defined genotypes. The 693 aa type 5 was isolated only from the laboratory tick stock; genotypes 1, 2 and 3 were identified in ticks from the four Kenyan field sites and appeared to be derivatives of the shorter RA86 genotype found in Muguga laboratory stock genotype 4. By contrast no large indels have yet been observed between R. microplus sequences from Australia, South America or Africa. Evidence that selection contributes to the observed sequence variation was provided by analysis of ratio of synonymous and non-synonymous substitutions and application of the selective neutrality and neutral evolution tests to the primary data. Phylogenetic analysis clustered sequences from all Ra86 size types and Bm86, into four major clades based on amino acid substitutions, but there was no evidence that these groupings correlated with geographical separation of R. appendiculatus populations. PMID:27051976

  18. An improved method for the simultaneous determination of /sup 224/Ra, /sup 226/Ra and /sup 228/Ra in water, soils and sediments

    SciTech Connect

    Lucas, H.F.

    1987-01-01

    The naturally occurring concentrations of radium (/sup 226/Ra and /sup 228/Ra) in public and private water supplies have been studied for many years. Both general surveys ad local studies have established the geographical regions where well waters exceed 3 pCi/L (1-17). In general, the /sup 226/Ra was determined by the emanation method, while the /sup 228/Ra was determined from the beta activity of the /sup 228/Ac daughter. In a recent review (18) of the methods used ''a number of approved analytic methods can bear improvement, especially the method for 228Ra.'' The purpose of the work described here was to develop an improved method for the simultaneous determination of /sup 226/Ra and /sup 228/Ra. 22 refs., 3 tabs.

  19. Uranium series disequilibria in ground waters from a fractured bedrock aquifer (Morungaba Granitoids--Southern Brazil): implications to the hydrochemical behavior of dissolved U and Ra.

    PubMed

    Reyes, Erika; Marques, Leila S

    2008-10-01

    Activity concentrations of dissolved (234)U, (238)U, (226)Ra and (228)Ra were determined in ground waters from two deep wells drilled in Morungaba Granitoids (Southern Brazil). Sampling was done monthly for little longer than 1 year. Significant disequilibrium between (238)U, (234)U and (226)Ra were observed in all samples. The variation of (238)U and (234)U activity concentrations and (234)U/(238)U activity ratios is related to seasonal changes. Although the distance between the two wells is short (about 900 m), systematic differences of activity concentrations of U isotopes, as well as of (234)U/(238)U, (226)Ra/(234)U and (228)Ra/(226)Ra activity ratios were noticed, indicating distinct host rock-water interactions. Slightly acidic ground water percolation through heterogeneous host rock, associated with different recharge processes, may explain uranium and radium isotope behavior. PMID:18514535

  20. The estimation and potential radiobiological significance of the intake of 228Ra by early Ra dial workers in Illinois.

    PubMed

    Keane, A T; Lucas, H F; Markun, F; Essling, M A; Holtzman, R B

    1986-09-01

    We made radiochemical determinations of 226Ra and the 228Ra-decay product, 228Th, in samples of bone from former Ra dial workers who belonged to a major cohort of Ra-exposed persons under study for health effects at our institution. Most of the former workers were long-term residents of two communities supplied with drinking water containing elevated natural levels of 228Ra and 226Ra, so determinations also were made of radioactivity in samples of bone from long-term residents not occupationally exposed to Ra. The 228Th activity of the bones of the former workers, after correction for the presence of natural radioactivity, showed that some had significant occupational intakes of 228Ra, contrary to published reports that 228Ra was never used by the Illinois company that had employed the cohort of early workers. For 14 workers hired in the years 1920-23, the calculated ratio of the occupational intake of 228Ra to 226Ra activity averaged 0.15 (coefficient of variation 0.65), whereas for three workers hired in 1924, it was not significantly different from zero (mean 0.05, coefficient of variation 1.5). The risk of radiogenic cancer for the typical worker hired before 1924 may have been nearly twice that incurred in the absence of the 228Ra component of the Ra intakes. PMID:3744831

  1. Relationship between air pollution and positivity of RA-related autoantibodies in individuals without established RA: a report on SERA

    PubMed Central

    Gan, Ryan W; Deane, Kevin D; Zerbe, Gary O; Demoruelle, M Kristen; Weisman, Michael H; Buckner, Jane H; Gregersen, Peter K; Mikuls, Ted R; O’Dell, James R; Keating, Richard M; Holers, V Michae; Norris, Jill M

    2013-01-01

    Introduction Studies suggest that respiratory exposures including smoking, proximity to traffic and air pollution might be associated with development of rheumatoid arthritis (RA). RA-related autoantibodies are predictive of the development of RA. Objective We evaluated the relationship between RA-related autoantibodies and exposure to particulate matter (PM), a measure of air pollution of interest to health, in individuals without RA. Methods The Studies of the Etiology of Rheumatoid Arthritis (SERA) is a multicentre study following first-degree relatives (FDRs) of a proband with RA. FDRs are without the 1987 ACR (American College of Rheumatology) classifiable RA at enrolment and are followed for the development of RA-related autoimmunity. RA-related autoantibody outcomes as well as tender and swollen joint outcomes were assessed. Exposure to PM was assigned using ambient air pollution monitoring data and interpolated with inverse distance weighting spatial analyses using Geographic Information Systems. PM exposures were linked to FDR’s residential zip codes. Results RA-related autoantibodies as well as tender or swollen joints are not associated with ambient PM concentrations. Discussion While other respiratory exposures may be associated with increased risk of RA, our data suggest that ambient PM is not associated with autoantibodies and joint signs among individuals without RA, but at increased risk of developing RA. PMID:23572338

  2. Sorption of (226)Ra from oil effluents onto synthetic cation exchangers.

    PubMed

    Al Attar, Lina; Safia, Bassam

    2013-07-30

    Increasing environmental awareness is being urged for the safe disposal of (226)Ra-contaminated production water generated in the oil industry. Birnessite, antimony silicate and their cationic derivatives were studied for the take-up of (226)Ra using the batch-type method under experimentally determined parameters, viz. contact time, solution-solid ratio and (226)Ra concentration. Data was expressed in terms of distribution coefficients. Sorption experiments were performed in different concentrations of nitric acid in order to speculate the mechanism of (226)Ra uptake. Variation in the magnitude of sorption efficiency of the materials in the presence of the major components of waste streams, i.e. Na(+), K(+) and Ca(2+), revealed that K(+) was the greatest competitor and Na(+) the least. The application of the materials to sorb (226)Ra from actual oil co-production water samples, collected from Der Ezzor and Al Fourat petroleum companies (DEZPC and AFPC), was interpreted in terms of the exchange properties of the materials and water characterisation. Of the parameters studied, the selectivity of materials was shown to be greatly dependent on the pH of wastewater to be treated. PMID:23623032

  3. Error-control and processes optimization of (223/224)Ra measurement using Delayed Coincidence Counter (RaDeCC).

    PubMed

    Xiaoqing, Cheng; Lixin, Yi; Lingling, Liu; Guoqiang, Tang; Zhidong, Wang

    2015-11-01

    RaDeCC has proved to be a precise and standard way to measure (224)Ra and (223)Ra in water samples and successfully made radium a tracer of several environmental processes. In this paper, the relative errors of (224)Ra and (223)Ra measurement in water samples via a Radium Delayed Coincidence Count system are analyzed through performing coincidence correction calculations and error propagation. The calculated relative errors range of 2.6% ∼ 10.6% for (224)Ra and 9.6% ∼ 14.2% for (223)Ra. For different radium activities, effects of decay days and counting time on final radium relative errors are evaluated and the results show that these relative errors can decrease by adjusting the two measurement factors. Finally, to minimize propagated errors in Radium activity, a set of optimized RaDeCC measurement parameters are proposed. PMID:26233651

  4. IL-1 receptor-antagonist (IL-1Ra) knockout mice show anxiety-like behavior by aging.

    PubMed

    Wakabayashi, Chisato; Numakawa, Tadahiro; Odaka, Haruki; Ooshima, Yoshiko; Kiyama, Yuji; Manabe, Toshiya; Kunugi, Hiroshi; Iwakura, Yoichiro

    2015-07-10

    Interleukin 1 (IL-1) plays a critical role in stress responses, and its mRNA is induced in the brain by restraint stress. Previously, we reported that IL-1 receptor antagonist (IL-1Ra) knockout (KO) mice, which lacked IL-1Ra molecules that antagonize the IL-1 receptor, showed anti-depression-like behavior via adrenergic modulation at the age of 8 weeks. Here, we report that IL-1Ra KO mice display an anxiety-like phenotype that is induced spontaneously by aging in the elevated plus-maze (EPM) test. This anxiety-like phenotype was improved by the administration of diazepam. The expression of the anxiety-related molecule glucocorticoid receptor (GR) was significantly reduced in 20-week-old but not in 11-week-old IL-1Ra KO mice compared to wild-type (WT) littermates. The expression of the mineralocorticoid receptor (MR) was not altered between IL-1Ra KO mice and WT littermates at either 11 or 20 weeks old. Analysis of monoamine concentration in the hippocampus revealed that tryptophan, the serotonin metabolite 5-hydroxyindole acetic acid (5-HIAA), and the dopamine metabolite homovanillic acid (HVA) were significantly increased in 20-week-old IL-1Ra KO mice compared to littermate WT mice. These findings strongly suggest that the anxiety-like behavior observed in older mice was caused by the complicated alteration of monoamine metabolism and/or GR expression in the hippocampus. PMID:26002078

  5. Evolution of retinoic acid receptors and retinoic acid signaling.

    PubMed

    Gutierrez-Mazariegos, Juliana; Schubert, Michael; Laudet, Vincent

    2014-01-01

    Retinoic acid (RA) is a vitamin A-derived morphogen controlling important developmental processes in vertebrates, and more generally in chordates, including axial patterning and tissue formation and differentiation. In the embryo, endogenous RA levels are controlled by RA synthesizing and degrading enzymes and the RA signal is transduced by two retinoid receptors: the retinoic acid receptor (RAR) and the retinoid X receptor (RXR). Both RAR and RXR are members of the nuclear receptor superfamily of ligand-activated transcription factors and mainly act as heterodimers to activate the transcription of target genes in the presence of their ligand, all-trans RA. This signaling pathway was long thought to be a chordate innovation, however, recent findings of gene homologs involved in RA signaling in the genomes of a wide variety of non-chordate animals, including ambulacrarians (sea urchins and acorn worms) and lophotrochozoans (annelids and mollusks), challenged this traditional view and suggested that the RA signaling pathway might have a more ancient evolutionary origin than previously thought. In this chapter, we discuss the evolutionary history of the RA signaling pathway, and more particularly of the RARs, which might have experienced independent gene losses and duplications in different animal lineages. In sum, the available data reveal novel insights into the origin of the RA signaling pathway as well as into the evolutionary history of the RARs. PMID:24962881

  6. Strategy and planning for chemopreventive drug development: clinical development plans II.

    PubMed

    Kelloff, G J; Crowell, J A; Hawk, E T; Steele, V E; Lubet, R A; Boone, C W; Covey, J M; Doody, L A; Omenn, G S; Greenwald, P; Hong, W K; Parkinson, D R; Bagheri, D; Baxter, G T; Blunden, M; Doeltz, M K; Eisenhauer, K M; Johnson, K; Knapp, G G; Longfellow, D G; Malone, W F; Nayfield, S G; Seifried, H E; Swall, L M; Sigman, C C

    1996-01-01

    This is the second publication of Clinical Development Plans from the National Cancer Institute, Division of Cancer Prevention and Control, Chemoprevention Branch and Agent Development Committee. The Clinical Development Plans summarize the status of promising chemopreventive agents regarding evidence for safety and chemopreventive efficacy in preclinical and clinical studies. They also contain the strategy for further development of these drugs, addressing pharmacodynamics, drug effect measurements, intermediate biomarkers for monitoring efficacy, toxicity, supply and formulation, regulatory approval, and proposed clinical trials. Sixteen new Clinical Development Plans are presented here: curcumin, dehydroepiandrosterone, folic acid, genistein, indole-3-carbinol, perillyl alcohol, phenethyl isothiocyanate, 9-cis-retinoic acid, 13-cis-retinoic acid, l-selenomethionine and 1, 4-phenylenebis(methylene)selenocyanate, sulindac sulfone, tea, ursodiol, vitamin A, and (+)-vorozole. The objective of publishing these plans is to stimulate interest and thinking among the scientific community on the prospects for developing these and future generations of chemopreventive drugs. PMID:9154168

  7. Dissolution of [²²⁶Ra]BaSO₄ and partial separation of ²²⁶Ra from radium/barium sulfate: A new treatment method for NORM waste from petroleum industry.

    PubMed

    Al Abdullah, Jamal; Al Masri, M S; Amin, Yusr

    2016-01-01

    Complete dissolution of [(226)Ra]BaSO4 precipitate was successfully performed using NaNO2 as a reducing agent in acidic solution at room temperature. Results showed a significant effect of acid and NaNO2 concentrations and temperature on the dissolution efficiency. The method was successfully used for separation of radium from NORM scale samples from the petroleum industry; sufficient volume reduction of NORM waste was achieved. The obtained (226)Ra solution was purified using two separation methods. The dissolution method can be of great interest in the development of radiochemical analysis of radium isotopes. PMID:26623931

  8. A soluble class II cytokine receptor, IL-22RA2, is a naturally occurring IL-22 antagonist

    PubMed Central

    Xu, Wenfeng; Presnell, Scott R.; Parrish-Novak, Julia; Kindsvogel, Wayne; Jaspers, Steve; Chen, Zhi; Dillon, Stacey R.; Gao, Zeren; Gilbert, Teresa; Madden, Karen; Schlutsmeyer, Stacy; Yao, Lena; Whitmore, Theodore E.; Chandrasekher, Yasmin; Grant, Francis J.; Maurer, Mark; Jelinek, Laura; Storey, Harold; Brender, Ty; Hammond, Angie; Topouzis, Stavros; Clegg, Christopher H.; Foster, Donald C.

    2001-01-01

    IL-22 is an IL-10 homologue that binds to and signals through the class II cytokine receptor heterodimer IL-22RA1/CRF2–4. IL-22 is produced by T cells and induces the production of acute-phase reactants in vitro and in vivo, suggesting its involvement in inflammation. Here we report the identification of a class II cytokine receptor designated IL-22RA2 (IL-22 receptor-α 2) that appears to be a naturally expressed soluble receptor. IL-22RA2 shares amino acid sequence homology with IL-22RA1 (also known as IL-22R, zcytor11, and CRF2–9) and is physically adjacent to IL-20Rα and IFN-γR1 on chromosome 6q23.3–24.2. We demonstrate that IL-22RA2 binds specifically to IL-22 and neutralizes IL-22-induced proliferation of BaF3 cells expressing IL-22 receptor subunits. IL-22RA2 mRNA is highly expressed in placenta and spleen by Northern blotting. PCR analysis using RNA from various tissues and cell lines showed that IL-22RA2 was expressed in a range of tissues, including those in the digestive, female reproductive, and immune systems. In situ hybridization revealed the dominant cell types expressing IL-22RA2 were mononuclear cells and epithelium. Because IL-22 induces the expression of acute phase reactants, IL-22RA2 may play an important role as an IL-22 antagonist in the regulation of inflammatory responses. PMID:11481447

  9. Retinoic acid regulates embryonic development of mammalian submandibular salivary glands.

    PubMed

    Wright, Diana M; Buenger, Deanna E; Abashev, Timur M; Lindeman, Robert P; Ding, Jixiang; Sandell, Lisa L

    2015-11-01

    Organogenesis is orchestrated by cell and tissue interactions mediated by molecular signals. Identification of relevant signals, and the tissues that generate and receive them, are important goals of developmental research. Here, we demonstrate that Retinoic Acid (RA) is a critical signaling molecule important for morphogenesis of mammalian submandibular salivary glands (SMG). By examining late stage RA deficient embryos of Rdh10 mutant mice we show that SMG development requires RA in a dose-dependent manner. Additionally, we find that active RA signaling occurs in SMG tissues, arising earlier than any other known marker of SMG development and persisting throughout gland morphogenesis. At the initial bud stage of development, we find RA production occurs in SMG mesenchyme, while RA signaling occurs in epithelium. We also demonstrate active RA signaling occurs in glands cultured ex vivo, and treatment with an inhibitor of RA signaling blocks growth and branching. Together these data identify RA signaling as a direct regulator of SMG organogenesis. PMID:26278034

  10. Production and applications of rosmarinic acid and structurally related compounds.

    PubMed

    Kim, Gun-Dong; Park, Yong Seek; Jin, Young-Ho; Park, Cheung-Seog

    2015-03-01

    Rosmarinic acid (α-o-caffeoyl-3,4-dihydroxyphenyllactic acid; RA) is a naturally occurring hydroxylated compound commonly found in species of the subfamily Nepetoideae of the Lamiaceae and Boraginaceae, such as Rosmarinus officinalis, Salvia officinalis, and Perilla frutescens. RA is biosynthesized from the amino acids L-phenylalanine and L-tyrosine by eight enzymes that include phenylalanine ammonia lyase and cinnamic acid 4-hydroxylase. RA can also be chemically produced by the esterification of caffeic acid and 3,4-dihydroxyphenyllactic acid. RA and its numerous derivatives containing one or two RA with other aromatic moieties are well known and include lithospermic acid, yunnaneic acid, salvianolic acid, and melitric acid. Recently, RA and its derivatives have attracted interest for their biological activities, which include anti-inflammatory, anti-oxidant, anti-angiogenic, anti-tumor, and anti-microbial functions. Clinically, RA attenuates T cell receptor-mediated signaling, attenuates allergic diseases like allergic rhinitis and asthma, and 2,4-dinitrofluorobenzene-induced atopic dermatitis-like symptoms, protects from neurotoxicity, and slows the development of Alzheimer's disease. These attributes have increased the demand for the biotechnological production and application of RA and its derivatives. The present review discusses the function and application of RA and its derivatives including the molecular mechanisms underlying clinical efficacy. PMID:25620368

  11. High-Speed RaPToRS

    NASA Astrophysics Data System (ADS)

    Henchen, Robert; Esham, Benjamin; Becker, William; Pogozelski, Edward; Padalino, Stephen; Sangster, Thomas; Glebov, Vladimir

    2008-11-01

    The High-Speed Rapid Pneumatic Transport of Radioactive Samples (HS-RaPToRS) system, designed to quickly and safely move radioactive materials, was assembled and tested at the Mercury facility of the Naval Research Laboratory (NRL) in Washington D.C. A sample, which is placed inside a four-inch-diameter carrier, is activated before being transported through a PVC tube via airflow. The carrier travels from the reaction chamber to the end station where it pneumatically brakes prior to the gate. A magnetic latch releases the gate when the carrier arrives and comes to rest. The airflow, optical carrier-monitoring devices, and end gate are controlled manually or automatically with LabView software. The installation and testing of the RaPToRS system at NRL was successfully completed with transport times of less than 3 seconds. The speed of the carrier averaged 16 m/s. Prospective facilities for similar systems include the Laboratory for Laser Energetics and the National Ignition Facility.

  12. Ra-224 and Ra-226: A New Method for Measuring Groundwater Seepage in Lake Michigan

    NASA Astrophysics Data System (ADS)

    Stevens, K. R.; Buyan, A. C.; Waples, J. T.

    2008-12-01

    Radium isotopes have been used to estimate groundwater discharge (GWD) in coastal marine waters for decades, but this technique has never before been used in the Laurentian Great Lakes. In this study, we used a RAD7 radon-in-air monitor to measure naturally-occurring radium isotopes Ra-224 (half-life= 3.64 d) and Ra-226 (half-life = 1600 a) in groundwater and three shallow water sites along Lake Michigan's Wisconsin coastline. Radium-224 activities in groundwater ranged from 1153 dpm m-3 in a deep aquifer (New Berlin well no.7) to 31 dpm m-3 in a shallow aquifer (Pryor well). Nearshore Lake Michigan measurements of Ra-224 were lowest at Red Arrow Beach (0.2 dpm m-3), higher in the Milwaukee harbor (GLWI slip, 1.1 dpm m-3) and highest at Harrington Beach (4.1 dpm m-3) and correspond well with groundwater seepage estimates made by Cherkauer et al. (1990) using alternate methods (i.e., where higher radium activity is indicative of higher GWD). These Ra-224 measurements are the first ever made in Lake Michigan (and presumably any of the Great Lakes) and we conclude that, by sampling offshore radium activity gradients, this RAD7 technique is a viable method for directly measuring GWD in Lake Michigan and other freshwater systems.

  13. Gene expression analysis in RA: towards personalized medicine

    PubMed Central

    Burska, A N; Roget, K; Blits, M; Soto Gomez, L; van de Loo, F; Hazelwood, L D; Verweij, C L; Rowe, A; Goulielmos, G N; van Baarsen, L G M; Ponchel, F

    2014-01-01

    Gene expression has recently been at the forefront of advance in personalized medicine, notably in the field of cancer and transplantation, providing a rational for a similar approach in rheumatoid arthritis (RA). RA is a prototypic inflammatory autoimmune disease with a poorly understood etiopathogenesis. Inflammation is the main feature of RA; however, many biological processes are involved at different stages of the disease. Gene expression signatures offer management tools to meet the current needs for personalization of RA patient's care. This review analyses currently available information with respect to RA diagnostic, prognostic and prediction of response to therapy with a view to highlight the abundance of data, whose comparison is often inconclusive due to the mixed use of material source, experimental methodologies and analysis tools, reinforcing the need for harmonization if gene expression signatures are to become a useful clinical tool in personalized medicine for RA patients. PMID:24589910

  14. Preparing concentrated carrier-free /sup 228/Ra

    SciTech Connect

    Volynskii, L.D.; Garbuzov, V.M.; Tsirlin, V.A.

    1988-05-01

    A scheme has been devised for processing large amounts of old thorium salts to obtain concentrated carrier-free /sup 228/Ra preparations. The process includes simple regeneration of the original thorium salt. The main stages in concentrating the /sup 228/Ra are precipitation and separation of thorium peroxide, isolating the radium with a carrier, ion-exchange separation of the radium from the carrier, and final purification by electrolysis. The /sup 228/Ra recovery is 70%.

  15. [Evaluation of joint inflammation by MRI in patients with RA].

    PubMed

    Sumida, Takayuki; Sugihara, Makoto; Hirota, Tomoya; Horikoshi, Masanobu; Suzuki, Takeshi

    2012-02-01

    We compared the characteristics of MRI imaging and US imaging on joint inflammation in patients with rheumatoid arthritis (RA) . MRI imaging is worth for diagnosis of RA at the early stage, evaluation of drug treatment effects, and a new measure for true remission. US imaging is also useful for estimation of therapy and a criteria for complete remission, and cheep machine. We hope that both imaging technologies will be a standard for diagnosis and therapy evaluation in RA patients. PMID:22298072

  16. RaPToRS Sample Delivery System

    NASA Astrophysics Data System (ADS)

    Henchen, Robert; Shibata, Kye; Krieger, Michael; Pogozelski, Edward; Padalino, Stephen; Glebov, Vladimir; Sangster, Craig

    2010-11-01

    At various labs (NIF, LLE, NRL), activated material samples are used to measure reaction properties. The Rapid Pneumatic Transport of Radioactive Samples (RaPToRS) system quickly and safely moves these radioactive samples through a closed PVC tube via airflow. The carrier travels from the reaction chamber to the control and analysis station, pneumatically braking at the outlet. A reversible multiplexer routes samples from various locations near the shot chamber to the analysis station. Also, the multiplexer allows users to remotely load unactivated samples without manually approaching the reaction chamber. All elements of the system (pneumatic drivers, flow control valves, optical position sensors, multiplexers, Geiger counters, and release gates at the analysis station) can be controlled manually or automatically using a custom LabVIEW interface. A prototype is currently operating at NRL in Washington DC. Prospective facilities for Raptors systems include LLE and NIF.

  17. Anti-Diabetic Effects of Madecassic Acid and Rotundic Acid.

    PubMed

    Hsu, Yuan-Man; Hung, Yi-chih; Hu, Lihong; Lee, Yi-ju; Yin, Mei-chin

    2015-12-01

    Anti-diabetic effects of madecassic acid (MEA) and rotundic acid (RA) were examined. MEA or RA at 0.05% or 0.1% was supplied to diabetic mice for six weeks. The intake of MEA, not RA, dose-dependently lowered plasma glucose level and increased plasma insulin level. MEA, not RA, intake dose-dependently reduced plasminogen activator inhibitor-1 activity and fibrinogen level; as well as restored antithrombin-III and protein C activities in plasma of diabetic mice. MEA or RA intake decreased triglyceride and cholesterol levels in plasma and liver. Histological data agreed that MEA or RA intake lowered hepatic lipid droplets, determined by ORO stain. MEA intake dose-dependently declined reactive oxygen species (ROS) and oxidized glutathione levels, increased glutathione content and maintained the activity of glutathione reductase and catalase in the heart and kidneys of diabetic mice. MEA intake dose-dependently reduced interleukin (IL)-1β, IL-6, tumor necrosis factor-α and monocyte chemoattractant protein-1 levels in the heart and kidneys of diabetic mice. RA intake at 0.1% declined cardiac and renal levels of these inflammatory factors. These data indicated that MEA improved glycemic control and hemostatic imbalance, lowered lipid accumulation, and attenuated oxidative and inflammatory stress in diabetic mice. Thus, madecassic acid could be considered as an anti-diabetic agent. PMID:26633490

  18. Anti-Diabetic Effects of Madecassic Acid and Rotundic Acid

    PubMed Central

    Hsu, Yuan-Man; Hung, Yi-chih; Hu, Lihong; Lee, Yi-ju; Yin, Mei-chin

    2015-01-01

    Anti-diabetic effects of madecassic acid (MEA) and rotundic acid (RA) were examined. MEA or RA at 0.05% or 0.1% was supplied to diabetic mice for six weeks. The intake of MEA, not RA, dose-dependently lowered plasma glucose level and increased plasma insulin level. MEA, not RA, intake dose-dependently reduced plasminogen activator inhibitor-1 activity and fibrinogen level; as well as restored antithrombin-III and protein C activities in plasma of diabetic mice. MEA or RA intake decreased triglyceride and cholesterol levels in plasma and liver. Histological data agreed that MEA or RA intake lowered hepatic lipid droplets, determined by ORO stain. MEA intake dose-dependently declined reactive oxygen species (ROS) and oxidized glutathione levels, increased glutathione content and maintained the activity of glutathione reductase and catalase in the heart and kidneys of diabetic mice. MEA intake dose-dependently reduced interleukin (IL)-1β, IL-6, tumor necrosis factor-α and monocyte chemoattractant protein-1 levels in the heart and kidneys of diabetic mice. RA intake at 0.1% declined cardiac and renal levels of these inflammatory factors. These data indicated that MEA improved glycemic control and hemostatic imbalance, lowered lipid accumulation, and attenuated oxidative and inflammatory stress in diabetic mice. Thus, madecassic acid could be considered as an anti-diabetic agent. PMID:26633490

  19. Laser trapping of 225Ra and 226Ra with repumping by room-temperature blackbody radiation.

    PubMed

    Guest, J R; Scielzo, N D; Ahmad, I; Bailey, K; Greene, J P; Holt, R J; Lu, Z-T; O'Connor, T P; Potterveld, D H

    2007-03-01

    We have demonstrated Zeeman slowing and capture of neutral 225Ra and 226Ra atoms in a magneto-optical trap. The intercombination transition 1S0-->3P1 is the only quasicycling transition in radium and was used for laser-cooling and trapping. Repumping along the 3D1-->1P1 transition extended the lifetime of the trap from milliseconds to seconds. Room-temperature blackbody radiation was demonstrated to provide repumping from the metastable 3P0 level. We measured the isotope shift and hyperfine splittings on the 3D1-->1P1 transition with the laser-cooled atoms, and set a limit on the lifetime of the 3D1 level based on the measured blackbody repumping rate. Laser-cooled and trapped radium is an attractive system for studying fundamental symmetries. PMID:17359153

  20. Determination of gross alpha, 224Ra, 226Ra, and 228Ra activities in drinking water using a single sample preparation procedure.

    PubMed

    Parsa, Bahman; Obed, Reynaldo N; Nemeth, William K; Suozzo, Gail P

    2005-12-01

    The current federal and New Jersey State regulations have greatly increased the number of gross alpha and radium tests for public and private drinking water supplies. The determination of radium isotopes in water generally involves lengthy and complicated processes. In this study, a new approach is presented for the determination of gross alpha, 224Ra, 226Ra, and 228Ra activities in water samples. The method includes a single sample preparation procedure followed by alpha counting and gamma-ray spectroscopy. The sample preparation technique incorporates an EPA-approved co-precipitation methodology for gross alpha determination with a few alterations and improvements. Using 3-L aliquots of sample, spiked with 133Ba tracer, the alpha-emitting radionuclides are isolated by a BaSO4 and Fe(OH)3 co-precipitation scheme. First the gross alpha-particle activity of the sample is measured with a low-background gas-flow proportional counter, followed by radium isotopes assay by gamma-ray spectroscopy, using the same prepared sample. Gamma-ray determination of 133Ba tracer is used to assess the radium chemical recovery. The 224Ra, 226Ra, and 228Ra activities in the sample are measured through their gamma-ray-emitting decay products, 212Pb, 214Pb/214Bi, and 228Ac, respectively. In cases where 224Ra determination is required, the gamma-ray counting should be performed within 2-4 d from sample collection. To measure 226Ra activity in the sample, the gamma-ray spectroscopy can be repeated 21 d after sample preparation to ensure that 226Ra and its progeny have reached the equilibrium state. At this point, the 228Ac equilibration with parent 228Ra is already established. Analysis of aliquots of de-ionized water spiked with NIST-traceable 230Th, 224Ra, 226Ra, and 228Ra standards demonstrated the accuracy and precision of this method. Various performance evaluation samples were also assayed for gross alpha as well as radium isotope activity determination using this procedure and the

  1. Paraprofessional Staff in Transition: The Sophomore RA Experience

    ERIC Educational Resources Information Center

    Brandt Brecheisen, Shannon M.

    2015-01-01

    The sophomore resident assistant (RA) experience exists at the point where the sophomore experience and the RA position intersect. Sophomore students contend with specific transition struggles and challenges unique to their class standing as they make decisions about their sense of purpose and future career, and those who choose to become RAs face…

  2. 6-Formylindolo(3,2-b)Carbazole (FICZ) Modulates the Signalsome Responsible for RA-Induced Differentiation of HL-60 Myeloblastic Leukemia Cells

    PubMed Central

    Bunaciu, Rodica P.; LaTocha, Dorian H.; Varner, Jeffrey D.; Yen, Andrew

    2015-01-01

    6-Formylindolo(3,2-b)carbazole (FICZ) is a photoproduct of tryptophan and an endogenous high affinity ligand for aryl hydrocarbon receptor (AhR). It was previously reported that, in patient-derived HL-60 myeloblastic leukemia cells, retinoic acid (RA)-induced differentiation is driven by a signalsome containing c-Cbl and AhR. FICZ enhances RA-induced differentiation, assessed by expression of the membrane differentiation markers CD38 and CD11b, cell cycle arrest and the functional differentiation marker, inducible oxidative metabolism. Moreover, FICZ augments the expression of a number of the members of the RA-induced signalsome, such as c-Cbl, Vav1, Slp76, PI3K, and the Src family kinases Fgr and Lyn. Pursuing the molecular signaling responsible for RA-induced differentiation, we characterized, using FRET and clustering analysis, associations of key molecules thought to drive differentiation. Here we report that, assayed by FRET, AhR interacts with c-Cbl upon FICZ plus RA-induced differentiation, whereas AhR constitutively interacts with Cbl-b. Moreover, correlation analysis based on the flow cytometric assessment of differentiation markers and western blot detection of signaling factors reveal that Cbl-b, p-p38α and pT390-GSK3β, are not correlated with other known RA-induced signaling components or with a phenotypic outcome. We note that FICZ plus RA elicited signaling responses that were not typical of RA alone, but may represent alternative differentiation-driving pathways. In clusters of signaling molecules seminal to cell differentiation, FICZ co-administered with RA augments type and intensity of the dynamic changes induced by RA. Our data suggest relevance for FICZ in differentiation-induction therapy. The mechanism of action includes modulation of a SFK and MAPK centered signalsome and c-Cbl-AhR association. PMID:26287494

  3. Measurement of 224Ra and 226Ra activities in natural waters using a radon-in-air monitor

    USGS Publications Warehouse

    Kim, G.; Burnett, W.C.; Dulaiova, H.; Swarzenski, P.W.; Moore, W.S.

    2001-01-01

    We report a simple new technique for measuring low-level radium isotopes (224Ra and 226Ra) in natural waters. The radium present in natural waters is first preconcentrated onto MnO2-coated acrylic fiber (Mn fiber) in a column mode. The radon produced from the adsorbed radium is then circulated through a closed air-loop connected to a commercial radon-in-air monitor. The monitor counts alpha decays of radon daughters (polonium isotopes) which are electrostatically collected onto a silicon semiconductor detector. Count data are collected in energy-specific windows, which eliminate interference and maintain very low backgrounds. Radium-224 is measured immediately after sampling via 220Rn (216Po), and 226Ra is measured via 222Rn (218Po) after a few days of ingrowth of 222Rn. This technique is rapid, simple, and accurate for measurements of low-level 224Ra and 226Ra activities without requiring any wet chemistry. Rapid measurements of short-lived 222Rn and 224Ra, along with long-lived 226Ra, may thus be made in natural waters using a single portable system for environmental monitoring of radioactivity as well as tracing of various geochemical and geophysical processes. The technique could be especially useful for the on-site rapid determination of 224Ra which has recently been found to occur at elevated activities in some groundwater wells.

  4. Rainfall Manipulation Plot Study (RaMPS)

    DOE Data Explorer

    Blair, John [Kansas State University; Fay, Phillip [USDA-ARS; Knapp, Alan [Colorado State University; Collins, Scott [University of New Mexico; Smith, Melinda [Yale University

    Rainfall Manipulation Plots facility (RaMPs) is a unique experimental infrastructure that allows us to manipulate precipitation events and temperature, and assess population community, and ecosystem responses in native grassland. This facility allows us to manipulate the amount and timing of individual precipitation events in replicated field plots at the Konza Prairie Long-Term Ecological Research (LTER) site. Questions we are addressing include: • What is the relative importance of more extreme precipitation patterns (increased climatic variability) vs. increased temperatures (increased climatic mean) with regard to their impact on grassland ecosystem structure and function? Both projected climate change factors are predicted to decrease soil water availability, but the mechanisms by which this resource depletion occurs differ. • Will altered precipitation patterns, increased temperatures and their interaction increase opportunities for invasion by exotic species? • Will long-term (6-10 yr) trajectories of community and ecosystem change in response to more extreme precipitation patterns continue at the same rate as initial responses from years 1-6? Or will non-linear change occur as potential ecological thresholds are crossed? And will increased temperatures accelerate these responses? Data sets are available as ASCII files, in Excel spreadsheets, and in SAS format. (Taken from http://www.konza.ksu.edu/ramps/backgrnd.html

  5. Input overload: Contributions of retinoic acid signaling feedback mechanisms to heart development and teratogenesis.

    PubMed

    D'Aniello, Enrico; Waxman, Joshua S

    2015-03-01

    Appropriate levels of retinoic acid (RA) signaling are critical for normal heart development in vertebrates. A fascinating property of RA signaling is the thoroughness by which positive and negative feedback are employed to promote proper embryonic RA levels. In the present short review, we first cover the advancement of hypotheses regarding the impact of RA signaling on cardiac specification. We then discuss our current understanding of RA signaling feedback mechanisms and the implications of recent studies, which have indicated improperly maintained RA signaling feedback can be a contributing factor to developmental malformations. PMID:25418431

  6. The role of CYP26 enzymes in defining appropriate retinoic acid exposure during embryogenesis.

    PubMed

    Pennimpede, Tracie; Cameron, Don A; MacLean, Glenn A; Li, Hui; Abu-Abed, Suzan; Petkovich, Martin

    2010-10-01

    Retinoic acid (RA) is a pleiotropic derivative of vitamin A, or retinol, which is responsible for all of the bioactivity associated with this vitamin. The teratogenic influences of vitamin A deficiency and excess RA in rodents were first observed more than 50 years ago. Efforts over the last 15-20 years have refined these observations by defining the molecular mechanisms that control RA availability and signaling during murine embryonic development. This review will discuss our current understanding of the role of RA in teratogenesis, with specific emphasis on the essential function of the RA catabolic CYP26 enzymes in preventing teratogenic consequences caused by uncontrolled distribution of RA. Particular focus will be paid to the RA-sensitive tissues of the caudal and cranial regions, the limb, and the testis, and how genetic mutation of factors controlling RA distribution have revealed important roles for RA during embryogenesis. PMID:20842651

  7. Progress toward an EDM measurement in {sup225}Ra.

    SciTech Connect

    Holt, R. J.; Ahmad, I.; Bailey, K.; Graner, B.; Greene, J. P.; Korsch, W.; Lu, Z.-T.; Mueller, P.; O'Connor, T. P.; Sulai, I. A.; Trimble, W. L.

    2010-11-01

    Permanent electric dipole moments (EDMs) in atoms or molecules are a signature of time-reversal and parity violation and represent an important window onto physics beyond the Standard Model. We are developing a next generation EDM search based on laser-cooled and trapped {sup 225}Ra atoms. Due to octupole deformation of the nucleus, {sup 225}Ra is predicted to be two to three orders of magnitude more sensitive to T-violating interactions than {sup 199}Hg, which currently sets the most stringent limits in the nuclear sector. We will discuss progress toward realizing a first EDM measurement for {sup 225}Ra.

  8. Concurrent determination of 224Ra, 226Ra, 228Ra, and unsupported 212Pb in a single analysis for drinking water and wastewater: dissolved and suspended fractions.

    PubMed

    Parsa, Bahman; Obed, Reynaldo N; Nemeth, William K; Suozzo, Gail

    2004-02-01

    A technique has been developed for the measurement of 224Ra, 226Ra, 228Ra, and unsupported 2t2Pb concurrently in a single analysis. The procedure can be applied to both drinking water and wastewater, including the dissolved and suspended fractions of a sample. For drinking water samples, using 3-L aliquots, the radium isotopes are isolated by a fast PbSO4 co-precipitation and then quantified by gamma-ray spectroscopy. The radium isotopes 224Ra, 226Ra, and 228Ra are measured through their gamma-ray-emitting decay products, 212Pb, 214Pb (and/or 214Bi), and 228Ac, respectively. Because of the short half-life of 224Ra (T1/2 = 3.66 d), the precipitate should be counted within 4 d of the sample collection date. In case the measurement of unsupported 212Pb (T1/2 = 10.64 h) is required, the gamma-ray analysis should be initiated as soon as possible, preferably on the same day of collection. The counting is repeated after about 21 d to ensure the 226Ra progeny are in equilibrium with their parent. At this point, the 228Ac equilibration with its 228Ra parent is already established. In the case of samples containing suspended materials, an aliquot of sample is filtered and then the filtrate is treated as described above for drinking water samples. The suspended fraction of sample, collected on the filter, is directly analyzed by gamma-ray spectroscopy with no further chemical separation. Aliquots of de-ionized water spiked with various radium standards were analyzed to check the accuracy and precision of the method. In addition, analysis results of actual samples using this method were compared with the ones performed using U.S. Environmental Protection Agency-approved procedures, and the measured values were in close agreement. This method simplifies the analytical procedures and reduces the labor while achieving the precision, accuracy, and minimum detection concentration requirements of EPA's Regulations. PMID:14744047

  9. Microbial release of 226Ra2+ from (Ba,Ra)SO4 sludges from uranium mine wastes.

    PubMed Central

    Fedorak, P M; Westlake, D W; Anders, C; Kratochvil, B; Motkosky, N; Anderson, W B; Huck, P M

    1986-01-01

    226Ra2+ is removed from uranium mine effluents by coprecipitation with BaSO4. (Ba,Ra)SO4 sludge samples from two Canadian mine sites were found to contain active heterotrophic populations of aerobic, anaerobic, denitrifying, and sulfate-reducing bacteria. Under laboratory conditions, sulfate reduction occurred in batch cultures when carbon sources such as acetate, glucose, glycollate, lactate, or pyruvate were added to samples of (Ba,Ra)SO4 sludge. No external sources of nitrogen or phosphate were required for this activity. Further studies with lactate supplementation showed that once the soluble SO4(2-) in the overlying water was depleted, Ba2+ and 226Ra2+ were dissolved from the (Ba,Ra)SO4 sludge, with the concurrent production of S2-. Levels of dissolved 226Ra2+ reached approximately 400 Bq/liter after 10 weeks of incubation. Results suggest that the ultimate disposal of these sludges must maintain conditions to minimize the activity of the indigenous sulfate-reducing bacteria to ensure that unacceptably high levels of 226Ra2+ are not released to the environment. PMID:3752993

  10. Microbiota and bile acid profiles in retinoic acid-primed mice that exhibit accelerated liver regeneration

    PubMed Central

    Liu, Hui-Xin; Hu, Ying; Wan, Yu-Jui Yvonne

    2016-01-01

    Background & Aims All-trans Retinoic acid (RA) regulates hepatic lipid and bile acid homeostasis. Similar to bile acid (BA), RA accelerates partial hepatectomy (PHx)-induced liver regeneration. Because there is a bidirectional regulatory relationship between gut microbiota and BA synthesis, we examined the effect of RA in altering the gut microbial population and BA composition and established their relationship with hepatic biological processes during the active phases of liver regeneration. Methods C57BL/6 mice were treated with RA orally followed by 2/3 PHx. The roles of RA in shifting gut microbiota and BA profiles as well as hepatocyte metabolism and proliferation were studied. Results RA-primed mice exhibited accelerated hepatocyte proliferation revealed by higher numbers of Ki67-positive cells compared to untreated mice. Firmicutes and Bacteroidetes phyla dominated the gut microbial community (>85%) in both control and RA-primed mice after PHx. RA reduced the ratio of Firmicutes to Bacteroidetes, which was associated with a lean phenotype. Consistently, RA-primed mice lacked transient lipid accumulation normally found in regenerating livers. In addition, RA altered BA homeostasis and shifted BA profiles by increasing the ratio of hydrophilic to hydrophobic BAs in regenerating livers. Accordingly, metabolic regulators fibroblast growth factor 21, Sirtuin1, and their downstream targets AMPK and ERK1/2 were more robustly activated in RA-primed than unprimed regenerating livers. Conclusions Priming mice with RA resulted in a lean microbiota composition and hydrophilic BA profiles, which were associated with facilitated metabolism and enhanced cell proliferation. PMID:26701854

  11. Seasonal changes in submarine groundwater discharge to coastal salt ponds estimated using 226Ra and 228Ra as tracers

    USGS Publications Warehouse

    Hougham, A.L.; Moran, S.B.; Masterson, J.P.; Kelly, R.P.

    2008-01-01

    Submarine groundwater discharge (SGD) to coastal southern Rhode Island was estimated from measurements of the naturally-occurring radioisotopes 226Ra (t1/2 = 1600??y) and 228Ra (t1/2 = 5.75??y). Surface water and porewater samples were collected quarterly in Winnapaug, Quonochontaug, Ninigret, Green Hill, and Pt. Judith-Potter Ponds, as well as nearly monthly in the surface water of Rhode Island Sound, from January 2002 to August 2003; additional porewater samples were collected in August 2005. Surface water activities ranged from 12-83??dpm 100??L- 1 (60??dpm = 1??Bq) and 21-256??dpm 100??L- 1 for 226Ra and 228Ra, respectively. Porewater 226Ra activities ranged from 16-736??dpm 100??L- 1 (2002-2003) and 95-815??dpm 100??L- 1 (2005), while porewater 228Ra activities ranged from 23-1265??dpm 100??L- 1. Combining these data with a simple box model provided average 226Ra-based submarine groundwater fluxes ranging from 11-159??L m- 2 d- 1 and average 228Ra-derived fluxes of 15-259??L m- 2 d- 1. Seasonal changes in Ra-derived SGD were apparent in all ponds as well as between ponds, with SGD values of 30-472??L m- 2 d- 1 (Winnapaug Pond), 6-20??L m- 2 d- 1 (Quonochontaug Pond), 36-273??L m- 2 d- 1 (Ninigret Pond), 29-76??L m- 2 d- 1 (Green Hill Pond), and 19-83??L m- 2 d- 1 (Pt. Judith-Potter Pond). These Ra-derived fluxes are up to two orders of magnitude higher than results predicted by a numerical model of groundwater flow, estimates of aquifer recharge for the study period, and values published in previous Ra-based SGD studies in Rhode Island. This disparity may result from differences in the type of flow (recirculated seawater versus fresh groundwater) determined using each technique, as well as variability in porewater Ra activity. ?? 2007 Elsevier B.V. All rights reserved.

  12. Ra: The Sun for Science and Humanity

    NASA Technical Reports Server (NTRS)

    1996-01-01

    To guide the development of the Ra Strategic Framework, we defined scientific and applications objectives. For our primary areas of scientific interest, we choose the corona, the solar wind, the Sun's effect on the Earth, and solar theory and model development. For secondary areas of scientific interest, we selected sunspots, the solar constant, the Sun's gravitational field, helioseismology and the galactic cosmic rays. We stress the importance of stereoscopic imaging, observations at high spatial, spectral, and temporal resolutions, as well as of long duration measurements. Further exploration of the Sun's polar regions is also important, as shown already by the Ulysses mission. From an applications perspective, we adopted three broad objectives that would derive complementary inputs for the Strategic Framework. These were to identify and investigate: possible application spin-offs from science missions, possible solar-terrestrial missions dedicated to a particular application, and possible future applications that require technology development. The Sun can be viewed as both a source of resources and of threats. Our principal applications focus was that of threat mitigation, by examining ways to improve solar threat monitoring and early warning systems. We compared these objectives to the mission objectives of past, current, and planned international solar missions. Past missions (1962-1980) seem to have been focused on improvement of scientific knowledge, using multiple instrument spacecraft. A ten year gap followed this period, during which the results from previous missions were analyzed and solar study programmes were prepared in international organizations. Current missions (1990-1996) focus on particular topics such as the corona, solar flares, and coronal mass ejections. In planned missions, Sun/Earth interactions and environmental effects of solar activity are becoming more important. The corona is the centre of interest of almost all planned missions

  13. Rapid determination of 226Ra in emergency urine samples

    DOE PAGESBeta

    Maxwell, Sherrod L.; Culligan, Brian K.; Hutchison, Jay B.; Utsey, Robin C.; McAlister, Daniel R.

    2014-02-27

    A new method has been developed at the Savannah River National Laboratory (SRNL) that can be used for the rapid determination of 226Ra in emergency urine samples following a radiological incident. If a radiological dispersive device event or a nuclear accident occurs, there will be an urgent need for rapid analyses of radionuclides in urine samples to ensure the safety of the public. Large numbers of urine samples will have to be analyzed very quickly. This new SRNL method was applied to 100 mL urine aliquots, however this method can be applied to smaller or larger sample aliquots as needed.more » The method was optimized for rapid turnaround times; urine samples may be prepared for counting in <3 h. A rapid calcium phosphate precipitation method was used to pre-concentrate 226Ra from the urine sample matrix, followed by removal of calcium by cation exchange separation. A stacked elution method using DGA Resin was used to purify the 226Ra during the cation exchange elution step. This approach combines the cation resin elution step with the simultaneous purification of 226Ra with DGA Resin, saving time. 133Ba was used instead of 225Ra as tracer to allow immediate counting; however, 225Ra can still be used as an option. The rapid purification of 226Ra to remove interferences using DGA Resin was compared with a slightly longer Ln Resin approach. A final barium sulfate micro-precipitation step was used with isopropanol present to reduce solubility; producing alpha spectrometry sources with peaks typically <40 keV FWHM (full width half max). This new rapid method is fast, has very high tracer yield (>90 %), and removes interferences effectively. The sample preparation method can also be adapted to ICP-MS measurement of 226Ra, with rapid removal of isobaric interferences.« less

  14. Concentration of {sup 226}Ra in human teeth

    SciTech Connect

    Yamamoto, Masayoishi; Ueno, Kaoru; Hinoide, Moriyo; Ohkubo, Yoshiteru

    1994-11-01

    {sup 226}Ra concentrations in human teeth from several cities, mainly Tokyo, Japan, were determined with emphasis on the measurement of low-level {sup 226}Ra by alpha-ray spectrometry following chemical separation. No appreciable differences in {sup 226}Ra concentration were found among various permanent teeth samples of different age groups in Tokyo. The mean {sup 226}Ra concentration for Tokyo was 0.51 {+-} 0.06 mBq (g CA){sup -1}. {sup 226}Ra concentration [mean: 0.67 {+-} 0.11 mBq (g Ca){sup -1}] in teeth in western regions of the country was statistically higher than that [mean: 0.48 {+-} 0.09 mBq (g Ca){sup -1}] in eastern ones. The mean {sup 226}Ra concentration [0.51 mBq (g CA){sup -1}] in teeth from Tokyo was less than the concentration [1.11 mBq (g CA){sup -1}] reported for vertebral bone samples of this city. 27 refs., 1 fig., 5 tabs.

  15. Coelimination and Survival in Gene Network Evolution: Dismantling the RA-Signaling in a Chordate.

    PubMed

    Martí-Solans, Josep; Belyaeva, Olga V; Torres-Aguila, Nuria P; Kedishvili, Natalia Y; Albalat, Ricard; Cañestro, Cristian

    2016-09-01

    The bloom of genomics is revealing gene loss as a pervasive evolutionary force generating genetic diversity that shapes the evolution of species. Outside bacteria and yeast, however, the understanding of the process of gene loss remains elusive, especially in the evolution of animal species. Here, using the dismantling of the retinoic acid metabolic gene network (RA-MGN) in the chordate Oikopleura dioica as a case study, we combine approaches of comparative genomics, phylogenetics, biochemistry, and developmental biology to investigate the mutational robustness associated to biased patterns of gene loss. We demonstrate the absence of alternative pathways for RA-synthesis in O. dioica, which suggests that gene losses of RA-MGN were not compensated by mutational robustness, but occurred in a scenario of regressive evolution. In addition, the lack of drastic phenotypic changes associated to the loss of RA-signaling provides an example of the inverse paradox of Evo-Devo. This work illustrates how the identification of patterns of gene coelimination-in our case five losses (Rdh10, Rdh16, Bco1, Aldh1a, and Cyp26)-is a useful strategy to recognize gene network modules associated to distinct functions. Our work also illustrates how the identification of survival genes helps to recognize neofunctionalization events and ancestral functions. Thus, the survival and extensive duplication of Cco and RdhE2 in O. dioica correlated with the acquisition of complex compartmentalization of expression domains in the digestive system and a process of enzymatic neofunctionalization of the Cco, while the surviving Aldh8 could be related to its ancestral housekeeping role against toxic aldehydes. PMID:27406791

  16. Determining groundwater Ra end-member values for the estimation of the magnitude of submarine groundwater discharge using Ra isotope tracers

    NASA Astrophysics Data System (ADS)

    Cho, Hyung-Mi; Kim, Guebuem

    2016-04-01

    Radium isotopes (228Ra and 226Ra) are excellent tracers of submarine groundwater discharge (SGD). To estimate SGD magnitudes, information on the end-member values of Ra concentrations in groundwater is critical; however, the distribution characteristics of Ra in coastal aquifers are poorly understood. In this study, we show that Ra concentrations in coastal groundwater are primarily dependent on salinity based on the data (n > 500) obtained from global coastal aquifers, although previous end-member calculations averaged all Ra concentrations without considering salinity. If we assume that SGD is composed mainly of seawater infiltrating the aquifer, previous estimates of SGD for the Atlantic Ocean and the global ocean were overestimated twofold to threefold. This may be similar for other applications using different Ra isotopes. Our study highlights that the end-members of Ra isotopes in groundwater should be carefully considered when estimating SGD using Ra isotope mass balances in the ocean.

  17. Leaching of radionuclides from uranium ore and mill tailings ( Ra- 226, Tn-230).

    USGS Publications Warehouse

    Landa, E.R.

    1982-01-01

    The major part of the extractable uranium is associated with a readily acid-soluble fraction in both ore and tailings. The major part of the extractable 226Ra was associated with an iron, manganese hydrous-oxide fraction in the ore and tailings. Thorium-230 was the least leachable of the radionuclides studied. The major portion of the extractable 230Th was associated with alkaline-earth sulphate precipitates, organic matter, or both. The specific effects of milling on each of the nuclides are discussed.-Author

  18. Importance of ALDH1A enzymes in determining human testicular retinoic acid concentrations

    PubMed Central

    Arnold, Samuel L.; Kent, Travis; Hogarth, Cathryn A.; Schlatt, Stefan; Prasad, Bhagwat; Haenisch, Michael; Walsh, Thomas; Muller, Charles H.; Griswold, Michael D.; Amory, John K.; Isoherranen, Nina

    2015-01-01

    Retinoic acid (RA), the active metabolite of vitamin A, is required for spermatogenesis and many other biological processes. RA formation requires irreversible oxidation of retinal to RA by aldehyde dehydrogenase enzymes of the 1A family (ALDH1A). While ALDH1A1, ALDH1A2, and ALDH1A3 all form RA, the expression pattern and relative contribution of these enzymes to RA formation in the testis is unknown. In this study, novel methods to measure ALDH1A protein levels and intrinsic RA formation were used to accurately predict RA formation velocities in individual human testis samples and an association between RA formation and intratesticular RA concentrations was observed. The distinct localization of ALDH1A in the testis suggests a specific role for each enzyme in controlling RA formation. ALDH1A1 was found in Sertoli cells, while only ALDH1A2 was found in spermatogonia, spermatids, and spermatocytes. In the absence of cellular retinol binding protein (CRBP)1, ALDH1A1 was predicted to be the main contributor to intratesticular RA formation, but when CRBP1 was present, ALDH1A2 was predicted to be equally important in RA formation as ALDH1A1. This study provides a comprehensive novel methodology to evaluate RA homeostasis in human tissues and provides insight to how the individual ALDH1A enzymes mediate RA concentrations in specific cell types. PMID:25502770

  19. HLA-D region genes and rheumatoid arthritis (RA): importance of DR and DQ genes in conferring susceptibility to RA.

    PubMed Central

    Singal, D P; Green, D; Reid, B; Gladman, D D; Buchanan, W W

    1992-01-01

    The distribution of HLA-D region antigens was studied in three groups (I, IIa, and IIb) of patients with rheumatoid arthritis (RA): group I comprised 43 patients with mild, non-progressive RA, controlled by non-steroidal anti-inflammatory drugs without progression or erosions; group II comprised 94 patients with severe disease, who had earlier been treated with non-steroidal anti-inflammatory drugs and all had incomplete response requiring treatment with gold (sodium aurothiomalate). Of these, 46 patients (group IIa) responded to gold and the disease was well controlled, and the remaining 48 patients (group IIb) did not respond to gold and developed gold induced toxic reactions, including thrombocytopenia or proteinuria, or both. HLA-D region antigens were defined by serological and molecular (Southern blot analysis and oligonucleotide typing) techniques. The results show that DR4 was significantly increased in all three groups of patients. The prevalence of DR1, or DR1 in DR4 negative patients, and DR3 and DR4 associated DQw7 specificities, however, showed differences in these three groups of patients. The prevalence of DR1 and of DR1 in DR4 negative patients was increased only in patients with mild (group I) RA, but not in patients with severe (groups IIa and IIb) disease. On the other hand, the prevalence of DR4 associated DQw7 was significantly increased in patients with severe disease, but not in patients with mild RA. In addition, DR3 was significantly increased only in patients with severe disease who developed gold induced toxic reactions (group IIb). These data suggest that the HLA-D region genes which cause susceptibility to mild RA may be different from those causing susceptibility to severe RA. The results suggest that both DR and DQ (A, B) genes may be important in conferring susceptibility to RA: DR in mild disease and DQ in severe RA. Images PMID:1371662

  20. The "RA" Expeditions: The Archaeological and Anthropological Background. The "RA" Expeditions: The Coriolis Effect. The "RA" Expeditions: The Papyrus Reed. Learning Experiences for Coastal and Oceanic Awareness Studies, Nos. 211, 212, 213. [Project COAST].

    ERIC Educational Resources Information Center

    Delaware Univ., Newark. Coll. of Education.

    Included are three units related to coastal and oceanic awareness. These are: (1) The "RA" Expeditions: The Archaeological and Anthropological Background; (2) The "RA" Expeditions: The Coriolis Effect; and (3) The "RA" Expeditions: The Papyrus Reed. Each of the three units are designed for students in grades 6-12. Each unit contains teacher…

  1. Synthesis and characterization of lanthanum phosphate nanoparticles as carriers for 223Ra and 225Ra for targeted alpha therapy

    DOE PAGESBeta

    Rojas, J. V.; Woodward, J. D.; Chen, N.; Rondinone, A. J.; Castano, C. H.; Mirzadeh, S.

    2015-03-19

    Targeted alpha therapy (TAT) has the potential for killing specific tumor cells with minimum collateral damage to surrounding healthy tissue. Radionuclides such as 223Ra, 225Ra, and 225Ac are of special interest for radiotherapeutic applications as they emit multiple -particles during their decay. Utilizing appropriate carriers capable of retaining both the parent radioisotope as well as daughter products is important for the effective delivery of the radioisotope to the tumor site while mitigating global in vivo radiotoxicity. Methods. In this work, core and core+2 shells (NPs with 2 additional layers of cold LaPO4 deposited on the core surfaces) LaPO4 nanoparticles (NPs)more » were synthesized containing either 223Ra or 225Ra/225Ac and the retention of the parents and daughters within the NPs in vitro was investigated. Results. The NPs crystallized in rhabdophane phase with mean diameters of 3.4 and 6.3 nm for core and core+2 shells, respectively. The core LaPO 4 NPs retained up to 88% of 223Ra over 35 days. However, in the core+2 shell NPs, the retention of 223Ra and its daughter, 211Pb, was improved to > 99.9% over 27 days. Additionally, the retention of 225Ra/225Ac parents was > 99.98% and ~80% for the 221Fr and 213Bi daughters over 35 days for the core+2 shell NPs. Conclusions. These results suggest that LaPO4 NPs are potentially effective carriers of radium isotopes.« less

  2. An experimental analysis of the contribution of 224Ra and 226Ra and progeny to the gross alpha-particle activity of water samples.

    PubMed

    Arndt, Michael F; West, Lynn E

    2008-05-01

    The gross alpha-particle activity of water samples analyzed by EPA Method 900.0 is investigated as a function of residue mass and geometry, time between sample collection and analysis, and time between sample preparation and analysis for samples containing 224Ra, 212Pb, and 226Ra. It is shown that the gross alpha-particle activity due to 224Ra and its progeny can be up to 10 times the 224Ra activity at collection time and that due to 212Pb progeny can be up to 3 times the 212Pb activity at collection time. In samples with roughly equal activities of 224Ra and 226Ra analyzed soon after collection, it is shown that the gross alpha-particle activity is approximately constant with time because the decay of 224Ra and its progeny is offset by the ingrowth of 226Ra progeny. PMID:18403967

  3. Depletion of retinoic acid receptors initiates a novel positive feedback mechanism that promotes teratogenic increases in retinoic acid.

    PubMed

    D'Aniello, Enrico; Rydeen, Ariel B; Anderson, Jane L; Mandal, Amrita; Waxman, Joshua S

    2013-01-01

    Normal embryonic development and tissue homeostasis require precise levels of retinoic acid (RA) signaling. Despite the importance of appropriate embryonic RA signaling levels, the mechanisms underlying congenital defects due to perturbations of RA signaling are not completely understood. Here, we report that zebrafish embryos deficient for RA receptor αb1 (RARαb1), a conserved RAR splice variant, have enlarged hearts with increased cardiomyocyte (CM) specification, which are surprisingly the consequence of increased RA signaling. Importantly, depletion of RARαb2 or concurrent depletion of RARαb1 and RARαb2 also results in increased RA signaling, suggesting this effect is a broader consequence of RAR depletion. Concurrent depletion of RARαb1 and Cyp26a1, an enzyme that facilitates degradation of RA, and employment of a novel transgenic RA sensor line support the hypothesis that the increases in RA signaling in RAR deficient embryos are the result of increased embryonic RA coupled with compensatory RAR expression. Our results support an intriguing novel mechanism by which depletion of RARs elicits a previously unrecognized positive feedback loop that can result in developmental defects due to teratogenic increases in embryonic RA. PMID:23990796

  4. Sequence analysis and expression regulation of rbp4 by 9-cis-RA in Megalobrama amblycephala.

    PubMed

    Xu, Mengxia; Huang, Chunxiao; Chen, Nan; Wu, Xinjie; Zhu, Kecheng; Wang, Weimin; Wang, Huanling

    2015-04-01

    Retinol-binding protein 4 (rbp4) is mainly synthesized in the liver, where it binds retinol and then enters the bloodstream, delivering retinol to cells. The full-length cDNA coding rbp4 was cloned from Megalobrama amblycephala. The amino acid sequence showed strong homology with the homologues of other vertebrates, and all structural and functional domains were highly conserved. The mRNA levels in different tissues and development stages detected by quantitative real-time PCR revealed that M. amblycephala rbp4 was highly expressed in liver (P < 0.001), but the lower levels were also detected in eyes, kidney, intestine, and spleen. During the different development stages, the rbp4 mRNA appeared until 28 hours post-fertilization (hpf), underwent a slight drop, and then gradually increased after 50 hpf. In addition, the promoter sequence of M. amblycephala rbp4 was obtained using thermal asymmetric interlaced PCR. Two single nucleotide polymorphism sites (-385A>G and -329C>T) were found in the promoter. Transfection with recombinant plasmids of two different haplotypes (GT, AC) showed that 9-cis-retinoic acid (RA) increased the promoter activity, but the AC haplotype was more sensitive to RA. PMID:25274419

  5. Mechanisms of retinoic acid signalling and its roles in organ and limb development

    PubMed Central

    Cunningham, Thomas J.; Duester, Gregg

    2015-01-01

    Retinoic acid (RA) signalling has a central role during vertebrate development. RA synthesized in specific locations regulates transcription by interacting with nuclear RA receptors (RARs) bound to RA response elements (RAREs) near target genes. RA was first implicated in signalling on the basis of its teratogenic effects on limb development. Genetic studies later revealed that endogenous RA promotes forelimb initiation by repressing fibroblast growth factor 8 (Fgf8). Insights into RA function in the limb serve as a paradigm for understanding how RA regulates other developmental processes. In vivo studies have identified RAREs that control repression of Fgf8 during body axis extension or activation of homeobox (Hox) genes and other key regulators during neuronal differentiation and organogenesis. PMID:25560970

  6. Affinity of rosmarinic acid to human serum albumin and its effect on protein conformation stability.

    PubMed

    Peng, Xin; Wang, Xiangchao; Qi, Wei; Su, Rongxin; He, Zhimin

    2016-02-01

    Rosmarinic acid (RA) is a natural polyphenol contained in many aromatic plants with promising biological activities. The interaction between RA and human serum albumin (HSA) was investigated by multi-spectroscopic, electrochemistry, molecular docking and molecular dynamics simulation methods. The fluorescence emission of HSA was quenched by RA through a combined static and dynamic quenching mechanism, but the static quenching was the major constituent. Fluorescence experiments suggested that RA was bound to HSA with moderately strong binding affinity through hydrophobic interaction. The probable binding location of RA was located near site I of HSA. Additionally, as shown by the Fourier transform infrared (FT-IR) and circular dichroism (CD) spectra, RA can result in conformational and structural alterations of HSA. Furthermore, the molecular dynamics studies were used to investigate the stability of the HSA and HSA-RA system. Altogether, the results can provide an important insight for the applications of RA in the food industry. PMID:26304336

  7. IL-33 enhances retinoic acid signaling on CD4+ T cells.

    PubMed

    Gajardo, Tania; Pérez, Francisco; Terraza, Claudia; Campos-Mora, Mauricio; Noelle, Randolph J; Pino-Lagos, Karina

    2016-09-01

    Several molecules have been described as CD4+ T cells differentiation modulators and among them retinoic acid (RA) and more recently, IL-33, have been studied. Due to the similarities in T helper cell skewing properties between RA and IL-33, we asked whether IL-33 intersects, directly or indirectly, the RA signaling pathway. Total CD4+ T cells from DR5-luciferase mice were activated in the presence of RA with or without IL-33, and RA signaling was visualized using ex vivo imaging. Our results demonstrate that IL-33 itself is able to trigger RA signaling on CD4+ T cells, which is highly increased when IL-33 is added in conjunction with RA. This study presents IL-33 as a potential player that may synergize with RA in controlling T cell differentiation, and suggests that IL-33 may be an attractive target in controlling T cell differentiation in vivo. PMID:27322964

  8. Effect of surfactants on Ra-sHSPI - A small heat shock protein from the cattle tick Rhipicephalus annulatus

    NASA Astrophysics Data System (ADS)

    Siddiqi, Mohammad Khursheed; Shahein, Yasser E.; Hussein, Nahla; Khan, Rizwan H.

    2016-09-01

    Electrostatic interaction plays an important role in protein aggregation phenomenon. In this study, we have checked the effect of anionic - Sodium Dodecyl Sulfate (SDS) and cationic-Cetyltrimethyl Ammonium Bromide (CTAB) surfactant on aggregation behavior of Ra-sHSPI, a small heat shock protein purified from Rhipicephalus annulatus tick. To monitor the effect of these surfactants, we have employed several spectroscopic methods such as Rayleigh light scattering measurements, ANS (8-Anilinonaphthalene-1-sulfonic acid) fluorescence measurements, ThT (Thioflavin T) binding assays, Far-UV CD (Circular Dichroism) and dynamic light scattering measurements. In the presence of anionic surfactant-SDS, Ra-sHSPI forms amyloid fibrils, in contrast, no amyloid formation was observed in presence of cationic surfactant at low pH. Enhancement of ANS fluorescence intensity confirms the exposition of more hydrophobic patches during aggregation. ThT binding assay confirms the amyloid fibrillar nature of the SDS induced Ra-sHSPI aggregates and supported by PASTA 2.0 (prediction of amyloid structural aggregation) software. This study demonstrates the crucial role of charge during amyloid fibril formation at low pH in Ra-sHSPI.

  9. Retinoid resistance and multifaceted impairment of retinoic acid synthesis in glioblastoma.

    PubMed

    Campos, Benito; Weisang, Sarah; Osswald, Florian; Ali, Ramadan; Sedlmeier, Georg; Bageritz, Josephine; Mallm, Jan-Philipp; Hartmann, Christian; von Deimling, Andreas; Popanda, Odillia; Goidts, Violaine; Plass, Christoph; Unterberg, Andreas; Schmezer, Peter; Burhenne, Jürgen; Herold-Mende, Christel

    2015-10-01

    Measuring concentrations of the differentiation-promoting hormone retinoic acid (RA) in glioblastoma tissues would help to understand the reason why RA treatment has been inefficient in clinical trials involving brain tumor patients. Here, we apply a recently established extraction and measurement protocol to screen glioblastoma tissues for the levels of the RA precursor retinol and biologically active RA. Combining this approach with mRNA analyses of 26 tumors and 8 normal brains, we identify a multifaceted disturbance of RA synthesis in glioblastoma, involving multiple aldehyde dehydrogenase 1 family and retinol dehydrogenase enzymes. Through database studies and methylation analyses, we narrow down chromosomal deletions and aberrant promoter hypermethylation as potential mechanisms accounting for these alterations. Employing chromatin immunoprecipitation analyses and cell-culture studies, we further show that chromatin at RA target genes is poised to RA substitution, but most glioblastoma cell cultures are completely resistant to RA treatment. This paradoxical RA response is unrelated to alternative RA signaling through the fatty acid-binding protein 5/peroxisome proliferator-activated receptor delta axis. Our data suggest a multifaceted disturbance of RA synthesis in glioblastoma and contribute to reconsider current RA treatment strategies. PMID:25944104

  10. Determination of 226Ra in urine samples by alpha spectrometry.

    PubMed

    Kehagia, K; Potiriadis, C; Bratakos, S; Koukouliou, V; Drikos, G

    2007-01-01

    A radiation protection system to assess the internal contamination of workers during decontamination activities in an abounded fertilizer industry in the region of Attika, Greece, has been implemented. This system concerns, among other radionuclides, 226Ra. Because of the low 226Ra activities in urine, alpha spectrometry was used as the determination method after radiochemical separation. Radium was co precipitated with lead sulphate and purified using anion and cation exchange techniques. The source for the alpha spectrometric measurement was prepared by the electrodeposition of radium, from an aqueous/ethanol solution, onto stainless steel. The tracer used was 229Th. The chemical yield and the activity concentration were calculated via its daughter radionuclide 217At. Using the time-evolution formulas to calculate the 217At growth from its parent radionuclide 225Ra, a computer software was developed. This software was incorporated in a database, which automatically calculates and stores the results. PMID:17827131

  11. Rapid determination of 226Ra in environmental samples

    SciTech Connect

    Maxwell, Sherrod L.; Culligan, Brian K.

    2012-02-04

    A new rapid method for the determination of {sup 228}Ra in natural water samples has been developed at the SRNL/EBL (Savannah River National Lab/ Environmental Bioassay Laboratory) that can be used for emergency response or routine samples. While gamma spectrometry can be employed with sufficient detection limits to determine {sup 228}Ra in solid samples (via {sup 228}Ac) , radiochemical methods that employ gas flow proportional counting techniques typically provide lower MDA (Minimal Detectable Activity) levels for the determination of {sup 228}Ra in water samples. Most radiochemical methods for {sup 228}Ra collect and purify {sup 228}Ra and allow for {sup 228}Ac daughter ingrowth for ~36 hours. In this new SRNL/EBL approach, {sup 228}Ac is collected and purified from the water sample without waiting to eliminate this delay. The sample preparation requires only about 4 hours so that {sup 228}Ra assay results on water samples can be achieved in < 6 hours. The method uses a rapid calcium carbonate precipitation enhanced with a small amount of phosphate added to enhance chemical yields (typically >90%), followed by rapid cation exchange removal of calcium. Lead, bismuth, uranium, thorium and protactinium isotopes are also removed by the cation exchange separation. {sup 228}Ac is eluted from the cation resin directly onto a DGA Resin cartridge attached to the bottom of the cation column to purify {sup 228}Ac. DGA Resin also removes lead and bismuth isotopes, along with Sr isotopes and {sup 90}Y. La is used to determine {sup 228}Ac chemical yield via ICP-MS, but {sup 133}Ba can also be used instead if ICP-MS assay is not available. Unlike some older methods, no lead or strontium holdback carriers or continual readjustment of sample pH is required.

  12. Retinoic acid signaling regulates sonic hedgehog and bone morphogenetic protein signalings during genital tubercle development.

    PubMed

    Liu, Liqing; Suzuki, Kentaro; Nakagata, Naomi; Mihara, Kenichiro; Matsumaru, Daisuke; Ogino, Yukiko; Yashiro, Kenta; Hamada, Hiroshi; Liu, Zhonghua; Evans, Sylvia M; Mendelsohn, Cathy; Yamada, Gen

    2012-02-01

    Retinoic acid (RA) plays pivotal roles in organogenesis, and both excessive and reduced amounts of RA cause developmental abnormalities. Reproductive organs are susceptible to teratogen toxigenicity, and the genital tubercle (GT) is one such representative organ. The physiological function of endogenous RA signaling and the mechanisms of RA-induced teratogenicity are poorly understood during the GT development. The objective of this study is to understand the developmental and teratogenic roles of RA during GT development by analyzing genetically modified mouse models. We found dynamic patterns of gene expression for the RA-synthesizing enzyme, Raldh2, and for the RA-catabolizing enzyme, Cyp26b1, during GT development. Rarb, an indicator gene for RA signaling, starts its expression in the prospective corpus cavernosum penis and in the urethral plate epithelium (UE), which plays central roles during GT development. Excessive RA signaling in Cyp26b1(-/-) mutants leads to abnormal extents of cell proliferation and differentiation during GT development, and also upregulates expression of growth factor signalings. They include Sonic hedgehog (Shh) signaling and Bone morphogenetic protein (Bmp) signaling, which are expressed in the UE and its bilateral mesenchyme. RA signaling positively regulatesShh and Bmp4 expression during GT development as testified also by the experiment of RA administration and analyses of loss-of-function of RA signaling mutants. Thus, RA signaling is involved in the developmental cascade necessary for UE formation and GT development. PMID:22127979

  13. Human Gastric Epithelial Cells Contribute to Gastric Immune Regulation by Providing Retinoic Acid to Dendritic Cells

    PubMed Central

    Bimczok, Diane; Kao, John Y.; Zhang, Min; Cochrun, Steven; Mannon, Peter; Peter, Shajan; Wilcox, Charles M.; Mönkemüller, Klaus E.; Harris, Paul R.; Grams, Jayleen M.; Stahl, Richard D.; Smith, Phillip D.; Smythies, Lesley E.

    2014-01-01

    Despite the high prevalence of chronic gastritis caused by H. pylori, the gastric mucosa has received little investigative attention as a unique immune environment. Here, we analyzed whether retinoic acid (RA), an important homeostatic factor in the small intestinal mucosa, also contributes to gastric immune regulation. We report that human gastric tissue contains high levels of the RA precursor molecule, retinol, and that gastric epithelial cells express both RA biosynthesis genes and RA response genes, indicative of active RA biosynthesis. Moreover, primary gastric epithelial cells cultured in the presence of retinol synthesized RA in vitro and induced RA biosynthesis in co-cultured monocytes through an RA-dependent mechanism, suggesting that gastric epithelial cells may also confer the ability to generate RA on gastric DCs. Indeed, DCs purified from gastric mucosa had similar levels of aldehyde dehydrogenase activity and RA biosynthesis gene expression as small intestinal DCs, although gastric DCs lacked CD103. In H. pylori-infected gastric mucosa, gastric RA biosynthesis gene expression was severely disrupted, which may lead to reduced RA signaling and thus contribute to disease progression. Collectively, our results support a critical role for RA in human gastric immune regulation. PMID:25249167

  14. RAPID DETERMINATION OF RA-226 IN ENVIRONMENTAL SAMPLES

    SciTech Connect

    Maxwell, S.

    2012-01-03

    A new rapid method for the determination of {sup 226}Ra in environmental samples has been developed at the Savannah River Site Environmental Lab (Aiken, SC, USA) that can be used for emergency response or routine sample analyses. The need for rapid analyses in the event of a Radiological Dispersive Device or Improvised Nuclear Device event is well-known. In addition, the recent accident at Fukushima Nuclear Power Plant in March, 2011 reinforces the need to have rapid analyses for radionuclides in environmental samples in the event of a nuclear accident. {sup 226}Ra (T1/2 = 1,620 years) is one of the most toxic of the long-lived alpha-emitters present in the environment due to its long life and its tendency to concentrate in bones, which increases the internal radiation dose of individuals. The new method to determine {sup 226}Ra in environmental samples utilizes a rapid sodium hydroxide fusion method for solid samples, calcium carbonate precipitation to preconcentrate Ra, and rapid column separation steps to remove interferences. The column separation process uses cation exchange resin to remove large amounts of calcium, Sr Resin to remove barium and Ln Resin as a final purification step to remove {sup 225}Ac and potential interferences. The purified {sup 226}Ra sample test sources are prepared using barium sulfate microprecipitation in the presence of isopropanol for counting by alpha spectrometry. The method showed good chemical recoveries and effective removal of interferences. The determination of {sup 226}Ra in environmental samples can be performed in less than 16 h for vegetation, concrete, brick, soil, and air filter samples with excellent quality for emergency or routine analyses. The sample preparation work takes less than 6 h. {sup 225}Ra (T1/2 = 14.9 day) tracer is used and the {sup 225}Ra progeny {sup 217}At is used to determine chemical yield via alpha spectrometry. The rapid fusion technique is a rugged sample digestion method that ensures that any

  15. Process waste assessment: Color print processing (RA-4)

    SciTech Connect

    Catlett, P.

    1994-05-01

    The Kodak RA-4 process is used to develop prints and overhead transparencies from photographic negatives. The assessment was based on usage, effluent discharge, and final disposition of waste generated by the process. Two options explored were bleach-fix regeneration and the conversion to a digital image processing system. The RA-4 process is process is environmentally sound and generates a relatively small amount of waste. The bleach-fix option would provide only a small effluent reduction. The digital imaging conversion option, if fully implemented, could greatly reduce waste generated in the photo lab.

  16. Protective Effect of RA on Myocardial Infarction-Induced Cardiac Fibrosis via AT1R/p38 MAPK Pathway Signaling and Modulation of the ACE2/ACE Ratio.

    PubMed

    Liu, Qiaofeng; Tian, Jingwei; Xu, Yanan; Li, Chunmei; Meng, Xiangjing; Fu, Fenghua

    2016-09-01

    Rosmarinic acid (α-o-caffeoyl-3,4-dihydroxyphenyllactic acid, RA) is a major active constituent of Rosmarinus officinalis Linn. (rosemary) having significant anti-inflammatory, anti-apoptotic, and antioxidant effects. However, the cardioprotection of RA is still not understood. The present study was designed, for the first time, to investigate the cardioprotection of RA on myocardial infarction (MI)-induced cardiac fibrosis and to clarify the possible mechanisms. MI was induced in adult rats by left anterior descending coronary artery ligation, and animals were then administered RA (50, 100, or 200 mg/kg) by gavage. Compared with the model group, RA treatment ameliorated changes in the left ventricular systolic pressure (LVSP), +dp/dtmax, and -dp/dtmax after 4 weeks. This was associated with attenuation of infarct size, collagen volume fraction (CVF), expression of collagen I, collagen III, alpha smooth muscle actin (α-SMA), and hydroxyproline (Hyp) concentrations. RA treatment was also associated with decreased angiotensin-converting enzyme (ACE) expression and increased ACE2 expression, as well as decreased expression of angiotensin type 1 receptor (AT1R) and phospho-p38 mitogen-activated protein kinase (p38 MAPK). Thus, RA can protect against cardiac dysfunction and fibrosis following MI, likely due to decreasing ACE expression and increasing ACE2 expression via the AT1R/p38 MAPK pathway. PMID:27538767

  17. Induction of CYP26A1 by Metabolites of Retinoic Acid: Evidence That CYP26A1 Is an Important Enzyme in the Elimination of Active Retinoids

    PubMed Central

    Topletz, Ariel R.; Tripathy, Sasmita; Foti, Robert S.; Shimshoni, Jakob A.; Nelson, Wendel L.

    2015-01-01

    All-trans-retinoic acid (atRA), the active metabolite of vitamin A, induces gene transcription via binding to nuclear retinoic acid receptors (RARs). The primary hydroxylated metabolites formed from atRA by CYP26A1, and the subsequent metabolite 4-oxo-atRA, bind to RARs and potentially have biologic activity. Hence, CYP26A1, the main atRA hydroxylase, may function either to deplete bioactive retinoids or to form active metabolites. This study aimed to determine the role of CYP26A1 in modulating RAR activation via formation and elimination of active retinoids. After treatment of HepG2 cells with atRA, (4S)-OH-atRA, (4R)-OH-atRA, 4-oxo-atRA, and 18-OH-atRA, mRNAs of CYP26A1 and RARβ were increased 300- to 3000-fold, with 4-oxo-atRA and atRA being the most potent inducers. However, >60% of the 4-OH-atRA enantiomers were converted to 4-oxo-atRA in the first 12 hours of treatment, suggesting that the activity of the 4-OH-atRA was due to 4-oxo-atRA. In human hepatocytes, atRA, 4-OH-atRA, and 4-oxo-atRA induced CYP26A1 and 4-oxo-atRA formation was observed from 4-OH-atRA. In HepG2 cells, 4-oxo-atRA formation was observed even in the absence of CYP26A1 activity and this formation was not inhibited by ketoconazole. In human liver microsomes, 4-oxo-atRA formation was supported by NAD+, suggesting that 4-oxo-atRA formation is mediated by a microsomal alcohol dehydrogenase. Although 4-oxo-atRA was not formed by CYP26A1, it was depleted by CYP26A1 (Km = 63 nM and intrinsic clearance = 90 μl/min per pmol). Similarly, CYP26A1 depleted 18-OH-atRA and the 4-OH-atRA enantiomers. These data support the role of CYP26A1 to clear bioactive retinoids, and suggest that the enzyme forming active 4-oxo-atRA may be important in modulating retinoid action. PMID:25492813

  18. Excessive feedback of Cyp26a1 promotes cell non-autonomous loss of retinoic acid signaling.

    PubMed

    Rydeen, Ariel; Voisin, Norine; D'Aniello, Enrico; Ravisankar, Padmapriyadarshini; Devignes, Claire-Sophie; Waxman, Joshua S

    2015-09-01

    Teratogenic levels of retinoic acid (RA) signaling can cause seemingly contradictory phenotypes indicative of both increases and decreases of RA signaling. However, the mechanisms underlying these contradictory phenotypes are not completely understood. Here, we report that using a hyperactive RA receptor to enhance RA signaling in zebrafish embryos leads to defects associated with gain and loss of RA signaling. While the gain-of-function phenotypes arise from an initial increase in RA signaling, using genetic epistasis analysis we found that the loss-of-function phenotypes result from a clearing of embryonic RA that requires a rapid and dramatic increase in cyp26a1 expression. Thus, the sensitivity of cyp26a1 expression to increased RA signaling causes an overcompensation of negative feedback and loss of embryonic RA signaling. Additionally, we used blastula transplantation experiments to test if Cyp26a1, despite its cellular localization, can limit RA exposure to neighboring cells. We find that enhanced Cyp26a1 expression limits RA signaling in the local environment, thus providing the first direct evidence that Cyp26 enzymes can have cell non-autonomous consequences on RA levels within tissues. Therefore, our results provide novel insights into the teratogenic mechanisms of RA signaling and the cellular mechanisms by which Cyp26a1 expression can shape a RA gradient. PMID:26116175

  19. Changes in Gene Expression Profiling of Apoptotic Genes in Neuroblastoma Cell Lines upon Retinoic Acid Treatment

    PubMed Central

    Celay, Jon; Blanco, Idoia; Lázcoz, Paula; Rotinen, Mirja; Castresana, Javier S.; Encío, Ignacio

    2013-01-01

    To determine the effect of retinoic acid (RA) in neuroblastoma we treated RA sensitive neuroblastoma cell lines with 9-cis RA or ATRA for 9 days, or for 5 days followed by absence of RA for another 4 days. Both isomers induced apoptosis and reduced cell density as a result of cell differentiation and/or apoptosis. Flow cytometry revealed that 9-cis RA induced apoptosis more effectively than ATRA. The expression profile of apoptosis and survival pathways was cell line specific and depended on the isomer used. PMID:23650528

  20. "LJ" Series "Redefining RA": Keeping up with Genres

    ERIC Educational Resources Information Center

    Wyatt, Neal

    2008-01-01

    Genre is a hot issue in readers' advisory (RA) circles right now. Many people are looking at how genre functions and morphs. Studying a genre is not a new idea. Over two decades ago, and even longer in less formal ways, librarians began gathering to study genres--asking such questions as in what genre does this book fit and why, what are its…

  1. Observation of the negative ions: Ra[sup [minus

    SciTech Connect

    Zhao, X.; Nadeau, M.; Garwan, M.A.; Kilius, L.R.; Litherland, A.E. )

    1993-11-01

    The negative ions of the isotopes [sup 226]Ra, [sup 231]Pa, and [sup 244]Pu have been observed by means of accelerator mass spectrometry and their properties compared with the negative ions of Th and U. The electron affinities of all these elements have been estimated to be similar and greater than 50 meV.

  2. Improved experimental limit on the EDM of 225Ra

    NASA Astrophysics Data System (ADS)

    Bishof, Michael; Bailey, Kevin; Dietrich, Matthew R.; Greene, John P.; Holt, Roy J.; Kalita, Mukut R.; Korsch, Wolfgang; Lemke, Nathan D.; Lu, Zheng-Tian; Mueller, Peter; O'Connor, Tom P.; Parker, Richard H.; Rabga, Tenzin; Singh, Jaideep T.

    2015-10-01

    Searches for permanent electric dipole moments (EDMs) in fundamental and composite particles are sensitive probes of beyond-standard-model symmetry violation that could explain the dominance of matter over anti-matter. The 225Ra (t1/2 = 15d, I = 1/2) atom is a particularly attractive system to use for an EDM measurement because its large nuclear octupole deformation, closely spaced ground-state parity doublet, and large atomic mass make 225Ra uniquely sensitive to symmetry-violating interactions in the nuclear medium. We have developed an experiment to measure the EDM of 225Ra and demonstrated the first ``proof-of-principle'' measurement, giving a 95% confidence upper limit of 5E-22 e-cm. After implementing a vacuum upgrade, we have observed nuclear spin coherence after 20 s of free evolution - a factor of ten improvement over our earlier results - and have lowered the 225Ra EDM limit by over an order of magnitude. Upcoming experimental upgrades have the potential to further improve our EDM sensitivity by many orders of magnitude, allowing us to test symmetry violation at an unprecedented level. This work is supported by U.S. DOE, Office of Science, Office of Nuclear Physics, under Contract DE-AC02-06CH11357.

  3. Genome Sequence of Avirulent Riemerella anatipestifer Strain RA-JLLY

    PubMed Central

    Zhang, Rongrong; Luo, Qingping; Wen, Guoyuan; Ai, Diyun; Wang, Honglin; Luo, Ling; Wang, Hongcai

    2015-01-01

    Riemerella anatipestifer is an important bacterial pathogen associated with epizootic infections in waterfowl and various other birds. Riemerella anatipestifer strain RA-JLLY is an avirulent strain, isolated from the brain of an old duck in Hubei province, China. Here, we report the genome sequence of this species. PMID:26404587

  4. Anti-inflammatory roles of retinoic acid in rat brain astrocytes: Suppression of interferon-gamma-induced JAK/STAT phosphorylation.

    PubMed

    Choi, Woo-Hyuck; Ji, Kyung-Ae; Jeon, Sae-Bom; Yang, Myung-Soon; Kim, Ho; Min, Kyoung-Jin; Shong, Minho; Jou, Ilo; Joe, Eun-Hye

    2005-04-01

    The anti-inflammatory effect of retinoic acid (RA) has been investigated for several decades. However, the underlying mechanisms responsible for this effect are largely unknown. In this study, we demonstrate that 9-cis-RA (cRA) and all-trans-RA (tRA) inhibit interferon-gamma (IFN-gamma)-induced inflammatory responses in astrocytes. In primary cultured rat brain astrocytes and C6 astroglioma cells, both cRA and tRA decreased IFN-gamma-induced expression of interferon regulatory factor-1. Both RA isoforms also reduced IFN-gamma-induced activation of signal transducers and activators of transcription (STAT)1, STAT3, Janus kinase (JAK)1, and JAK2. This inhibitory effect was significant when cells were pre-treated with RA prior to IFN-gamma. Furthermore, the effect of pre-treated RA was abolished in the presence of cycloheximide, indicating a requirement for de novo protein synthesis. Suppressors of cytokine signaling (SOCS), which are negative regulators of the JAK/STAT pathway, may be candidate mediators of the anti-inflammatory function of RA. Both cRA and tRA induced SOCS3 mRNA expression. These results suggest that RA induces an anti-inflammatory effect by suppressing the activation of the JAK/STAT pathway in IFN-gamma-treated astrocytes. SOCS3 may be at least one of the mechanisms that mediate the anti-inflammatory roles of RA. PMID:15721283

  5. Improved limit on the 225Ra electric dipole moment

    NASA Astrophysics Data System (ADS)

    Bishof, Michael; Parker, Richard H.; Bailey, Kevin G.; Greene, John P.; Holt, Roy J.; Kalita, Mukut R.; Korsch, Wolfgang; Lemke, Nathan D.; Lu, Zheng-Tian; Mueller, Peter; O'Connor, Thomas P.; Singh, Jaideep T.; Dietrich, Matthew R.

    2016-08-01

    Background: Octupole-deformed nuclei, such as that of 225Ra, are expected to amplify observable atomic electric dipole moments (EDMs) that arise from time-reversal and parity-violating interactions in the nuclear medium. In 2015 we reported the first "proof-of-principle" measurement of the 225Ra atomic EDM. Purpose: This work reports on the first of several experimental upgrades to improve the statistical sensitivity of our 225Ra EDM measurements by orders of magnitude and evaluates systematic effects that contribute to current and future levels of experimental sensitivity. Method: Laser-cooled and trapped 225Ra atoms are held between two high-voltage electrodes in an ultrahigh-vacuum chamber at the center of a magnetically-shielded environment. We observe Larmor precession in a uniform magnetic field using nuclear-spin-dependent laser light scattering and look for a phase shift proportional to the applied electric field, which indicates the existence of an EDM. The main improvement to our measurement technique is an order-of-magnitude increase in spin-precession time, which is enabled by an improved vacuum system and a reduction in trap-induced heating. Results: We have measured the 225Ra atomic EDM to be less than 1.4 ×10-23e cm (95 % confidence upper limit), which is a factor of 36 improvement over our previous result. Conclusions: Our evaluation of systematic effects shows that this measurement is completely limited by statistical uncertainty. Combining this measurement technique with planned experimental upgrades, we project a statistical sensitivity at the 1 ×10-28e cm level and a total systematic uncertainty at the 4 ×10-29e cm level.

  6. Retinoic acid in alveolar development, maintenance and regeneration.

    PubMed Central

    Maden, Malcolm; Hind, Matthew

    2004-01-01

    Recent data suggest that exogenous retinoic acid (RA), the biologically active derivative of vitamin A, can induce alveolar regeneration in a rat model of experimental emphysema. Here, we describe a mouse model of disrupted alveolar development using dexamethasone administered postnatally. We show that the effects of dexamethasone are concentration dependent, dose dependent, long lasting and result in a severe loss of alveolar surface area. When RA is administered to these animals as adults, lung architecture and the surface area per unit of body weight are completely restored to normal. This remarkable effect may be because RA is required during normal alveolar development and administering RA re-awakens gene cascades used during development. We provide evidence that RA is required during alveologenesis in the mouse by showing that the levels of the retinoid binding proteins, the RA receptors and two RA synthesizing enzymes peak postnatally. Furthermore, an inhibitor of RA synthesis, disulphiram, disrupts alveologenesis. We also show that RA is required throughout life for the maintenance of lung alveoli because when rats are deprived of dietary retinol they lose alveoli and show the features of emphysema. Alveolar regeneration with RA may therefore be an important novel therapeutic approach to the treatment of respiratory diseases characterized by a reduced gas-exchanging surface area such as bronchopulmonary dysplasia and emphysema for which there are currently no treatments. PMID:15293808

  7. Permeability of rosmarinic acid in Prunella vulgaris and ursolic acid in Salvia officinalis extracts across Caco-2 cell monolayers

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Rosmarinic acid (RA), a caffeic acid derivative found in high concentrations in Prunella vulgaris (self-heal), and ursolic acid (UA), a pentacyclic triterpene acid concentrated in Salvia officinalis (sage), have been traditionally used to treat inflammation in the mouth, and may also be of benefit t...

  8. Inhibiting complex IL-17A and IL-17RA interactions with a linear peptide

    PubMed Central

    Liu, Shenping; Desharnais, Joel; Sahasrabudhe, Parag V.; Jin, Ping; Li, Wei; Oates, Bryan D.; Shanker, Suman; Banker, Mary Ellen; Chrunyk, Boris A.; Song, Xi; Feng, Xidong; Griffor, Matt; Jimenez, Judith; Chen, Gang; Tumelty, David; Bhat, Abhijit; Bradshaw, Curt W.; Woodnutt, Gary; Lappe, Rodney W.; Thorarensen, Atli; Qiu, Xiayang; Withka, Jane M.; Wood, Lauren D.

    2016-01-01

    IL-17A is a pro-inflammatory cytokine that has been implicated in autoimmune and inflammatory diseases. Monoclonal antibodies inhibiting IL-17A signaling have demonstrated remarkable efficacy, but an oral therapy is still lacking. A high affinity IL-17A peptide antagonist (HAP) of 15 residues was identified through phage-display screening followed by saturation mutagenesis optimization and amino acid substitutions. HAP binds specifically to IL-17A and inhibits the interaction of the cytokine with its receptor, IL-17RA. Tested in primary human cells, HAP blocked the production of multiple inflammatory cytokines. Crystal structure studies revealed that two HAP molecules bind to one IL-17A dimer symmetrically. The N-terminal portions of HAP form a β-strand that inserts between two IL-17A monomers while the C-terminal section forms an α helix that directly blocks IL-17RA from binding to the same region of IL-17A. This mode of inhibition suggests opportunities for developing peptide antagonists against this challenging target. PMID:27184415

  9. Inhibiting complex IL-17A and IL-17RA interactions with a linear peptide.

    PubMed

    Liu, Shenping; Desharnais, Joel; Sahasrabudhe, Parag V; Jin, Ping; Li, Wei; Oates, Bryan D; Shanker, Suman; Banker, Mary Ellen; Chrunyk, Boris A; Song, Xi; Feng, Xidong; Griffor, Matt; Jimenez, Judith; Chen, Gang; Tumelty, David; Bhat, Abhijit; Bradshaw, Curt W; Woodnutt, Gary; Lappe, Rodney W; Thorarensen, Atli; Qiu, Xiayang; Withka, Jane M; Wood, Lauren D

    2016-01-01

    IL-17A is a pro-inflammatory cytokine that has been implicated in autoimmune and inflammatory diseases. Monoclonal antibodies inhibiting IL-17A signaling have demonstrated remarkable efficacy, but an oral therapy is still lacking. A high affinity IL-17A peptide antagonist (HAP) of 15 residues was identified through phage-display screening followed by saturation mutagenesis optimization and amino acid substitutions. HAP binds specifically to IL-17A and inhibits the interaction of the cytokine with its receptor, IL-17RA. Tested in primary human cells, HAP blocked the production of multiple inflammatory cytokines. Crystal structure studies revealed that two HAP molecules bind to one IL-17A dimer symmetrically. The N-terminal portions of HAP form a β-strand that inserts between two IL-17A monomers while the C-terminal section forms an α helix that directly blocks IL-17RA from binding to the same region of IL-17A. This mode of inhibition suggests opportunities for developing peptide antagonists against this challenging target. PMID:27184415

  10. Choline kinase alpha expression during RA-induced neuronal differentiation: role of C/EBPβ.

    PubMed

    Domizi, Pablo; Aoyama, Chieko; Banchio, Claudia

    2014-04-01

    Neuronal differentiation is a complex process characterized by a halt in proliferation and extension of neurites from the cell body. This process is accompanied by changes in gene expression that mediate the redirection leading to neurite formation and function. Acceleration of membrane phospholipids synthesis is associated with neurite elongation, and phosphatidylcholine (PtdCho) is the major membrane phospholipid in mammalian cells. The transcription of two genes in particular encoding key enzymes in the CDP-choline pathway for PtdCho biosynthesis are stimulated; the Chka gene for choline kinase (CK) alpha isoform and the Pcyt1a gene for the CTP:phosphocholine cytidylyltransferase (CCT) alpha isoform. We report that the stimulation of CKα expression during retinoic acid (RA) induced differentiation depends on a promoter region that contains two CCAAT/Enhancer-binding Protein-β (C/EBPβ) sites. We demonstrate that during neuronal differentiation of Neuro-2a cells, RA induces Chka expression by a mechanism that involves ERK1/2 activation which triggers C/EBPβ expression. Elevated levels of C/EBPβ bind to the Chka proximal promoter (Box1) inducing CKα expression. In addition we identified a downstream sequence named Box2 which together with Box1 is required for the promoter to reach the full induction. This is the first elucidation of the mechanism by which the expression of Chka is coordinately regulated during neuronal differentiation. PMID:24440820

  11. Visualization of retinoic acid signaling in transgenic axolotls during limb development and regeneration

    PubMed Central

    Monaghan, James R.; Maden, Malcolm

    2012-01-01

    Retinoic acid (RA) plays a necessary role in limb development and regeneration, but the precise mechanism by which it acts during these processes is unclear. The role of RA in limb regeneration was first highlighted by the remarkable effect that it has on respecifying the proximodistal axis of the regenerating limb so that serially repeated limbs are produced. To facilitate the study of RA signaling during development and then during regeneration of the same structure we have turned to the axolotl, the master of vertebrate regeneration, and generated transgenic animals that fluorescently report RA signaling in vivo. Characterization of these animals identified an anterior segment of the developing embryo where RA signaling occurs revealing conserved features of the early vertebrate embryo. During limb development RA signaling was present in the developing forelimb bud mesenchyme, but was not detected during hindlimb development. During limb regeneration, RA signaling was surprisingly almost exclusively observed in the apical epithelium suggesting a different role of RA during limb regeneration. After the addition of supplemental RA to regenerating limbs that leads to pattern duplications, the fibroblast stem cells of the blastema responded showing that they are capable of transcriptionally responding to RA. These findings are significant because it means that RA signaling may play a multifunctional role during forelimb development and regeneration and that the fibroblast stem cells that regulate proximodistal limb patterning during regeneration are targets of RA signaling. PMID:22627291

  12. Inhibition of retinoic acid catabolism by minocycline: evidence for a novel mode of action?

    PubMed

    Regen, Francesca; Hildebrand, Martin; Le Bret, Nathalie; Herzog, Irmelin; Heuser, Isabella; Hellmann-Regen, Julian

    2015-06-01

    Retinoic acid (RA) represents an essential and highly potent endogenous retinoid with pronounced anti-inflammatory properties and potent anti-acne activity, and has recently been suggested to share a common anti-inflammatory mode of action with tetracycline antibiotics. We hypothesized that tetracyclines may directly interfere with RA homeostasis via inhibition of its local cytochrome P450 (CYP450)-mediated degradation, an essential component of tightly regulated skin RA homeostasis. To test this hypothesis, we performed controlled in vitro RA metabolism assays using rat skin microsomes and measured RA levels in a RA-synthesizing human keratinocyte cell line, both in the presence and in the absence of minocycline, a tetracycline popular in acne treatment. Interestingly, minocycline potently blocked RA degradation in rat skin microsomes, and strikingly enhanced RA levels in RA-synthesizing cell cultures, in a dose-dependent manner. These findings indicate a potential role for CYP-450-mediated RA metabolism in minocycline's pleiotropic mode of action and anti-acne efficacy and could account for the overlap between minocycline and RA-induced effects at the level of their molecular mode of action, but also clinically at the level of the rare side effect of pseudotumor cerebri, which is observed for both, RA and minocycline treatment. PMID:25810318

  13. Physiological insights into all-trans-retinoic acid biosynthesis

    PubMed Central

    Napoli, Joseph L.

    2011-01-01

    All-trans-retinoic acid (atRA) provides essential support to diverse biological systems and physiological processes. Epithelial differentiation and its relationship to cancer and embryogenesis have typified intense areas of interest into atRA function. Recently, however, interest in atRA action in the nervous system, the immune system, energy balance and obesity has increased considerably, especially concerning postnatal function. atRA action depends on atRA biosynthesis: defects in retinoid-dependent processes increasingly relate to defects in atRA biogenesis. Considerable evidence indicates that physiological atRA biosynthesis occurs via a regulated process, consisting of a complex interaction of retinoid binding-proteins and retinoid recognizing enzymes. An accrual of biochemical, physiological and genetic data have identified specific functional outcomes for the retinol dehydrogenases, RDH1, RDH10, and DHRS9, as physiological catalysts of the first step in atRA biosynthesis, and for the retinal dehydrogenases RALDH1, RALDH2, and RALDH3, as catalysts of the second and irreversible step. Each of these enzymes associates with explicit biological processes mediated by atRA. Redundancy occurs, but seems limited. Cumulative data supports a model of interactions among these enzymes with retinoid binding-proteins, with feedback regulation and/or control by atRA via modulating gene expression of multiple participants. The ratio apo-CRBP1/holo-CRBP1 participates by influencing retinol flux into and out of storage as retinyl esters, thereby modulating substrate to support atRA biosynthesis. atRA biosynthesis requires presence of both an RDH and an RALDH: conversely, absence of one isozyme of either step does not indicate lack of atRA biosynthesis at the site. PMID:21621639

  14. Calcineurin mediates homeostatic synaptic plasticity by regulating retinoic acid synthesis

    PubMed Central

    Arendt, Kristin L.; Zhang, Zhenjie; Ganesan, Subhashree; Hintze, Maik; Shin, Maggie M.; Tang, Yitai; Cho, Ahryon; Graef, Isabella A.; Chen, Lu

    2015-01-01

    Homeostatic synaptic plasticity is a form of non-Hebbian plasticity that maintains stability of the network and fidelity for information processing in response to prolonged perturbation of network and synaptic activity. Prolonged blockade of synaptic activity decreases resting Ca2+ levels in neurons, thereby inducing retinoic acid (RA) synthesis and RA-dependent homeostatic synaptic plasticity; however, the signal transduction pathway that links reduced Ca2+-levels to RA synthesis remains unknown. Here we identify the Ca2+-dependent protein phosphatase calcineurin (CaN) as a key regulator for RA synthesis and homeostatic synaptic plasticity. Prolonged inhibition of CaN activity promotes RA synthesis in neurons, and leads to increased excitatory and decreased inhibitory synaptic transmission. These effects of CaN inhibitors on synaptic transmission are blocked by pharmacological inhibitors of RA synthesis or acute genetic deletion of the RA receptor RARα. Thus, CaN, acting upstream of RA, plays a critical role in gating RA signaling pathway in response to synaptic activity. Moreover, activity blockade-induced homeostatic synaptic plasticity is absent in CaN knockout neurons, demonstrating the essential role of CaN in RA-dependent homeostatic synaptic plasticity. Interestingly, in GluA1 S831A and S845A knockin mice, CaN inhibitor- and RA-induced regulation of synaptic transmission is intact, suggesting that phosphorylation of GluA1 C-terminal serine residues S831 and S845 is not required for CaN inhibitor- or RA-induced homeostatic synaptic plasticity. Thus, our study uncovers an unforeseen role of CaN in postsynaptic signaling, and defines CaN as the Ca2+-sensing signaling molecule that mediates RA-dependent homeostatic synaptic plasticity. PMID:26443861

  15. Calcineurin mediates homeostatic synaptic plasticity by regulating retinoic acid synthesis.

    PubMed

    Arendt, Kristin L; Zhang, Zhenjie; Ganesan, Subhashree; Hintze, Maik; Shin, Maggie M; Tang, Yitai; Cho, Ahryon; Graef, Isabella A; Chen, Lu

    2015-10-20

    Homeostatic synaptic plasticity is a form of non-Hebbian plasticity that maintains stability of the network and fidelity for information processing in response to prolonged perturbation of network and synaptic activity. Prolonged blockade of synaptic activity decreases resting Ca(2+) levels in neurons, thereby inducing retinoic acid (RA) synthesis and RA-dependent homeostatic synaptic plasticity; however, the signal transduction pathway that links reduced Ca(2+)-levels to RA synthesis remains unknown. Here we identify the Ca(2+)-dependent protein phosphatase calcineurin (CaN) as a key regulator for RA synthesis and homeostatic synaptic plasticity. Prolonged inhibition of CaN activity promotes RA synthesis in neurons, and leads to increased excitatory and decreased inhibitory synaptic transmission. These effects of CaN inhibitors on synaptic transmission are blocked by pharmacological inhibitors of RA synthesis or acute genetic deletion of the RA receptor RARα. Thus, CaN, acting upstream of RA, plays a critical role in gating RA signaling pathway in response to synaptic activity. Moreover, activity blockade-induced homeostatic synaptic plasticity is absent in CaN knockout neurons, demonstrating the essential role of CaN in RA-dependent homeostatic synaptic plasticity. Interestingly, in GluA1 S831A and S845A knockin mice, CaN inhibitor- and RA-induced regulation of synaptic transmission is intact, suggesting that phosphorylation of GluA1 C-terminal serine residues S831 and S845 is not required for CaN inhibitor- or RA-induced homeostatic synaptic plasticity. Thus, our study uncovers an unforeseen role of CaN in postsynaptic signaling, and defines CaN as the Ca(2+)-sensing signaling molecule that mediates RA-dependent homeostatic synaptic plasticity. PMID:26443861

  16. 76 FR 63701 - Culturally Significant Objects Imported for Exhibition Determinations: “Johan Zoffany RA: Society...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-10-13

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF STATE Culturally Significant Objects Imported for Exhibition Determinations: ``Johan Zoffany RA: Society Observed... determine that the objects to be included in the exhibition ``Johan Zoffany RA: Society Observed,''...

  17. The ability of Helianthus annuus L. and Brassica juncea to uptake and translocate natural uranium and 226Ra under different milieu conditions.

    PubMed

    Vera Tomé, F; Blanco Rodríguez, P; Lozano, J C

    2009-01-01

    Seedlings of Helianthus annuus L. (HA) and Brassica juncea (BJ) were used to test the effect of the pH, the presence of phosphates, and the addition of ethylene-diamine-tetraacetic acid (EDTA) or citrate on the uptake and the translocation of uranium isotopes ((238)U, (235)U, and (234)U) and (226)Ra. The results indicated that the presence of phosphates generally reduces the uptake and transfer of uranium from the roots to the shoots of HA. In the case of BJ, while phosphate enhanced the retention of uranium by roots, the translocation was poorer. Likewise, for (226)Ra, the best translocation was in the absence of phosphates for both species. The addition of citrate increased the translocation of uranium for both species, but had no clear effect on the transfer of (226)Ra. The effect of EDTA was much more moderate both for uranium and for (226)Ra, and for both plant species. Only noticeable was a slightly better uptake of (226)Ra by BJ at neutral pH, although the translocation was lower. PMID:18848715

  18. Fast electric dipole transitions in Ra-Ac nuclei

    SciTech Connect

    Ahmad, I.

    1985-01-01

    Lifetime of levels in /sup 225/Ra, /sup 225/Ac, and /sup 227/Ac have been measured by delayed coincidence techniques and these have been used to determine the E1 gamma-ray transition probabilities. The reduced E1 transition probabilities. The reduced E1 transition probabilities in /sup 225/Ra and /sup 225/Ac are about two orders of magnitude larger than the values in mid-actinide nuclei. On the other hand, the E1 rate in /sup 227/Ac is similar to those measured in heavier actinides. Previous studies suggest the presence of octupole deformation in all the three nuclei. The present investigation indicates that fast E1 transitions occur for nuclei with octupole deformation. However, the studies also show that there is no one-to-one correspondence between E1 rate and octupole deformation. 13 refs., 4 figs.

  19. Protective effect of rosmarinic acid against oxidative stress biomarkers in liver and kidney of strepotozotocin-induced diabetic rats.

    PubMed

    Mushtaq, Nadia; Schmatz, Roberta; Ahmed, Mushtaq; Pereira, Luciane Belmonte; da Costa, Pauline; Reichert, Karine Paula; Dalenogare, Diéssica; Pelinson, Luana Paula; Vieira, Juliano Marchi; Stefanello, Naiara; de Oliveira, Lizielle Souza; Mulinacci, Nadia; Bellumori, Maria; Morsch, Vera Maria; Schetinger, Maria Rosa

    2015-12-01

    In the present study, we investigated the efficiency of rosmarinic acid (RA) in preventing the alteration of oxidative parameters in the liver and kidney of diabetic rats induced by streptozotocin (STZ). The animals were divided into six groups (n = 8): control, ethanol, RA 10 mg/kg, diabetic, diabetic/ethanol, and diabetic/RA 10 mg/kg. After 3 weeks of treatment, we found that TBARS levels in liver and kidney were significantly increased in the diabetic/saline group and the administration of RA prevented this increase in the liver and kidney (P < 0.05). Diabetes caused a significant decrease in the activity of superoxide dismutase (SOD) and catalase (CAT) in the diabetes/saline group (P < 0.05). However, the treatment with 10 mg/kg RA (antioxidant) prevented this alteration in SOD and CAT activity in the diabetic RA group (P < 0.05). In addition, RA reverses the decrease in ascorbic acid and non-protein-thiol (NPSH) levels in diabetic rats. The treatment with RA also prevented the decrease in the Delta-aminolevulinic acid dehydratase (ALA-D) activity in the liver and kidney of diabetic rats. Furthermore, RA did not have any effect on glycemic levels. These results indicate that RA effectively reduced the oxidative stress induced by STZ, suggesting that RA is a potential candidate for the prevention and treatment of pathological conditions in diabetic models. PMID:26452500

  20. AXIAL SKELETAL AND HOX EXPRESSION DOMAIN ALTERATIONS INDUCED BY RETINOIC ACID, VALPROIC ACID AND BROMOXYNIL DURING MURINE DEVELOPMENT

    EPA Science Inventory

    ABSTRACT

    Retinoic acid (RA) alters the developmental fate of the axial skeletal anlage. "Anteriorizations" or "posteriorizations", the assumption of characteristics of embryonic areas normally anterior or posterior to the affected tissues, are correlated with altered emb...

  1. Composition and Antioxidant Activity of Geopropolis Collected by Melipona subnitida (Jandaíra) Bees

    PubMed Central

    Alves de Souza, Silvana; Camara, Celso Amorim; Monica Sarmento da Silva, Eva; Silva, Tania Maria Sarmento

    2013-01-01

    An investigation of the geopropolis collected by Melipona subnitida (jandaíra) stingless bee led to the isolation and characterization of two phenylpropanoids, 6-O-p-coumaroyl-D-galactopyranose (1) and 6-O-cinnamoyl-1-O-p-coumaroyl-β-D-glucopyranose (2), and seven flavonoids, 7-O-methyl-naringenin (3), 7-O-methyl aromadendrin (4), 7,4′-di-O-methyl aromadendrin (5), 4′-O-methyl kaempferol (6), 3-O-methyl quercetin (7), 5-O-methyl aromadendrin (8), and 5-O-methyl kaempferol (9). The structure of the new phenylpropanoid (1) was established from IR, LC-ESI-MS, and NMR spectral data, including 2D NMR experiments. The extract and fractions demonstrated significant antioxidant activity in DPPH, ABTS, and β-carotene/linoleic acid tests. PMID:23935683

  2. Composition and Antioxidant Activity of Geopropolis Collected by Melipona subnitida (Jandaíra) Bees.

    PubMed

    Alves de Souza, Silvana; Camara, Celso Amorim; Monica Sarmento da Silva, Eva; Silva, Tania Maria Sarmento

    2013-01-01

    An investigation of the geopropolis collected by Melipona subnitida (jandaíra) stingless bee led to the isolation and characterization of two phenylpropanoids, 6-O-p-coumaroyl-D-galactopyranose (1) and 6-O-cinnamoyl-1-O-p-coumaroyl- β -D-glucopyranose (2), and seven flavonoids, 7-O-methyl-naringenin (3), 7-O-methyl aromadendrin (4), 7,4'-di-O-methyl aromadendrin (5), 4'-O-methyl kaempferol (6), 3-O-methyl quercetin (7), 5-O-methyl aromadendrin (8), and 5-O-methyl kaempferol (9). The structure of the new phenylpropanoid (1) was established from IR, LC-ESI-MS, and NMR spectral data, including 2D NMR experiments. The extract and fractions demonstrated significant antioxidant activity in DPPH, ABTS, and β -carotene/linoleic acid tests. PMID:23935683

  3. An improved limit on the EDM of 225 Ra

    NASA Astrophysics Data System (ADS)

    Bishof, Michael; Bailey, Kevin; Dietrich, Matthew R.; Greene, John P.; Holt, Roy J.; Kalita, Mukut R.; Korsch, Wolfgang; Lemke, Nathan D.; Lu, Zheng-Tian; Mueller, Peter; O'Connor, Thomas P.; Parker, Richard H.; Rabga, Tenzin; Singh, Jaideep T.

    2016-05-01

    Searches for permanent electric dipole moments (EDMs) are sensitive probes of symmetry violation that could explain the dominance of matter over anti-matter. The 225 Ra (t1/2 = 15 days, I = 1/2) atom is a particularly attractive system to use for an EDM measurement because its octupole-deformed nucleus, closely spaced ground-state parity doublet, and large nuclear charge make 225 Ra uniquely sensitive to symmetry-violating interactions in the nuclear medium. In 2015, we reported the first ``proof of principle'' measurement of the 225 Ra EDM, giving a 95% confidence upper limit of 5* 10-22 e-cm; representing the first EDM measurement using laser-trapped atoms as well as the first EDM measurement of an atom with an octupole-deformed nucleus. After implementing upgrades to our apparatus, we now observe nuclear spin coherence after 20 s of free evolution - a factor of ten improvement. A new EDM measurement based on the upgraded system improved the 95% confidence upper limit by a factor of 36. We also report on the progress of current experimental upgrades that have the potential to further improve our EDM sensitivity by many orders of magnitude, allowing us to test symmetry violation at an unprecedented level. This work is supported by U.S. DOE, Office of Science, Office of Nuclear Physics, under Contract DE-AC02-06CH11357.

  4. Search for a Permanent Electric Dipole Moment of 225Ra

    NASA Astrophysics Data System (ADS)

    Kalita, Mukut Ranjan

    The observation of a permanent electric dipole moment (EDM) in a non-degenerate system would indicate the violation of discrete symmetries of Time reversal (T) or combined application of Charge (C) and Parity (P) symmetry violation through the CPT theorem. The diamagnetic 225Ra atom with nuclear spin I=1/2 is a favorable candidate for an EDM search. Experimental sensitivity to its EDM is enhanced due to its high atomic mass and the increased Schiff moment of its octupole deformed nucleus. An experimental setup is developed where laser cooled neutral radium atoms are collected in a magneto-optical trap (MOT). The collected atoms are transported 1 meter with a far off-resonant optical dipole trap (ODT) and then the atoms are transferred to a second standing-wave ODT in an experimental chamber. The atoms are then optically polarized and allowed to Larmor precess in parallel and antiparallel electric and magnetic fields. The difference between the Larmor precession frequency for parallel and antiparallel fields is experimentally determined to measure the EDM. This thesis is about the first measurement of the EDM of the 225Ra atom where an upper limit of |d(225Ra)| < 5.0 x 10-22 e·cm (95% confidence) is reached. Keywords: Permanent EDM, CP violation, laser cooling and trapping, rare isotopes, radium.

  5. Modulation of human stratum corneum properties by salicylic acid and all-trans-retinoic acid.

    PubMed

    Piérard-Franchimont, C; Goffin, V; Piérard, G E

    1998-01-01

    Topical all-trans-retinoic acid (RA) has been reported to decrease the in vivo skin response to sodium lauryl sulfate (SLS). The converse was also shown with a synergistic effect of RA following prior applications of SLS. The reason for such effects is not clear. We employed measures of transepidermal water loss (TEWL), squamometry and sequential corneosurfametry to explore the protective activity of a 0.05% RA cream at the level of the stratum corneum. Nonionic oil-in-water emulsions with or without 5% salicylic acid (SA) served as test product references. Data indicated that the RA formulation was responsible for a stochastic impairment in the TEWL and for an increased intercorneocyte cohesion. SA and the unmedicated emulsion did not lead to similar TEWL changes. The squamometry test proved to be very sensitive to disclose the effects of SA and RA without, however, allowing to distinguish the difference in the physiological processes involved. The corneosurfametry bioassay did not show any protection or synergistic effect between RA or SA and SLS challenge on the stratum corneum. This is in contrast to a previous work showing a positive protective effect afforded by retinol against SLS. The combined effects of irritant compounds affecting the stratum corneum are complex. The precise reason for some of their biological consequences remains a conundrum. On balance, products such as SA and RA do not appear to afford protection or impairment to a surfactant challenge at the level of the stratum corneum. PMID:9885411

  6. The Effect of Stopping Smoking on Disease Activity in Rheumatoid Arthritis (RA). Data from BARFOT, a Multicenter Study of Early RA

    PubMed Central

    Andersson, Maria LE; Bergman, Stefan; Söderlin, Maria K

    2012-01-01

    Objective: We studied the effect of stopping smoking on disease activity in patients with RA. Methods: Between 1992 and 2005, 2,800 adult patients were included in the BARFOT early RA study in Sweden. Disease Activity Score 28 joints (DAS28), C-reactive protein (CRP), Health Assessment Questionnaire (HAQ), rheumatoid factor (RF), anti-CCP, general health and pain visual analog scales (VAS), EULAR response and treatment were registered at inclusion and at follow-up 2, 5 and 8 years. In 2010, a self-completion postal questionnaire was sent to 2,102 patients, enquiring about lifestyle factors, including cessation of smoking. Results: A total of 1,460 adult RA patients with disease duration ≤2 years were included in this study. Seventeen percent smoked in 2010. In total, 127 patients stopped smoking after inclusion in the study. Smoking cessation after inclusion in the study was negatively associated with EULAR good outcome at 8 years (OR 0.44, 95% CI 0.22–0.86, p=0.02), controlled for age, disease duration, sex, socioeconomic class, smoking status, RF, and DAS28 at inclusion. Conclusion: Seventeen percent of the RA patients smoked in 2010 in this large Swedish RA cohort. Stopping smoking after onset of RA did not change the poor prognosis of smokers with RA, but all RA patients need to stop smoking because of the high risk of cardiovascular mortality and morbidity and the association of smoking with vasculitis and noduli in RA. PMID:23115602

  7. PI3K/AKT and ERK regulate retinoic acid-induced neuroblastoma cellular differentiation

    SciTech Connect

    Qiao, Jingbo; Paul, Pritha; Lee, Sora; Qiao, Lan; Josifi, Erlena; Tiao, Joshua R.; Chung, Dai H.

    2012-08-03

    Highlights: Black-Right-Pointing-Pointer Retinoic acid (RA) induces neuroblastoma cells differentiation, which is accompanied by G0/G1 cell cycle arrest. Black-Right-Pointing-Pointer RA resulted in neuroblastoma cell survival and inhibition of DNA fragmentation; this is regulated by PI3K pathway. Black-Right-Pointing-Pointer RA activates PI3K and ERK1/2 pathway; PI3K pathway mediates RA-induced neuroblastoma cell differentiation. Black-Right-Pointing-Pointer Upregulation of p21 is necessary for RA-induced neuroblastoma cell differentiation. -- Abstract: Neuroblastoma, the most common extra-cranial solid tumor in infants and children, is characterized by a high rate of spontaneous remissions in infancy. Retinoic acid (RA) has been known to induce neuroblastoma differentiation; however, the molecular mechanisms and signaling pathways that are responsible for RA-mediated neuroblastoma cell differentiation remain unclear. Here, we sought to determine the cell signaling processes involved in RA-induced cellular differentiation. Upon RA administration, human neuroblastoma cell lines, SK-N-SH and BE(2)-C, demonstrated neurite extensions, which is an indicator of neuronal cell differentiation. Moreover, cell cycle arrest occurred in G1/G0 phase. The protein levels of cyclin-dependent kinase inhibitors, p21 and p27{sup Kip}, which inhibit cell proliferation by blocking cell cycle progression at G1/S phase, increased after RA treatment. Interestingly, RA promoted cell survival during the differentiation process, hence suggesting a potential mechanism for neuroblastoma resistance to RA therapy. Importantly, we found that the PI3K/AKT pathway is required for RA-induced neuroblastoma cell differentiation. Our results elucidated the molecular mechanism of RA-induced neuroblastoma cellular differentiation, which may be important for developing novel therapeutic strategy against poorly differentiated neuroblastoma.

  8. Bone-seeking radiopharmaceuticals for treatment of osseous metastases, Part 1: α therapy with 223Ra-dichloride.

    PubMed

    Pandit-Taskar, Neeta; Larson, Steven M; Carrasquillo, Jorge A

    2014-02-01

    Metastatic disease to bone is commonly seen in the advanced stages of many cancers. The cardinal symptom, pain, is often the cause of significant morbidity and reduced quality of life. Treatment of bone pain includes nonsteroidal analgesics and opiates; however, long-term use of these drugs is commonly associated with significant side effects, and tolerance is common. External-beam radiation therapy is effective mainly in localized disease sites. Bone-targeting radiopharmaceuticals are beneficial in the management of patients with multiple metastatic lesions. This article focuses on the 3 most commonly used agents: the Food and Drug Administration-approved (89)Sr-chloride, (153)Sm-ethylenediaminetetramethylene phosphonic acid (EDTMP), and (223)Ra-dichloride. We will discuss the physical characteristics, clinical data, dosage, and administration of these agents, including optimal patient selection and toxicity associated with their use. These radioactive agents have proven efficacy in the treatment of painful osseous metastases from prostate cancer and breast cancer. Significant recent advances include use of these agents in combination with chemotherapy and the use of the α emitter (223)Ra-dichloride in prostate cancer, primarily to improve survival and skeletal related events. The review is presented in 2 parts. The first will discuss the characteristics and clinical use of (223)Ra-dichloride, and the second will discuss the β emitters (89)Sr and (153)Sm-EDTMP. PMID:24343987

  9. MRA_1571 is required for isoleucine biosynthesis and improves Mycobacterium tuberculosis H37Ra survival under stress

    PubMed Central

    Sharma, Rishabh; Keshari, Deepa; Singh, Kumar Sachin; Yadav, Shailendra; Singh, Sudheer Kumar

    2016-01-01

    Threonine dehydratase is a pyridoxal 5-phosphate dependent enzyme required for isoleucine biosynthesis. Threonine dehydratase (IlvA) participates in conversion of threonine to 2-oxobutanoate and ammonia is released as a by-product. MRA_1571 is annotated to be coding for IlvA in Mycobacterium tuberculosis H37Ra (Mtb-Ra). We developed a recombinant (KD) Mtb-Ra strain by down-regulating IlvA. The growth studies on different carbon sources suggested reduced growth of KD compared to wild-type (WT), also, isoleucine concentration dependent KD growth restoration was observed. The expression profiling of IlvA suggested increased expression of IlvA during oxygen, acid and oxidative stress. In addition, KD showed reduced survival under pH, starvation, nitric oxide and peroxide stresses. KD was more susceptible to antimycobacterial agents such as streptomycin (STR), rifampicin (RIF) and levofloxacin (LVF), while, no such effect was noticeable when exposed to isoniazid. Also, an increase in expression of IlvA was observed when exposed to STR, RIF and LVF. The dye accumulation studies suggested increased permeability of KD to ethidium bromide and Nile Red as compared to WT. TLC and Mass studies confirmed altered lipid profile of KD. In summary down-regulation of IlvA affects Mtb growth, increases its susceptibility to stress and leads to altered cell wall lipid profile. PMID:27353854

  10. Retinoic Acid-mediated Nuclear Receptor Activation and Hepatocyte Proliferation

    PubMed Central

    Bushue, Nathan; Wan, Yu-Jui Yvonne

    2016-01-01

    Due to their well-known differentiation and apoptosis-inducing abilities, retinoic acid (RA) and its analogs have strong anti-cancer efficacy in human cancers. However, in vivo RA is a liver mitogen. While speculation has persisted that RA-mediated signaling is likely involved in hepatocyte proliferation during liver regeneration, direct evidence is still required. Findings in support of this proposition include observations that a release of retinyl palmitate (the precursor of RA) occurs in liver stellate cells following liver injury. Nevertheless, the biological action of this released vitamin A is virtually unknown. More likely is that the released vitamin A is converted to RA, the biological form, and then bound to a specific receptor (retinoid x receptor; RXRα), which is most abundantly expressed in the liver. Considering the mitogenic effects of RA, the RA-activated RXRα would likely then influence hepatocyte proliferation and liver tissue repair. At present, the mechanism by which RA stimulates hepatocyte proliferation is largely unknown. This review summarizes the activation of nuclear receptors (peroxisome proliferator activated receptor-α, pregnane x receptor, constitutive androstane receptor, and farnesoid x receptor) in an RXRα dependent manner to induce hepatocyte proliferation, providing a link between RA and its proliferative role.

  11. Organ- and species-specific biological activity of rosmarinic acid.

    PubMed

    Iswandana, R; Pham, B T; van Haaften, W T; Luangmonkong, T; Oosterhuis, D; Mutsaers, H A M; Olinga, P

    2016-04-01

    Rosmarinic acid (RA), a compound found in several plant species, has beneficial properties, including anti-inflammatory and antibacterial effects. We investigated the toxicity, anti-inflammatory, and antifibrotic effects of RA using precision-cut liver slices (PCLS) and precision-cut intestinal slices (PCIS) prepared from human, mouse, and rat tissue. PCLS and PCIS were cultured up to 48h in the absence or presence of RA. Gene expression of the inflammatory markers: IL-6, IL-8/CXCL1/KC, and IL-1β, as well as the fibrosis markers: pro-collagen 1a1, heat shock protein 47, α-smooth muscle actin, fibronectin (Fn2) and plasminogen activator inhibitor-1 (PAI-1) were evaluated by qPCR. RA was only toxic in murine PCIS. RA failed to mitigate the inflammatory response in most models, while it clearly reduced IL-6 and CXCL1/KC gene expression in murine PCIS at non-toxic concentrations. With regard to fibrosis, RA decreased the gene levels of Fn2 and PAI-1 in murine PCLS, and Fn2 in murine PCIS. Yet, no effect was observed on the gene expression of fibrosis markers in human and rat PCIS. In conclusion, we observed clear organ- and species-specific effects of RA. RA had little influence on inflammation. However, our study further establishes RA as a potential candidate for the treatment of liver fibrosis. PMID:26804033

  12. Ethanol Effects On Physiological Retinoic Acid Levels

    PubMed Central

    Napoli, Joseph L.

    2011-01-01

    Summary All-trans-retinoic acid (atRA) serves essential functions during embryogenesis and throughout post-natal vertebrate life. Insufficient or excess atRA causes teratogenic and/or toxic effects in the developing embryo: interference with atRA biosynthesis or signaling likely underlies some forms of cancer. Many symptoms of vitamin A (atRA precursor) deficiency and/or toxicity overlap with those of another pleiotropic agent—ethanol. These overlapping symptoms have prompted research to understand whether interference with atRA biosynthesis and/or action may explain (in part) pathology associated with excess ethanol consumption. Ethanol affects many aspects of retinoid metabolism and mechanisms of action site-specifically, but no robust data support inhibition of vitamin A metabolism, resulting in decreased atRA in vivo during normal vitamin A nutriture. Actually, ethanol either has no effect on or increases atRA at select sites. Despite this realization, insight into whether interactions between ethanol and retinoids represent cause vs. effect requires additional research. PMID:21766417

  13. Retinoic acid expands the evolutionarily reduced dentition of zebrafish

    PubMed Central

    Seritrakul, Pawat; Samarut, Eric; Lama, Tenzing T. S.; Gibert, Yann; Laudet, Vincent; Jackman, William R.

    2012-01-01

    Zebrafish lost anterior teeth during evolution but retain a posterior pharyngeal dentition that requires retinoic acid (RA) cell-cell signaling for its development. The purposes of this study were to test the sufficiency of RA to induce tooth development and to assess its role in evolution. We found that exposure of embryos to exogenous RA induces a dramatic anterior expansion of the number of pharyngeal teeth that later form and shifts anteriorly the expression patterns of genes normally expressed in the posterior tooth-forming region, such as pitx2 and dlx2b. After RA exposure, we also observed a correlation between cartilage malformations and ectopic tooth induction, as well as abnormal cranial neural crest marker gene expression. Additionally, we observed that the RA-induced zebrafish anterior teeth resemble in pattern and number the dentition of fish species that retain anterior pharyngeal teeth such as medaka but that medaka do not express the aldh1a2 RA-synthesizing enzyme in tooth-forming regions. We conclude that RA is sufficient to induce anterior ectopic tooth development in zebrafish where teeth were lost in evolution, potentially by altering neural crest cell development, and that changes in the location of RA synthesis correlate with evolutionary changes in vertebrate dentitions.—Seritrakul, P., Samarut, E., Lama, T. T. S., Gibert, Y., Laudet, V., Jackman, W. R. Retinoic acid expands the evolutionarily reduced dentition of zebrafish. PMID:22942074

  14. Spatiotemporal manipulation of retinoic acid activity in zebrafish hindbrain development via photo-isomerization.

    PubMed

    Xu, Lijun; Feng, Zhiping; Sinha, Deepak; Ducos, Bertrand; Ebenstein, Yuval; Tadmor, Arbel D; Gauron, Carole; Le Saux, Thomas; Lin, Shuo; Weiss, Shimon; Vriz, Sophie; Jullien, Ludovic; Bensimon, David

    2012-09-01

    All-trans retinoic acid (RA) is a key player in many developmental pathways. Most methods used to study its effects in development involve continuous all-trans RA activation by incubation in a solution of all-trans RA or by implanting all-trans RA-soaked beads at desired locations in the embryo. Here we show that the UV-driven photo-isomerization of 13-cis RA to the trans-isomer (and vice versa) can be used to non-invasively and quantitatively control the concentration of all-trans RA in a developing embryo in time and space. This facilitates the global or local perturbation of developmental pathways with a pulse of all-trans RA of known concentration or its inactivation by UV illumination. In zebrafish embryos in which endogenous synthesis of all-trans RA is impaired, incubation for as little as 5 minutes in 1 nM all-trans RA (a pulse) or 5 nM 13-cis RA followed by 1-minute UV illumination is sufficient to rescue the development of the hindbrain if performed no later than bud stage. However, if subsequent to this all-trans RA pulse the embryo is illuminated (no later than bud stage) for 1 minute with UV light (to isomerize, i.e. deactivate, all-trans RA), the rescue of hindbrain development is impaired. This suggests that all-trans RA is sequestered in embryos that have been transiently exposed to it. Using 13-cis RA isomerization with UV light, we further show that local illumination at bud stage of the head region (but not the tail) is sufficient to rescue hindbrain formation in embryos whose all-trans RA synthetic pathway has been impaired. PMID:22874920

  15. Redox control of retinoic acid receptor activity: a novel mechanism for retinoic acid resistance in melanoma cells.

    PubMed

    Demary, K; Wong, L; Liou, J S; Faller, D V; Spanjaard, R A

    2001-06-01

    Retinoic acid (RA) slows growth and induces differentiation of tumor cells through activation of RA receptors (RARs). However, melanoma cell lines display highly variable responsiveness to RA, which is a poorly understood phenomenon. By using Northern and Western blot analyses, we show that RA-resistant A375 and RA-responsive S91 melanoma cells express comparable levels of major components of RAR-signaling pathways. However, A375 cells have substantially higher intracellular reactive oxygen species (ROS) levels than S91 cells. Lowering ROS levels in A375 cells through hypoxic culture conditions restores RAR-dependent trans-activity, which could be further enhanced by addition of the antioxidant N-acetyl-cysteine. Hypoxia also enhances RAR activity in the moderately RA-responsive C32 cells, which have intermediate ROS levels. Conversely, increasing oxidative stress in highly RA-responsive S91 and B16 cells, which have low ROS levels, by treatment with H(2)O(2) impairs RAR activity. Consistent with these observations, RA more potently inhibited the proliferation of hypoxic A375 cells than that of normoxic cells. Oxidative states diminish, whereas reducing conditions enhance, DNA binding of retinoid X receptor/RAR heterodimers in vitro, providing a molecular basis for the observed inverse correlation between RAR activity and ROS levels. The redox state of melanoma cells provides a novel, epigenetic control mechanism of RAR activity and RA resistance. PMID:11356710

  16. Cutaneous retinoic acid levels determine hair follicle development and downgrowth.

    PubMed

    Okano, Junko; Levy, Clara; Lichti, Ulrike; Sun, Hong-Wei; Yuspa, Stuart H; Sakai, Yasuo; Morasso, Maria I

    2012-11-16

    Retinoic acid (RA) is essential during embryogenesis and for tissue homeostasis, whereas excess RA is well known as a teratogen. In humans, excess RA is associated with hair loss. In the present study, we demonstrate that specific levels of RA, regulated by Cyp26b1, one of the RA-degrading enzymes, are required for hair follicle (hf) morphogenesis. Mice with embryonic ablation of Cyp26b1 (Cyp26b1(-/-)) have excessive endogenous RA, resulting in arrest of hf growth at the hair germ stage. The altered hf development is rescued by grafting the mutant skin on immunodeficient mice. Our results show that normalization of RA levels is associated with reinitiation of hf development. Conditional deficiency of Cyp26b1 in the dermis (En1Cre;Cyp26b1f/-) results in decreased hair follicle density and specific effect on hair type, indicating that RA levels also influence regulators of hair bending. Our results support the model of RA-dependent dermal signals regulating hf downgrowth and bending. To elucidate target gene pathways of RA, we performed microarray and RNA-Seq profiling of genes differentially expressed in Cyp26b1(-/-) skin and En1Cre;Cyp26b1f/- tissues. We show specific effects on the Wnt-catenin pathway and on members of the Runx, Fox, and Sox transcription factor families, indicating that RA modulates pathways and factors implicated in hf downgrowth and bending. Our results establish that proper RA distribution is essential for morphogenesis, development, and differentiation of hfs. PMID:23007396

  17. Cutaneous Retinoic Acid Levels Determine Hair Follicle Development and Downgrowth*

    PubMed Central

    Okano, Junko; Levy, Clara; Lichti, Ulrike; Sun, Hong-Wei; Yuspa, Stuart H.; Sakai, Yasuo; Morasso, Maria I.

    2012-01-01

    Retinoic acid (RA) is essential during embryogenesis and for tissue homeostasis, whereas excess RA is well known as a teratogen. In humans, excess RA is associated with hair loss. In the present study, we demonstrate that specific levels of RA, regulated by Cyp26b1, one of the RA-degrading enzymes, are required for hair follicle (hf) morphogenesis. Mice with embryonic ablation of Cyp26b1 (Cyp26b1−/−) have excessive endogenous RA, resulting in arrest of hf growth at the hair germ stage. The altered hf development is rescued by grafting the mutant skin on immunodeficient mice. Our results show that normalization of RA levels is associated with reinitiation of hf development. Conditional deficiency of Cyp26b1 in the dermis (En1Cre;Cyp26b1f/−) results in decreased hair follicle density and specific effect on hair type, indicating that RA levels also influence regulators of hair bending. Our results support the model of RA-dependent dermal signals regulating hf downgrowth and bending. To elucidate target gene pathways of RA, we performed microarray and RNA-Seq profiling of genes differentially expressed in Cyp26b1−/− skin and En1Cre;Cyp26b1f/− tissues. We show specific effects on the Wnt-catenin pathway and on members of the Runx, Fox, and Sox transcription factor families, indicating that RA modulates pathways and factors implicated in hf downgrowth and bending. Our results establish that proper RA distribution is essential for morphogenesis, development, and differentiation of hfs. PMID:23007396

  18. Distinct binding determinants for 9-cis retinoic acid are located within AF-2 of retinoic acid receptor alpha.

    PubMed Central

    Tate, B F; Allenby, G; Janocha, R; Kazmer, S; Speck, J; Sturzenbecker, L J; Abarzúa, P; Levin, A A; Grippo, J F

    1994-01-01

    Retinoids exert their physiological action by interacting with two families of nuclear receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), which regulate gene expression by forming transcriptionally active heterodimeric RAR/RXR or homodimeric RXR/RXR complexes on DNA. Retinoid receptor activity resides in several regions, including the DNA and ligand binding domains, a dimerization interface, and both a ligand-independent (AF-1) and a ligand-dependent (AF-2) transactivation function. While 9-cis retinoic acid (RA) alone is the cognate ligand for the RXRs, both 9-cis RA and all-trans RA (t-RA) compete for binding with high affinity to the RARs. This latter observation suggested to us that the two isomers may interact with a common binding site. Here we report that RAR alpha has two distinct but overlapping binding sites for 9-cis RA and t-RA. Truncation of a human RAR alpha to 419 amino acids yields a receptor that binds both t-RA and 9-cis RA with high affinity, but truncation to amino acid 404 yields a mutant receptor that binds only t-RA with high affinity. Remarkably, this region also defines a C-terminal boundary for AF-2, as addition of amino acids 405 to 419 restores receptor-mediated gene activity to a truncated human RAR alpha lacking this region. It is interesting to speculate that binding of retinoid stereoisomers to unique sites within an RAR may function with AF-2 to cause differential activation of retinoid-responsive gene pathways. Images PMID:8139538

  19. Direct photoaffinity labeling of cellular retinoic acid-binding protein I (CRABP-I) with all-trans-retinoic acid: identification of amino acids in the ligand binding site.

    PubMed

    Chen, G; Radominska-Pandya, A

    2000-10-17

    Cellular retinoic acid-binding proteins I and II (CRABP-I and -II, respectively) are transport proteins for all-trans-retinoic acid (RA), an active metabolite of vitamin A (retinol), and have been reported to be directly involved in the metabolism of RA. In this study, direct photoaffinity labeling with [11,12-(3)H]RA was used to identify amino acids comprising the ligand binding site of CRABP-I. Photoaffinity labeling of CRABP-I with [(3)H]RA was light- and concentration-dependent and was protected by unlabeled RA and various retinoids, indicating that the labeling was directed to the RA-binding site. Photolabeled CRABP-I was hydrolyzed with endoproteinase Lys-C to yield radioactive peptides, which were separated by reversed-phase HPLC for analysis by Edman degradation peptide sequencing. This method identified five modified amino acids from five separate HPLC fractions: Trp7, Lys20, Arg29, Lys38, and Trp109. All five amino acids are located within one side of the "barrel" structure in the area indicated by the reported crystal structure as the ligand binding site. This is the first direct identification of specific amino acids in the RA-binding site of CRABPs by photoaffinity labeling. These results provide significant information about the ligand binding site of the CRABP-I molecule in solution. PMID:11027136

  20. 226Ra or 226Ra/Ba dating of Holocene volcanic rocks: application to Mt. Etna and Merapi volcanoes

    NASA Astrophysics Data System (ADS)

    Condomines, M.; Gauthier, P. J.; Tanguy, J. C.; Gertisser, R.; Thouret, J. C.; Berthommier, P.; Camus, G.

    2005-02-01

    This paper shows how 226Ra- 230Th disequilibria can be used to date Holocene volcanic rocks from some well selected volcanoes. A systematic study of these disequilibria on historical or well-dated volcanic samples is indeed first required to test the applicability of this method. Two examples are described here to illustrate its potential. In the case of Mt. Etna, the good correlation observed between ( 226Ra) 0 activities at the time of eruption and Th contents in lava flows from the last two millennia [M. Condomines, J.C. Tanguy, V. Michaud, Magma dynamics at Mt. Etna: constraints from U-Th-Ra-Pb radioactive disequilibria and Sr isotopes in historical lavas, Earth Planet. Sci. Lett. 132 (1995) 25-41] is used to infer the ages of several newly analysed lava flows. The calculated ages are in good agreement with those deduced from the archaeomagnetic curve describing the variation of the geomagnetic field direction in southern Italy [J.C. Tanguy, I. Bucur, J.F.C. Thompson, Geomagnetic secular variation in Sicily and revised ages of historic lavas from Mt. Etna, Nature 318 (1985) 453-455, J.C. Tanguy, M. Le Goff, V. Chillemi, A. Paiotti, C. Principe, S. La Delfa, G. Patane, Variation séculaire de la direction du champ géomagnétique enregistrée par les laves de l'Etna et du Vésuve pendant les deux derniers millénaires, C. R. Acad. Sci. Paris 329 (1999) 557-564, J.C. Tanguy, M. Le Goff, C. Principe, S. Arrighi, V. Chillemi, A. Paiotti, S. La Delfa, G. Patane, Archaeomagnetic dating of Mediterranean volcanics of the last 2100 years: validity and limits. Earth Planet. Sci. Lett. 211 (2003) 111-124]. We also present a whole set of new U-series data on historical, recent, and older samples from Merapi (Indonesia), and show that the ( 226Ra)/Ba ratio has probably maintained a quasi-steady state value during at least the past four millennia, and can be used to infer the ( 226Ra) 0/Ba ratio of old volcanics at the time of eruption, and thus their ages. Comparison with

  1. All-Trans-Retinoic Acid Enhances Mitochondrial Function in Models of Human Liver.

    PubMed

    Tripathy, Sasmita; Chapman, John D; Han, Chang Y; Hogarth, Cathryn A; Arnold, Samuel L M; Onken, Jennifer; Kent, Travis; Goodlett, David R; Isoherranen, Nina

    2016-05-01

    All-trans-retinoic acid (atRA) is the active metabolite of vitamin A. The liver is the main storage organ of vitamin A, but activation of the retinoic acid receptors (RARs) in mouse liver and in human liver cell lines has also been shown. AlthoughatRA treatment improves mitochondrial function in skeletal muscle in rodents, its role in modulating mitochondrial function in the liver is controversial, and little data are available regarding the human liver. The aim of this study was to determine whetheratRA regulates hepatic mitochondrial activity.atRA treatment increased the mRNA and protein expression of multiple components of mitochondrialβ-oxidation, tricarboxylic acid (TCA) cycle, and respiratory chain. Additionally,atRA increased mitochondrial biogenesis in human hepatocytes and in HepG2 cells with and without lipid loading based on peroxisome proliferator activated receptor gamma coactivator 1αand 1βand nuclear respiratory factor 1 mRNA and mitochondrial DNA quantification.atRA also increasedβ-oxidation and ATP production in HepG2 cells and in human hepatocytes. Knockdown studies of RARα, RARβ, and PPARδrevealed that the enhancement of mitochondrial biogenesis andβ-oxidation byatRA requires peroxisome proliferator activated receptor delta. In vivo in mice,atRA treatment increased mitochondrial biogenesis markers after an overnight fast. Inhibition ofatRA metabolism by talarozole, a cytochrome P450 (CYP) 26 specific inhibitor, increased the effects ofatRA on mitochondrial biogenesis markers in HepG2 cells and in vivo in mice. These studies show thatatRA regulates mitochondrial function and lipid metabolism and that increasingatRA concentrations in human liver via CYP26 inhibition may increase mitochondrial biogenesis and fatty acidβ-oxidation and provide therapeutic benefit in diseases associated with mitochondrial dysfunction. PMID:26921399

  2. (226) RA AND (228) RA ACTIVITIES ASSOCIATED WITH AGRICULTURAL DRAINAGE PONDS AND WETLAND PONDS IN THE KANKAKEE WATERSHED, IL-IN, USA

    EPA Science Inventory

    Background radioactivity is elevated in many agricultural drainage ponds and also constructed wetland ponds in the Kankakee watershed. During 1995-1999, gross-a and -B activities were measured up to 455 and 1650 mBq L-1, respectively. 226Ra and 228Ra averaged 139 and 192 mBq L-01...

  3. Retinoic Acid in the Immune System

    PubMed Central

    Pino-Lagos, Karina; Benson, Micah J.; Noelle, Randolph J.

    2013-01-01

    On occasion, emerging scientific fields intersect and great discoveries result. In the last decade, the discovery of regulatory T cells (Treg) in immunity has revolutionized our understanding of how the immune system is controlled. Intersecting the rapidly emerging field of Treg function, has been the discovery that retinoic acid (RA) controls both the homing and differentiation of Treg. Instantly, the wealth and breadth of knowledge of the molecular basis for RA action, its receptors, and how it controls cellular differentiation can and will be exploited to understand its profound effects on Treg. Historically, vitamin A deprivation and repletion and RA agonists have been shown to profoundly affect immunity. Now these findings can be interpreted in light of the revelations that RA controls leukocyte homing and Treg function. PMID:19076350

  4. Opposite effects of the acute promyelocytic leukemia PML-retinoic acid receptor alpha (RAR alpha) and PLZF-RAR alpha fusion proteins on retinoic acid signalling.

    PubMed Central

    Ruthardt, M; Testa, U; Nervi, C; Ferrucci, P F; Grignani, F; Puccetti, E; Grignani, F; Peschle, C; Pelicci, P G

    1997-01-01

    Fusion proteins involving the retinoic acid receptor alpha (RAR alpha) and the PML or PLZF nuclear protein are the genetic markers of acute promyelocytic leukemias (APLs). APLs with the PML-RAR alpha or the PLZF-RAR alpha fusion protein are phenotypically indistinguishable except that they differ in their sensitivity to retinoic acid (RA)-induced differentiation: PML-RAR alpha blasts are sensitive to RA and patients enter disease remission after RA treatment, while patients with PLZF-RAR alpha do not. We here report that (i) like PML-RAR alpha expression, PLZF-RAR alpha expression blocks terminal differentiation of hematopoietic precursor cell lines (U937 and HL-60) in response to different stimuli (vitamin D3, transforming growth factor beta1, and dimethyl sulfoxide); (ii) PML-RAR alpha, but not PLZF-RAR alpha, increases RA sensitivity of hematopoietic precursor cells and restores RA sensitivity of RA-resistant hematopoietic cells; (iii) PML-RAR alpha and PLZF-RAR alpha have similar RA binding affinities; and (iv) PML-RAR alpha enhances the RA response of RA target genes (those for RAR beta, RAR gamma, and transglutaminase type II [TGase]) in vivo, while PLZF-RAR alpha expression has either no effect (RAR beta) or an inhibitory activity (RAR gamma and type II TGase). These data demonstrate that PML-RAR alpha and PLZF-RAR alpha have similar (inhibitory) effects on RA-independent differentiation and opposite (stimulatory or inhibitory) effects on RA-dependent differentiation and that they behave in vivo as RA-dependent enhancers or inhibitors of RA-responsive genes, respectively. Their different activities on the RA signalling pathway might underlie the different responses of PML-RAR alpha and PLZF-RAR alpha APLs to RA treatment. The PLZF-RAR alpha fusion protein contains an approximately 120-amino-acid N-terminal motif (called the POZ domain), which is also found in a variety of zinc finger proteins and a group of poxvirus proteins and which mediates protein

  5. Atomic Mass and Nuclear Binding Energy for Ra-186 (Radium)

    NASA Astrophysics Data System (ADS)

    Sukhoruchkin, S. I.; Soroko, Z. N.

    This document is part of the Supplement containing the complete sets of data of Subvolume B `Nuclei with Z = 55 - 100' of Volume 22 `Nuclear Binding Energies and Atomic Masses' of Landolt-Börnstein - Group I `Elementary Particles, Nuclei and Atoms', and additionally including data for nuclei with Z = 101 - 130. It provides atomic mass, mass excess, nuclear binding energy, nucleon separation energies, Q-values, and nucleon residual interaction parameters for atomic nuclei of the isotope Ra-186 (Radium, atomic number Z = 88, mass number A = 186).

  6. Testing of organic acids in engine coolants

    SciTech Connect

    Weir, T.W.

    1999-08-01

    The effectiveness of 30 organic acids as inhibitors in engine coolants is reported. Tests include glassware corrosion of coupled and uncoupled metals. FORD galvanostatic and cyclic polarization electrochemistry for aluminum pitting, and reserve alkalinity (RA) measurements. Details of each test are discussed as well as some general conclusions. For example, benzoic acid inhibits coupled metals well but is ineffective on cast iron when uncoupled. In benzoic acid inhibits coupled metals well but is ineffective on cast iron when uncoupled. In general, the organic acids provide little RA when titrated to a pH of 5.5, titration to a pH of 4.5 can result in precipitation of the acid. Trends with respect to acid chain length are reported also.

  7. 226Ra/238U disequilibrium in an upland organic soil exhibiting elevated natural radioactivity.

    PubMed

    Dowdall, Mark; O'Dea, John

    2002-01-01

    This paper presents the results of a study into the anomalous 226Ra/238U disequilibrium (226Ra/238U of 0.5-9) exhibited by an upland organic soil in Co. Donegal, Ireland. Radiochemical speciation of 226Ra, 238U and 225Ra indicates that in this organic soil the high 226Ra/238U ratio is due to loss of 235U relative to 226Ra via oxidation and mobilisation of 238U in the upper layers of the soil and subsequent loss in solution. At the lower, more reducing depths of the soil profile, 238U and 226Ra are essentially in equilibrium. Loss of 238U appears to occur primarily from the easily oxidised organic and iron oxide fractions of the soil, samples exhibiting high 226Ra/238U ratios displaying significantly lower 238U levels in these fractions than samples whose ratio is below the average value for the soil of the valley. Selective enrichment of 226Ra by plants or preferential leaching of 226Ra from the underlying rock is not supported by the results of this study. PMID:11848154

  8. Transition to turbulent thermal convection beyond Ra=1010 detected in numerical simulations

    NASA Astrophysics Data System (ADS)

    Vincent, Alain P.; Yuen, David A.

    2000-05-01

    We have conducted high-resolution two-dimensional calculations for a Boussinesq convection model with a Prandtl number of unity in an aspect-ratio 3 box, going from Rayleigh numbers between 108 to 1014. A grid of 1024×3076 grid points consisting of a cosine-sine basis set has been employed for free-slip boundary conditions. We have found evidence for a transition involving the branching of plumes at a Rayleigh number of 1010. Inside the core of these ``superplumes,'' the structure is extremely complex. There may be another transition at Ra of 1012, where a secondary instability may develop in regions of the local Rayleigh number which becomes supercritical inside the core of the complex ``superplumes.'' For Ra of 108 to 1010, Ra follows a 13 power law in the Nusselt-Rayleigh number relationship. From Ra of 1010 to 1012, Ra follows a 12 power law. Above this value the Nusselt number becomes insensitive to the variation in the global Rayleigh number and this is due to the development of small-scale convection cells vertically aligned in the interior of the extremely high Ra number flow. The global Reynolds number scales as Re~Ra1/4 up to Ra of 1014. Scaling relationships based on global properties would not work in extremely high Ra situations beyond Ra of 1012 because of the complex turbulent layered convection in the core of the flow and the severe degradation of the boundary layers.

  9. Smoking and Subclinical ILD in RA versus the Multi-Ethnic Study of Atherosclerosis.

    PubMed

    Johnson, Cheilonda; Giles, Jon T; Bathon, Joan; Lederer, David; Hoffman, Eric A; Barr, R Graham; Danoff, Sonye K

    2016-01-01

    A population-based cohort showed an association between cigarette smoking and subclinical parenchymal lung disease defined as regions of increased computed tomography (CT) lung densitometry. This technique has not been applied to the rheumatoid arthritis (RA) population where associated ILD is highly prevalent. The association between cumulative cigarette smoking and volume of areas of high attenuation (HAA: >-600 and <-250 Hounsfield Units) on full inspiratory CT was compared in 172 RA participants and 3,969 controls in a general population sample. Multivariable regression models were used to adjust for demography, anthropometrics, percent emphysema, and CT parameters. The mean cumulative cigarette smoking exposure was 25 (IQR 10-42) and 15(IQR 5-31) pack-years for the RA and non-RA cohorts, respectively. Mean HAA was 153(±57) cm3 and 129(±50) cm3 in the RA and non-RA cohorts, respectively. Each 10 cigarette pack-year increment was associated with a higher HAA by 0.03% (95% CI, 0.007-0.05%) in RA patients and by 0.008% (95% CI, 0.003-0.01%) in those without RA (interaction p = 0.001). Cigarette smoking was associated with higher lung attenuation; with a magnitude of association more pronounced in those with RA than in the general population. These data suggest that cigarette smoking may be a more potent ILD risk factor for RA patients than in the general population. PMID:27050433

  10. Smoking and Subclinical ILD in RA versus the Multi-Ethnic Study of Atherosclerosis

    PubMed Central

    Johnson, Cheilonda; Giles, Jon T.; Bathon, Joan; Lederer, David; Hoffman, Eric A.; Barr, R. Graham; Danoff, Sonye K.

    2016-01-01

    A population-based cohort showed an association between cigarette smoking and subclinical parenchymal lung disease defined as regions of increased computed tomography (CT) lung densitometry. This technique has not been applied to the rheumatoid arthritis (RA) population where associated ILD is highly prevalent. The association between cumulative cigarette smoking and volume of areas of high attenuation (HAA: >-600 and <-250 Hounsfield Units) on full inspiratory CT was compared in 172 RA participants and 3,969 controls in a general population sample. Multivariable regression models were used to adjust for demography, anthropometrics, percent emphysema, and CT parameters. The mean cumulative cigarette smoking exposure was 25 (IQR 10–42) and 15(IQR 5–31) pack-years for the RA and non-RA cohorts, respectively. Mean HAA was 153(±57) cm3 and 129(±50) cm3 in the RA and non-RA cohorts, respectively. Each 10 cigarette pack-year increment was associated with a higher HAA by 0.03% (95% CI, 0.007–0.05%) in RA patients and by 0.008% (95% CI, 0.003–0.01%) in those without RA (interaction p = 0.001). Cigarette smoking was associated with higher lung attenuation; with a magnitude of association more pronounced in those with RA than in the general population. These data suggest that cigarette smoking may be a more potent ILD risk factor for RA patients than in the general population. PMID:27050433

  11. The Bayo Canyon/radioactive lanthanum (RaLa) program

    SciTech Connect

    Dummer, J.E.; Taschner, J.C.; Courtright, C.C.

    1996-04-01

    LANL conducted 254 radioactive lanthanum (RaLa) implosion experiments Sept. 1944-March 1962, in order to test implosion designs for nuclear weapons. High explosives surrounding common metals (surrogates for Pu) and a radioactive source containing up to several thousand curies of La, were involved in each experiment. The resulting cloud was deposited as fallout, often to distances of several miles. This report was prepared to summarize existing records as an aid in evaluating the off-site impact, if any, of this 18-year program. The report provides a historical setting for the program, which was conducted in Technical Area 10, Bayo Canyon about 3 miles east of Los Alamos. A description of the site is followed by a discussion of collateral experiments conducted in 1950 by US Air Force for developing an airborne detector for tracking atmospheric nuclear weapons tests. All known off-site data from the RaLa program are tabulated and discussed. Besides the radiolanthanum, other potential trace radioactive material that may have been present in the fallout is discussed and amounts estimated. Off-site safety considerations are discussed; a preliminary off-site dose assessment is made. Bibliographical data on 33 persons important to the program are presented as footnotes.

  12. Investigations On The EnviSAT RA2 Tropospheric Correction

    NASA Astrophysics Data System (ADS)

    Blarel, F.; Legresy, B.

    2013-12-01

    The Center for the Topography of Oceans and the Hydrosphere (CTOH), the Altimeter Data Service of the LEGOS laboratory pursue an effort to validate and improve ENVISAT RA2 altimetry. We investigate the stability and reliability of different corrections for the altimetric measurements. With the one before last ENVISAT RA2 processing (v1.0), the ICE Validation chain of the CTOH detected some issues with the Dry Tropospheric Correction (DTC) over the Cryosphere. Here we present the validation of the latest reprocessing (v2.1) of ENVISAT data. We observe the limitation of this re-processed DTC, especially the jump observed at cycle 44 over Antarctica which causes significant local trend and suspect changes in the variability of this correction over time. We investigated a solution and re- compute this correction all over the globe with the ERA Interim ECMWF pressure fields and using directly the altimetric range measurement rather than any external digital elevation model (DEM). We present the results of this investigation, the statistics of previous (DTC_v2.1) and new corrections (DTC_ctoh) and in the context of different surfaces. The improvement is significant, and we discuss the aspects and impacts of this improvement, in terms of meteorological-fields, procedure, and location.

  13. Deciphering the binding patterns and conformation changes upon the bovine serum albumin-rosmarinic acid complex.

    PubMed

    Peng, Xin; Wang, Xiangchao; Qi, Wei; Huang, Renliang; Su, Rongxin; He, Zhimin

    2015-08-01

    Rosmarinic acid (RA) is an importantly and naturally occurring polyphenol from plants of the mint family with potent biological activities. Here, the in vitro interaction of RA with bovine serum albumin (BSA) has been investigated using various biophysical approaches as well as molecular modeling methods, to ascertain its binding mechanism and conformational changes. The fluorescence results demonstrated that the fluorescence quenching of BSA by RA was mainly the result of the formation of a ground state BSA-RA complex, and BSA had one high affinity RA binding site with a binding constant of 4.18 × 10(4) mol L(-1) at 298 K. Analysis of thermodynamic parameters revealed that hydrophobic and hydrogen bond interactions were the dominant intermolecular force in the complex formation. The primary binding site of RA in BSA (site I) had been identified by site marker competitive experiments. The distance between RA and the tryptophan residue of BSA was evaluated at 3.12 nm based on Förster's theory of non-radiation energy transfer. The UV-vis absorption, synchronous fluorescence, three-dimensional fluorescence, 8-anilino-1-naphthalenesulfonic acid (ANS) fluorescence, circular dichroism (CD), and Fourier transform infrared (FT-IR) spectra confirmed that the conformation and structure of BSA were altered in the presence of RA. Moreover, the nuclear magnetic spectroscopy showed that the aromatic groups of RA took part in the binding reaction during the BSA-RA complexation. In addition, the molecular picture of the interaction mechanism between BSA and RA at the atomic level was well examined by molecular docking and dynamics studies. In brief, RA can bind to BSA with noncovalent bonds in a relatively stable way, and these findings will be beneficial to the functional food research of RA. PMID:26146359

  14. Role of Acinus in Regulating Retinoic Acid-Responsive Gene Pre-mRNA Splicing

    PubMed Central

    Wang, Fang; Soprano, Kenneth J.; Soprano, Dianne Robert

    2014-01-01

    Acinus-S’ is a co-repressor for retinoic acid receptor (RAR)-dependent gene transcription and has been suggested to be involved in RNA processing. In this study the role of Acinus isoforms in regulating pre-mRNA splicing was explored using in vivo splicing assays. Both Acinus-L and Acinus-S’, with the activity of Acinus-L higher than that of Acinus-S’, increase the splicing of a retinoic acid (RA)-responsive minigene containing a weak 5′ splice site but not a RA-responsive minigene containing a strong 5′ splice site. RA treatment further enhances the splicing of the weak 5′ splice site by Acinus in a dose- and time-dependent manner, suggesting a RA-dependent activity in addition to a RA-independent activity of Acinus. The RA-independent effect of Acinus occurs to varying degrees using minigene constructs containing several different promoters while the RA-dependent splicing activity of Acinus is specific for transcripts derived from the minigene driven by a RA response element (RARE)-containing promoter. This suggests that the ligand-dependent splicing activity of Acinus is related to the RA-activated RAR bound to the RARE. The RRM domain is necessary for the RA-dependent splicing activity of Acinus and the RA-independent splicing activity of Acinus is repressed by RNPS1. Importantly, measurement of the splicing of endogenous human RARβ and Bcl-x in vivo demonstrates that Acinus stimulates the use of the weaker alternative 5′ splice site of these two genes in a RA-dependent manner for RARβ and a RA-independent manner for Bcl-x. Taken together, these studies demonstrate that Acinus functions in both RAR-dependent splicing and RAR-dependent transcription. PMID:25205379

  15. Antioxidant activity and sensory evaluation of a rosmarinic acid-enriched extract of Salvia officinalis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    An extract of S. officinalis (garden sage) was developed using supercritical fluid extraction, followed by hot water extraction. The resulting extract was enriched in polyphenols, including rosmarinic acid (RA), which has shown promising health benefits in animals. The extract contained RA at a conc...

  16. Vitamin E supplementation does not prevent ethanol-reduced hepatic retinoic acid levels in rats

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Chronic, excessive ethanol intake can increase retinoic acid (RA) catabolism by inducing cytochrome P450 2E1 (CYP2E1). Vitamin E (VE) is an antioxidant implicated in CYP2E1 inhibition. In the current study, we hypothesized that VE supplementation inhibits CYP2E1 and decreases RA catabolism, thereby ...

  17. Elevated carbon dioxide levels enhance rosmarinic acid production in spearmint plantlets

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The C20 diterpene rosmarinic acid (RA) is synthesized in the phenylpropanoid pathway and is constitutively expressed in spearmint (Mentha spicata L.) plantlets grown in vitro. RA levels within plantlet leaves were found to be readily manipulated by the nutritional and physical environments. Higher...

  18. PALATAL EXPRESSION OF TGFB ISOFORMS IN NORMAL AND RETINOIC ACID-TREATED EMBRYOS

    EPA Science Inventory

    Retinoic Acid (RA) is know to induce cleft palate in all mammalian species tested. he aetiology of RA-induced cleft palate has been extensively investigated in C57B16 mouse embryos by one of us 1. e have recently shown distinct site- and stage-specific expression pattern of the R...

  19. Study of soil-plant transfer of 226Ra under greenhouse conditions.

    PubMed

    Soudek, Petr; Petrová, Sárka; Benesová, Dagmar; Kotyza, Jan; Vágner, Martin; Vanková, Radomíra; Vanek, Tomás

    2010-06-01

    A soil-plant transfer study was performed using soil from a former uranium ore processing factory in South Bohemia. We present the results from greenhouse experiments which include estimates of the time required for phytoremediation. The accumulation of (226)Ra by different plant species from a mixture of garden soil and contaminated substrate was extremely variable, ranging from 0.03 to 2.20 Bq (226)Ra/g DW. We found differences in accumulation of (226)Ra between plants from the same genus and between cultivars of the same plant species. The results of (226)Ra accumulation showed a linear relation between concentration of (226)Ra in plants and concentration of (226)Ra in soil mixtures. On the basis of these results we estimated the time required for phytoremediation, but this appears to be too long for practical purposes. PMID:18823682

  20. IL2RA and IL7RA genes confer susceptibility for multiple sclerosis in two independent European populations.

    PubMed

    Weber, F; Fontaine, B; Cournu-Rebeix, I; Kroner, A; Knop, M; Lutz, S; Müller-Sarnowski, F; Uhr, M; Bettecken, T; Kohli, M; Ripke, S; Ising, M; Rieckmann, P; Brassat, D; Semana, G; Babron, M-C; Mrejen, S; Gout, C; Lyon-Caen, O; Yaouanq, J; Edan, G; Clanet, M; Holsboer, F; Clerget-Darpoux, F; Müller-Myhsok, B

    2008-04-01

    Multiple sclerosis (MS) is the most common chronic inflammatory neurologic disorder diagnosed in young adults and, due to its chronic course, is responsible for a substantial economic burden. MS is considered to be a multifactorial disease in which both genetic and environmental factors intervene. The well-established human leukocyte antigen (HLA) association does not completely explain the genetic impact on disease susceptibility. However, identification and validation of non-HLA-genes conferring susceptibility to MS has proven to be difficult probably because of the small individual contribution of each of these genes. Recently, associations with two single nucleotide polymorphisms (SNPs) in the IL2RA gene (rs12722489, rs2104286) and one SNP in the IL7RA gene (rs6897932) have been reported by several groups. These three SNPs were genotyped in a French and a German population of MS patients using the hME assay by the matrix-assisted laser desorption/ionization time of flight technology (Sequenom, San Diego, CA, USA). We show that these SNPs do contribute to the risk of MS in these two unrelated European MS patient populations with odds ratios varying from 1.1 to 1.5. The discovery and validation of new genetic risk factors in independent populations may help toward the understanding of MS pathogenesis by providing valuable information on biological pathways to be investigated. PMID:18354419

  1. Laser-trapping of {sup 225}Ra and {sup 226}Ra with repumping by room-temperature blackbody radiation.

    SciTech Connect

    Guest, J. R.; Scielzo, N. D.; Ahmad, I.; Bailey, K.; Greene, J. P.; Holt, R. J.; Lu, Z.-T.; O'Connor, T. P.; Potterveld, D. H.; Physics; Enrico Fermi Inst.; Univ. of Chicago

    2007-02-27

    We have demonstrated Zeeman slowing and capture of neutral {sup 225}Ra and {sup 226}Ra atoms in a magneto-optical trap. The intercombination transition {sup 1}S{sub 0} {yields} {sup 3}P{sub 1} is the only quasicycling transition in radium and was used for laser-cooling and trapping. Repumping along the {sup 3}D{sub 1} {yields} {sup 1}P{sub 1} transition extended the lifetime of the trap from milliseconds to seconds. Room-temperature blackbody radiation was demonstrated to provide repumping from the metastable {sup 3}P{sub 0} level. We measured the isotope shift and hyperfine splittings on the {sup 3}D{sub 1} {yields} {sup 1}P{sub 1} transition with the laser-cooled atoms, and set a limit on the lifetime of the {sup 3}D{sub 1} level based on the measured blackbody repumping rate. Laser-cooled and trapped radium is an attractive system for studying fundamental symmetries.

  2. Production of Ra225 precursor for Ac225/Bi213 generators. Final CRADA Report.

    SciTech Connect

    Ehst, D. A.; Nuclear Engineering Division

    2009-10-02

    Russian subcontractors shipped two small deliveries of Ra225 to PNNL for evaluation. The activity was close to the requisite amount in the subcontract. The first labeled properly; the second did not. This showed that the Russians could supply Ra225 to the US; however they proved unable to meet future demands for larger amounts of activity. The US DOE attempts to get Ra225 from Russian should be terminated; the Russians, under Rosatom, are not interested in this business.

  3. Flow rates and reaction rates in the Galapagos Rise spreading center hydrothermal system as inferred from 228Ra/226Ra in vesicomyid clam shells

    PubMed Central

    Turekian, Karl K.; Cochran, J. Kirk

    1986-01-01

    The 228Ra/226Ra ratios in a previously dated vesicomyid clam shell were used to determine that seawater was in contact with mid-oceanic-ridge basalt glass for 22-45 years prior to arrival to the surface at 350°C at the Galapagos Rise Spreading Center. The minimum rate of reaction for the 45-year sojourn time, based on a water/rock ratio of 2.8 derived from 226Ra concentrations, is 8 g of basalt altered per kg of seawater per year. PMID:16593746

  4. Retinoic acid expands the evolutionarily reduced dentition of zebrafish.

    PubMed

    Seritrakul, Pawat; Samarut, Eric; Lama, Tenzing T S; Gibert, Yann; Laudet, Vincent; Jackman, William R

    2012-12-01

    Zebrafish lost anterior teeth during evolution but retain a posterior pharyngeal dentition that requires retinoic acid (RA) cell-cell signaling for its development. The purposes of this study were to test the sufficiency of RA to induce tooth development and to assess its role in evolution. We found that exposure of embryos to exogenous RA induces a dramatic anterior expansion of the number of pharyngeal teeth that later form and shifts anteriorly the expression patterns of genes normally expressed in the posterior tooth-forming region, such as pitx2 and dlx2b. After RA exposure, we also observed a correlation between cartilage malformations and ectopic tooth induction, as well as abnormal cranial neural crest marker gene expression. Additionally, we observed that the RA-induced zebrafish anterior teeth resemble in pattern and number the dentition of fish species that retain anterior pharyngeal teeth such as medaka but that medaka do not express the aldh1a2 RA-synthesizing enzyme in tooth-forming regions. We conclude that RA is sufficient to induce anterior ectopic tooth development in zebrafish where teeth were lost in evolution, potentially by altering neural crest cell development, and that changes in the location of RA synthesis correlate with evolutionary changes in vertebrate dentitions. PMID:22942074

  5. Rapid method for the determination of 226Ra in hydraulic fracturing wastewater samples

    DOE PAGESBeta

    Maxwell, Sherrod L.; Culligan, Brian K.; Warren, Richard A.; McAlister, Daniel R.

    2016-03-24

    A new method that rapidly preconcentrates and measures 226Ra from hydraulic fracturing wastewater samples was developed in the Savannah River Environmental Laboratory. The method improves the quality of 226Ra measurements using gamma spectrometry by providing up to 100x preconcentration of 226Ra from this difficult sample matrix, which contains very high levels of calcium, barium, strontium, magnesium and sodium. The high chemical yield, typically 80-90%, facilitates a low detection limit, important for lower level samples, and indicates method ruggedness. Ba-133 tracer is used to determine chemical yield and correct for geometry-related counting issues. The 226Ra sample preparation takes < 2 hours.

  6. ENVISAT RA-2/MWR Cross-Calibration and Validation Results

    NASA Astrophysics Data System (ADS)

    Benveniste, J.; Ra-2/Mwr Cross-Calibration; Validation Team

    2003-04-01

    ESA launched its environmental research satellite, ENVISAT, on 1 March 2002. It carries a suite of 10 instruments offering opportunities for a broad range of scientific research and applications. In particular ENVISAT carries a radar altimeter (RA-2), a microwave radiometer (MWR) and a precise tracking system (DORIS). The evaluation of the quality of the ENVISAT Altimetry geophysical data products, the validation against in-situ data and models and the cross-calibration on ERS-2 and other flying altimeters has been performed during the commissioning phase within a team of scientists drawn up from the pre-launch announcement of opportunity. An overview of the objective and approach will be recalled and the results obtained from this teamwork will be presented.

  7. Retinoic acid induces Sertoli cell paracrine signals for spermatogonia differentiation but cell autonomously drives spermatocyte meiosis

    PubMed Central

    Raverdeau, Mathilde; Gely-Pernot, Aurore; Féret, Betty; Dennefeld, Christine; Benoit, Gérard; Davidson, Irwin; Chambon, Pierre; Mark, Manuel; Ghyselinck, Norbert B.

    2012-01-01

    Direct evidence for a role of endogenous retinoic acid (RA), the active metabolite of vitamin A in the initial differentiation and meiotic entry of spermatogonia, and thus in the initiation of spermatogenesis is still lacking. RA is synthesized by dedicated enzymes, the retinaldehyde dehydrogenases (RALDH), and binds to and activates nuclear RA receptors (RARA, RARB, and RARG) either within the RA-synthesizing cells or in the neighboring cells. In the present study, we have used a combination of somatic genetic ablations and pharmacological approaches in vivo to show that during the first, prepubertal, spermatogenic cycle (i) RALDH-dependent synthesis of RA by Sertoli cells (SC), the supporting cells of the germ cell (GC) lineage, is indispensable to initiate differentiation of A aligned into A1 spermatogonia; (ii) RARA in SC mediates the effects of RA, possibly through activating Mafb expression, a gene whose Drosophila homolog is mandatory to GC differentiation; (iii) RA synthesized by premeiotic spermatocytes cell autonomously induces meiotic initiation through controlling the RAR-dependent expression of Stra8. Furthermore, we show that RA of SC origin is no longer necessary for the subsequent spermatogenic cycles but essential to spermiation. Altogether, our data establish that the effects of RA in vivo on spermatogonia differentiation are indirect, via SC, but direct on meiotic initiation in spermatocytes, supporting thereby the notion that, contrary to the situation in the female, RA is necessary to induce meiosis in the male. PMID:23012458

  8. Retinoic acid treatment of fibroblasts causes a rapid decrease in ( sup 3 H)inositol uptake

    SciTech Connect

    Sinha, R.; Creek, K.E.; Silverman-Jones, C.; de Luca, L.M. )

    1989-04-01

    NIH 3T3 fibroblasts treated with all-trans-retinoic acid (RA) showed a dramatic decrease in the uptake of ({sup 3}H)inositol compared to solvent-treated controls. The onset of RA-induced inhibition of ({sup 3}H)inositol uptake was rapid with a 10-15% decrease occurring after 2-3 h of RA exposure and 60-70% reduction after 16 h of RA treatment. A progressive dose-dependent decrease in inositol uptake was found as the concentration of RA increased from 10{sup {minus}8} to 10{sup {minus}5} M and the effect was fully reversible within 48 h after RA removal. RA inhibition of inositol uptake was also observed in 3T3-Swiss and Balb/3T3 cells but not in two virally transformed 3T3 cell lines. Phlorizin, amiloride, and monensin inhibited inositol uptake by 66, 74, and 58%, respectively, and this inhibition was additive when the cells were treated with RA as well as these inhibitors. A decreased incorporation of ({sup 3}H)inositol into polyphosphoinositides was also observed in RA-treated cells but not to the same extent as for ({sup 3}H)inositol uptake. In conclusion, RA treatment of 3T3 fibroblasts decreases the uptake of ({sup 3}H)inositol by up to 70% within 8 to 10 h at near physiological concentrations in a reversible and specific manner.

  9. Massive Resurfacing of the Ionian Volcano Ra Patera

    NASA Technical Reports Server (NTRS)

    1996-01-01

    Four views of the volcano Ra Patera on Jupiter's moon Io showing changes seen on June 27th, 1996 by the Galileo spacecraft as compared to views seen by the Voyager spacecraft during the 1979 flybys. Clockwise from upper left is a Voyager 1 high resolution image, a Voyager 1 color image, a Galileo color image, and a Voyager 2 color image. North is to the top of the picture. Observations obtained by J. Spencer and others with the Hubble Space Telescope had indicated a major change in recent years. The Galileo images reveal the detailed morphology of new deposits. Dark materials, previously confined to a summit caldera, appear to have overflowed the caldera walls to produce a small flow to the south and a larger flow to the southeast. New bright deposits covering an area of about 40,000 square kilometers (the size of New Jersey) surround the dark materials. The morphology of the bright materials suggests emplacement as lava flows rather than pyroclastics. Notice the lobate margins and how the bright materials embay a plateau in the upper left. The Voyager 1 images also reveal relatively bright lava flows emanating from Ra Patera, especially to the northeast. The colors of the flows match those of sulfur plus SO2 frost. Images are 953 km wide. The Jet Propulsion Laboratory, Pasadena, CA manages the mission for NASA's Office of Space Science, Washington, DC. This image and other images and data received from Galileo are posted on the World Wide Web, on the Galileo mission home page at URL http://galileo.jpl.nasa.gov. Background information and educational context for the images can be found at URL http://www.jpl.nasa.gov/galileo/sepo

  10. Release of rosmarinic acid from semisolid formulations and its penetration through human skin ex vivo.

    PubMed

    Stelmakienė, Ada; Ramanauskienė, Kristina; Briedis, Vitalis

    2015-06-01

    The aim of this study was to evaluate the release of rosmarinic acid (RA) from the experimental topical formulations with the Melissa officinalis L. extract and to evaluate its penetration through undamaged human skin ex vivo. The results of the in vitro release study showed that higher amounts of RA were released from the emulsion vehicle when lemon balm extract was added in its dry form. An inverse correlation was detected between the released amount of RA and the consistency index of the formulation. Different penetration of RA into the skin may be influenced by the characteristics of the vehicle as well as by the form of the extract. The results of penetration assessment showed that the intensity of RA penetration was influenced by its lipophilic properties: RA was accumulating in the epidermis, while the dermis served as a barrier, impeding its deeper penetration. PMID:26011936

  11. Preparative separation and purification of rosmarinic acid from perilla seed meal via combined column chromatography.

    PubMed

    Tang, Weizhuo; Sun, Baoshan; Zhao, Yuqing

    2014-02-01

    In this study, the preparative separation and purification of rosmarinic acid (RA) from perilla seed meal (PSM), which is a by-product of edible oil production, was achieved using combined column chromatography over macroporous and polyamide resins. To optimize the RA enrichment process, the performance and separation characteristics of nine selected macroporous resins with different chemical and physical properties were investigated. SP825 resin was the most effective: the content of RA increased from 0.27% in the original extract to 16.58% in the 50% ethanol fraction (a 61.4-fold increase). During further purification treatment on polyamide resin, 90.23% pure RA could be obtained in the 70% ethanol fraction. RA with a higher purity (>95%) could also be easily obtained using one crystallization operation. The proposed method is simple, easily operated, cost-effective, and environmentally friendly and is suitable for both large-scale RA production and waste management. PMID:24381020

  12. U, Ra and Ba incorporation during precipitation of hydrothermal carbonates: Implications for {sup 226}Ra-Ba dating of impure travertines

    SciTech Connect

    Rihs, S.; Condomines, M.; Sigmarsson, O.

    2000-02-01

    The authors studied U, Ra and Ba incorporation in calcite in a natural CO{sub 2}-rich hydrothermal area from the French Massif Central. Along the western border of the Limagne graben, several springs are exploited for the petrification of various artifacts with calcite. These sites offer the opportunity to sample the water and the calcite layers downflow from the spring, and thus to follow the evolution of their U, Ra and Ba contents as precipitation proceeds. Results show that the apparent partition coefficients of U, Ra and Ba between water and calcite decrease during precipitation for the three elements. The authors found no direct relation between this variation and the main factors able to influence the partition coefficient, such as precipitation rate, which suggests that the incorporation of these trace elements could result from a composite process of adsorption and coprecipitation. Ra and Ba have a similar behavior, with an apparent partition coefficient decreasing from 0.80 to 0.47 for Ra and 0.96 to 0.68 for Ba, resulting in a small ({le}10%) variation of the Ra/Ba ratio. The apparent partition coefficient of U decreases from 0.38 to 0.20. These apparent coefficients are much higher than equilibrium values but might be applicable to natural systems with high precipitation rates. The authors also investigated the possibility of using the decay of the {sup 226}Ra-excess, or the decrease of the ({sup 226}Ra)/Ba ratio to date older deposits. Whereas the {sup 226}Ra initial activity at the time of deposition has not remained constant, and cannot be used for dating, the ({sup 226}Ra)/Ba method gives better results, when appropriate corrections for detrital contamination in Ba are made. Mixing diagrams using Th as an indicator of contamination allow calculation of the ({sup 226}Ra)/Ba ratio of the pure carbonate component. The calculated ages of five travertine layers range from 330 to 800 years, suggesting a mean deposition rate of about 1 cm/yr. The

  13. Distribution of (223)Ra and (224)Ra in the Bo Sea embayment in Tianjin and its implication of submarine groundwater discharge.

    PubMed

    Liu, Lingling; Yi, Lixin; Cheng, Xiaoqing; Tang, Guoqiang

    2015-12-01

    Submarine groundwater discharge (SGD) is now recognized as an important pathway between land and sea. In this study, in order to analyze the distribution of naturally occurring short-lived radium isotopes and the relative SGD effect in Bo Sea embayment, (223)Ra and (224)Ra were measured in three parts of the embayment with the radium-delayed coincidence counting (RaDeCC) system. Subsequently, the mixing process was studied by the calculation of diffusion coefficients (Kx and Kz) and advection velocities (Vx and Vz) based on the 2D advection-diffusion model. Additionally, the apparent residence ages and SGD flux were quantified based on the (224)Ra and (223)Ra activities. The results showed that the Ra activities exponentially decreased with the distance offshore, and both the Kx and Vx took the order of northern part > southern part > middle part. In vertical direction, there was the maximum value of Vz and minimum Kz in middle part and the maximum Kz and minimum Vz in southern part. The average ages for the northern, middle and southern parts were 4.28, 7.38 and 3.73 days, respectively. The final SGD flux yielded by (224)Ra was 0.09, 0.01 and 0.03 m d(-1) in the northern, middle and southern parts, respectively. The SGD flux yielded by (223)Ra was 0.08, 0.01 and 0.03 m d(-1) in northern, middle and southern parts, respectively. The result indicates that there is the fastest exchange rate and the biggest SGD flux in the southern part in Bo Sea embayment. PMID:26318773

  14. Tracking suspended particle transport via radium isotopes ((226)Ra and (228)Ra) through the Apalachicola-Chattahoochee-Flint River system.

    PubMed

    Peterson, Richard N; Burnett, William C; Opsahl, Stephen P; Santos, Isaac R; Misra, Sambuddha; Froelich, Philip N

    2013-02-01

    Suspended particles in rivers can carry metals, nutrients, and pollutants downstream which can become bioactive in estuaries and coastal marine waters. In river systems with multiple sources of both suspended particles and contamination sources, it is important to assess the hydrologic conditions under which contaminated particles can be delivered to downstream ecosystems. The Apalachicola-Chattahoochee-Flint (ACF) River system in the southeastern United States represents an ideal system to study these hydrologic impacts on particle transport through a heavily-impacted river (the Chattahoochee River) and one much less impacted by anthropogenic activities (the Flint River). We demonstrate here the utility of natural radioisotopes as tracers of suspended particles through the ACF system, where particles contaminated with arsenic (As) and antimony (Sb) have been shown to be contributed from coal-fired power plants along the Chattahoochee River, and have elevated concentrations in the surficial sediments of the Apalachicola Bay Delta. Radium isotopes ((228)Ra and (226)Ra) on suspended particles should vary throughout the different geologic provinces of this river system, allowing differentiation of the relative contributions of the Chattahoochee and Flint Rivers to the suspended load delivered to Lake Seminole, the Apalachicola River, and ultimately to Apalachicola Bay. We also use various geochemical proxies ((40)K, organic carbon, and calcium) to assess the relative composition of suspended particles (lithogenic, organic, and carbonate fractions, respectively) under a range of hydrologic conditions. During low (base) flow conditions, the Flint River contributed 70% of the suspended particle load to both the Apalachicola River and the bay, whereas the Chattahoochee River became the dominant source during higher discharge, contributing 80% of the suspended load to the Apalachicola River and 62% of the particles entering the estuary. Neither of these hydrologic

  15. Large 224Ra and 228Ra disequilibrium indicates intense groundwater processes in the Cabo Frio coastal system

    NASA Astrophysics Data System (ADS)

    Souza, Giovana; Silva-Filho, Emmanoel; Sanders, Christian; Marques, Eduardo; Caldeira, Pedro; Santos, Luiz Eduardo; Kutter, Vinicius; Smoak, Joseph

    2014-05-01

    Input of subterranean water, referred to as Submarine Groundwater Discharge (SGD), typically is a mixture of infiltrated seawater and terrestrially derived freshwater and includes all advective fluid flow between the land and the continental shelf, regardless of the source or composition of the fluids (Smoak et al., 2013; Burnett et al., 2003). A substantial flow of nutrient and metal input via SGD, which may contribute to coastal eutrophication, has been document in recent studies (Sanders et al., 2012; Santos et al., 2008). Direct measurements (e.g. seepage meters) of SGD are difficult on a regional scale. However, radium isotopes have been shown to be powerful tools to quantify SGD fluxes and indicate the sources (Sanders et al., 2012). The direct parent of each radium isotope is a thorium isotope. Thorium is strongly adsorbed to sediment and provides a source of radium, which is generated on a range of time scales. In freshwater, radium is strongly adsorbed to particles. However, under reducing conditions, low pH and/or increasing salinity, radium can be released into solution. These characteristics make radium an excellent tracer of brackish SGD and a net flux of nutrients and metals to the ocean. The coastal plain in the region of Cabo Frio and its surroundings consist of Quaternary deposits of continental sediments, coastal lagoons and marine sands forming a large coastal aquifer. During the winter of 2012 and summer of 2013 was performed a physicochemical characterization and measurements of radio isotopes in groundwater along a transect perpendicular to the beach. The high radio activities associated with the imbalance exists between the 224Ra and 228Ra can be useful tools in understanding the role of submarine groundwater discharge in this region highly productive and high marine biodiversity.

  16. Free radical oxidation of (E)-retinoic acid by prostaglandin H synthase.

    PubMed

    Samokyszyn, V M; Chen, T; Maddipati, K R; Franz, T J; Lehman, P A; Lloyd, R V

    1995-01-01

    Cooxidative metabolism of all-trans (E)-retinoic acid (RA) by prostaglandin H synthase was investigated employing ram seminal vesicle microsomes (RSVM) or purified, RSVM-derived enzyme. RA was shown to undergo hydroperoxide [H2O2 or 5-phenyl-4-penten-1-yl hydroperoxide (PPHP)]- or arachidonic acid-dependent cooxidation by microsomal prostaglandin H (PGH) synthase as evidenced by UV spectroscopic analysis of reaction mixtures. Cooxidation of RA by microsomal or purified PGH synthase, using PPHP as substrate, was characterized by uptake of dioxygen which was first order with respect to enzyme concentration. Dioxygen uptake was inhibited by the peroxidase reducing substrate 2-methoxyphenol. In addition, O2 uptake was inhibited by the spin trap nitrosobenzene. ESR spin trapping studies, using alpha-phenyl-N-tert-butylnitrone (PBN) as the spin trap, demonstrated the formation of RA-PBN adducts, characterized by hyperfine coupling constants of alpha H = 3.2 G and alpha N = 15.8 G. Reverse phase HPLC analysis of reaction mixtures demonstrated the formation of 4-hydroxy-RA, 5,6-epoxy-RA, 4-oxo-RA, (13Z)-retinoic acid, and other geometric isomers which were identified on the basis of cochromatography with synthetic standards, UV spectroscopy, and/or mass spectrometry. Mechanisms are proposed for the hydroperoxide-dependent, PGH synthase-catalyzed oxidation of RA that are consistent with these results. PMID:7548765

  17. Measurement of (238)U, (228)Ra, (226)Ra, (40)K and (137)Cs in foodstuffs samples collected from coastal areas of China.

    PubMed

    Tuo, Fei; Zhang, Qing; Zhou, Qiang; Xu, Cuihua; Zhang, Jing; Li, Wenhong; Zhang, Jianfeng; Su, Xu

    2016-05-01

    This study represents a total of 245 samples collected. The activities of (238)U, (228)Ra, (226)Ra, (40)K and (137)Cs were determined in samples of vegetables, tea, cereal (rice, wheat and corn), meat, poultry, freshwater product, seafood and seaweed that collected from the 30km safety zone of the Nuclear Power Plants (NPPs) area. All the samples radionuclide activities were quantified by using High Purity Germanium (HPGe) gamma spectrometry. The geometric mean concentrations (Bqkg(-1) wet weight) for (238)U, (228)Ra, (226)Ra, (40)K, and (137)Cs in all investigated foodstuffs samples, are 0.13, 0.16, 0.11, 68 and 0.02, respectively. The arithmetic mean concentrations (Bqkg(-1) wet weight) for (238)U, (228)Ra, (226)Ra, (40)K, and (137)Cs in all investigated foodstuffs samples, are 0.34, 0.65, 0.32, 111 and 0.09, respectively. Results of this study were compared with others, the measured values are the same with those of a previous investigation. Radiation doses due to the consumption of these foodstuffs to humans are estimated to comprise around 37-46% of the annual dose limit for public. PMID:26926376

  18. Ligand-dependent occupancy of the retinoic acid receptor beta 2 promoter in vivo.

    PubMed Central

    Dey, A; Minucci, S; Ozato, K

    1994-01-01

    Retinoic acid (RA) activates transcription of the RA receptor beta 2 (RAR beta 2) gene in embryonal carcinoma (EC) cells. This activation involves binding of the RAR/retinoid X receptor (RAR/RXR) heterodimer to the RA-responsive element (beta RARE). Dimethyl sulfate-based genomic footprinting was performed to examine occupancy of this promoter in P19 EC cells. No footprint was detected at the beta RARE prior to RA treatment, but a footprint was detected within the first hour of RA treatment. Concomitantly, other elements in the promoter, the cyclic AMP-responsive element and tetradecanoyl phorbol acetate-like-responsive element became footprinted. Footprints at these elements were induced by RA without requiring new protein synthesis and remained for the entire duration of RA treatment but rapidly reversed upon withdrawal of RA. A delayed protection observed at the initiator site was also reversed upon RA withdrawal. The RA-inducible footprint was not due to induction of factors that bind to these element, since in vitro assays showed that these factors are present in P19 cell extracts before RA treatment. Significantly, no RA-induced footprint was observed at any of these elements in P19 cells expressing a dominant negative RXR beta, in which RXR heterodimers are unable to bind to the beta RARE. Results indicate that binding of a liganded heterodimer receptor to the beta RARE is the initial event that allows other elements to gain access to the factors. In accordance, reporter analyses showed that a mutation in the beta RARE, but not those in other elements, abrogates RA activation of the promoter. It is likely that the RAR beta 2 promoter opens in a hierarchically ordered manner, signalled by the occupancy of liganded heterodimers. Images PMID:7969156

  19. Plasticity of photoreceptor-generating retinal progenitors revealed by prolonged retinoic acid exposure

    PubMed Central

    2011-01-01

    Background Retinoic acid (RA) is important for vertebrate eye morphogenesis and is a regulator of photoreceptor development in the retina. In the zebrafish, RA treatment of postmitotic photoreceptor precursors has been shown to promote the differentiation of rods and red-sensitive cones while inhibiting the differentiation of blue- and UV-sensitive cones. The roles played by RA and its receptors in modifying photoreceptor fate remain to be determined. Results Treatment of zebrafish embryos with RA, beginning at the time of retinal progenitor cell proliferation and prior to photoreceptor terminal mitosis, resulted in a significant alteration of rod and cone mosaic patterns, suggesting an increase in the production of rods at the expense of red cones. Quantitative pattern analyses documented increased density of rod photoreceptors and reduced local spacing between rod cells, suggesting rods were appearing in locations normally occupied by cone photoreceptors. Cone densities were correspondingly reduced and cone photoreceptor mosaics displayed expanded and less regular spacing. These results were consistent with replacement of approximately 25% of positions normally occupied by red-sensitive cones, with additional rods. Analysis of embryos from a RA-signaling reporter line determined that multiple retinal cell types, including mitotic cells and differentiating rods and cones, are capable of directly responding to RA. The RA receptors RXRγ and RARαb are expressed in patterns consistent with mediating the effects of RA on photoreceptors. Selective knockdown of RARαb expression resulted in a reduction in endogenous RA signaling in the retina. Knockdown of RARαb also caused a reduced production of rods that was not restored by simultaneous treatments with RA. Conclusions These data suggest that developing retinal cells have a dynamic sensitivity to RA during retinal neurogenesis. In zebrafish RA may influence the rod vs. cone cell fate decision. The RARαb receptor

  20. Role of retinoic acid metabolizing cytochrome P450s, CYP26, in inflammation and cancer

    PubMed Central

    Stevison, Faith; Jing, Jing; Tripathy, Sasmita; Isoherranen, Nina

    2016-01-01

    Vitamin A (retinol) and its active metabolite, all-trans-retinoic acid (atRA), play critical roles in regulating the differentiation, growth and migration of immune cells. Similarly, as critical signaling molecules in the regulation of the cell cycle, retinoids are important in cancers. Concentrations of atRA are tightly regulated in tissues, predominantly by the availability of retinol, synthesis of atRA by ALDH1A enzymes and metabolism and clearance of atRA by CYP26 enzymes. The ALDH1A and CYP26 enzymes are expressed in several cell types in the immune system and in cancer cells. In the immune system the ALDH1A and CYP26 enzymes appear to modulate RA concentrations. Consequently, alterations in the activity of ALDH1A and CYP26 enzymes are expected to change disease outcomes in inflammation. There is increasing evidence from various disease models of intestinal and skin inflammation that treatment with atRA has a positive effect on disease markers. However, whether aberrant atRA concentrations or atRA synthesis and metabolism play a role in inflammatory disease development and progression is not well understood. In cancers, especially in acute promyelocytic leukemia and neuroblastoma, increasing intracellular concentrations of atRA appears to provide clinical benefit. Inhibition of the CYP26 enzymes to increase atRA concentrations and combat therapy resistance has been pursued as a drug target in these cancers. This chapter covers the current knowledge of how atRA and retinol regulate the immune system and inflammation, how retinol and atRA metabolism is altered in inflammation and cancer and what roles atRA metabolizing enzymes have in immune responses and cancers. PMID:26233912

  1. A correlation between soil descriptions and {sup 226}Ra concentrations in Florida soils

    SciTech Connect

    Harrison, D.P.

    1992-12-31

    The soil radium content in Florida is highly variable. The range in radium concentrations, where the samples involved in this study are concerned, is from 0.1 pCi/g to 18.5 pCi/g. Low {sup 226}Ra concentrations (0.1 to 5 pCi/g) are evidenced in sands, moderate concentrations (5 to 11 pCi/g) are found in silt and gravel, and high {sup 226}Ra concentrations (>11 pCi/g) are found in soil horizons with shell, clay, and strata with phosphate. Strata containing phosphate yields a high concentration of {sup 226}Ra. The information obtained in this study, soil descriptions with their corresponding {sup 226}Ra concentrations, comes from geological cores drilled by geotechnical consultants with gamma spectrometry analysis performed by high resolution gamma spectroscopy. Concentration; of {sup 226}Ra generally increase with depth. These cores are usually terminated at 20 feet deep, with some cores being shallower than this due to hitting bedrock or encountering the water table. These frequency distributions give the core-logging geologist an approximate concentration of {sup 226}Ra based on the description of the soil. Since the correlation of {sup 226}Ra and soil descriptions can be used as a tool in assigning indoor radon potential, this study is of importance to land managers, contractors, developers, and regulating agencies who are attempting to place standards on tracts of land with {sup 226}Ra concentration used as a criterion.

  2. 238U- 230Th- 226Ra disequilibrium in young Mt. Shasta andesites and dacites

    NASA Astrophysics Data System (ADS)

    Volpe, Alan M.

    1992-11-01

    The paper describes 238U-series nuclides and 230Th/ 232Th ratios measured by mass spectrometry in mineral separates of young Mt. Shasta andesites and dacites. The results constrain the timing of recent calc-alkaline magma fractionation at this volcano. Hotlum, Misery Hill and Black Butte rocks show small, < 13% 230Th- 238U and < 6% 226Ra- 230Th, disequilibria. Plagioclase have 7-26% 226Ra excesses, magnetite and groundmass have 4-5% 226Ra deficits, and pyroxenes have equilibrium ( 226Ra/ 230Th) activity ratios. Internal ( 230Th)-( 238U)and Ba-normalized ( 226Ra)-( 230Th) isotope diagrams for Hotlum and Black Butte dacites suggest that closed-system Th-U and Ra-Th fractionation occurred less than 10,000 years ago. Significant 226Ra- 230Th disequilibria in the Black Butte dacite strongly suggests that this rock erupted more recently than 9400 years ago. Results for Hotlum andesites suggest a longer pre-eruption crystal residence time compared to the dacites. There may also have been recent open Ra-Th system changes in the melt composition. Initial Th/U ratios for the rocks are low (2.43-2.57), similar to those in mid-ocean ridge basalts (MORB), and preclude significant assimilation of crust with markedly different Th-U composition.

  3. Draft Genome of Janthinobacterium sp. RA13 Isolated from Lake Washington Sediment.

    PubMed

    McTaggart, Tami L; Shapiro, Nicole; Woyke, Tanja; Chistoserdova, Ludmila

    2015-01-01

    Sequencing the genome of Janthinobacterium sp. RA13 from Lake Washington sediment is announced. From the genome content, a versatile life-style is predicted, but not bona fide methylotrophy. With the availability of its genomic sequence, Janthinobacterium sp. RA13 presents a prospective model for studying microbial communities in lake sediments. PMID:25676775

  4. Draft Genome of Janthinobacterium sp. RA13 Isolated from Lake Washington Sediment

    PubMed Central

    McTaggart, Tami L.; Shapiro, Nicole; Woyke, Tanja

    2015-01-01

    Sequencing the genome of Janthinobacterium sp. RA13 from Lake Washington sediment is announced. From the genome content, a versatile life-style is predicted, but not bona fide methylotrophy. With the availability of its genomic sequence, Janthinobacterium sp. RA13 presents a prospective model for studying microbial communities in lake sediments. PMID:25676775

  5. IL-1Ra and its delivery strategies: inserting the association in perspective.

    PubMed

    Akash, Muhammad Sajid Hamid; Rehman, Kanwal; Chen, Shuqing

    2013-11-01

    Interleukin-1 receptor antagonist (IL-1Ra) is a naturally occurring anti-inflammatory antagonist of interleukin-1 family of pro-inflammatory cytokines. The broad spectrum anti-inflammatory effects of IL-1Ra have been investigated against various auto-immune diseases such as diabetes mellitus, rheumatoid arthritis. Despite of its outstanding broad spectrum anti-inflammatory effects, IL-1Ra has short biological half-life (4-6 h) and to cope with this problem, up till now, many delivery strategies have been applied either to extend the half-life and/or prolong the steady-state sustained release of IL-1Ra from its target site. Here in our present paper, we have provided an overview of all approaches attempted to prolong the duration of therapeutic effects of IL-1Ra either by fusing IL-1Ra using fusion protein technology to extend the half-life and/or development of new dosage forms using various biodegradable polymers to prolong its steady-state sustained release at the site of administration. These approaches have been characterized by their intended impact on either in vitro release characteristics and/or pharmacokinetic and pharmacodynamic parameters of IL-1Ra. We have also compared these delivery strategies with each other on the basis of bioactivity of IL-1Ra after fusion with fusion protein partner and/or encapsulation with biodegradable polymer. PMID:23794040

  6. [Uptake of radionuclides from soil to plant and the discovery of 226Ra, 232Th hyperaccumulator].

    PubMed

    Zhang, Zhi-Qiang; Chen, Di-Yun; Song, Gang; Yue, Yu-Mei

    2011-04-01

    11 sorts of plant samples and corresponding soil samples were collected in Conghua and Taishan, Pearl River Delta. The specific activity of 238U, 226Ra, 232Th and 40K of samples were investigated by using HPGe-gamma-ray spectra analysis. The results showed that the average specific activity of 238U, 226Ra, 232Th and 40K in soil samples were 151.8, 146.3, 226.6, 665.5 Bq/kg, which were higher than the average values of China and the world. The concentration of 238U in all sort of plants are very low and most of them are lower than detection limit, while the values of 226Ra, 232Th and 40K were high. The contents of 226Ra and 232Th in Dicranopteris dichotoma were the highest, whose average specific activity is 285.9, 986.2 Bq/kg respectively. The average bioconcentration factors (BFs)of 26Ra, 232Th of Dicranopteris dichotoma were 2.20, 4.23, respectively, the other 10 sort of plants have BFs of 2266Ra, 232Th were in the range of 10(-1)-10(-2). The bioconcentration factors and the translocation factors of 226Ra, 232Th of Dicranopteris dichotoma. were all bigger than 1, so Dicranopteris dichotoma can be defined as hyperaccumulator of 226Ra and 232Th. PMID:21717763

  7. A rapid HPLC method for simultaneous determination of tretinoin and isotretinoin in dermatological formulations.

    PubMed

    Tashtoush, Bassam M; Jacobson, Elaine L; Jacobson, Myron K

    2007-02-19

    A rapid method using an isocratic high-pressure liquid chromatography and UV detection for determination of both all-trans retinoic acid (tretinoin) and 13-cis retinoic acid (isotretinoin) in dermatological preparations is presented. Tretinoin and isotretinoin samples were extracted with acetonitrile by a procedure that can be completed in less than 10 min. Subsequent separation and quantification of amounts as low as 10 pmol was accomplished in less than 15 min using reversed-phase HPLC with isocratic elution with 0.01% trifluoroacetic acid (TFA)/acetonitrile (15:85, v/v). Validation experiments confirmed the precision and accuracy of the method. When applied to commercial tretinoin samples, recoveries of 104.9% for cream formulations and 107.7% for gel formulations were obtained. Application of the method for analysis of a tretinoin cream exposed to solar simulated light (SSL) demonstrated detection of the major photoisomerization product isotretinoin as well as 9-cis retinoic acid, demonstrating the utility of the method for studies of tretinoin photostability. The method should also facilitate studies of the formulation compatibility and photocompatibility of tretinoin with agents that may improve its clinical tolerability. PMID:17045442

  8. Search for Electric dipole moment (EDM) in laser cooled and trapped 225Ra atoms

    NASA Astrophysics Data System (ADS)

    Kalita, Mukut; Bailey, Kevin; Dietrich, Matthew; Green, John; Holt, Roy; Korsch, Wolfgang; Lu, Zheng-Tian; Lemke, Nathan; Mueller, Peter; O'Connor, Tom; Parker, Richard; Singh, Jaideep; Trimble, Will; Argonne National Laboratory Collaboration; University Of Chicago Collabration; University Of Kentucky Collaboration

    2014-05-01

    We are searching for an EDM of the diamagnetic 225Ra atom. 225Ra has nuclear spin I =1/2. Experimental sensitivity to its EDM is enhanced due to its heavy mass and the increased Schiff moment of its octupole deformed nucleus. Our experiment involves collecting laser cooled Ra atoms in a magneto-optical trap (MOT), transporting them 1 meter with a far off-resonant optical dipole trap (ODT) and then transferring the atoms to a second standing-wave ODT in our experimental chamber. We will report our recent experiences in polarizing and observing Larmor precession of 225Ra atoms in parallel electric and magnetic fields in a magnetically shielded region and progress towards a first measurement of the EDM of 225Ra. This work is supported by DOE, Office of Nuclear Physics, under contract No. DE-AC02-06CH11357 and contract No. DE-FG02-99ER41101.

  9. RA induces the neural-like cells generated from epigenetic modified NIH/3T3 cells.

    PubMed

    Zhang, Xi-Mei; Li, Qiu-Ming; Su, Dong-Ju; Wang, Ning; Shan, Zhi-Yan; Jin, Lian-Hong; Lei, Lei

    2010-03-01

    Recently, differentiated somatic cells had been reprogrammed to pluripotential state in vitro, and various tissue cells had been elicited from those cells. Epigenetic modifications allow differentiated cells to perpetuate the molecular memory needed for the cells to retain their identity. DNA methylation and histone deacetylation are important patterns involved in epigenetic modification, which take critical roles in regulating DNA expression. In this study, we dedifferentiated NIH/3T3 fibroblasts by 5-aza-2-deoxycytidine (5-aza-dC) and Trichstatin A (TSA) combination, and detected gene expression pattern, DNA methylation level, and differentiation potential of reprogrammed cells. As the results, embryonic marker Sox2, klf4, c-Myc and Oct4 were expressed in reprogrammed NIH/3T3 fibroblasts. Total DNA methylation level was significant decreased after the treatment. Moreover, exposure of the reprogrammed cells to all trans-retinoic acid (RA) medium elicited the generation of neuronal class IIIbeta-tubulin-positive, neuron-specific enolase (NSE)-positive, nestin-positive, and neurofilament light chain (NF-L)-positive neural-like cells. PMID:19263240

  10. atRA-induced apoptosis of mouse embryonic palate mesenchymal cells involves activation of MAPK pathway

    SciTech Connect

    Yu Zengli . E-mail: yuzengli@263.net; Xing Ying . E-mail: xingy@zzu.edu.cn

    2006-08-15

    Our previous studies have shown that atRA treatment resulted in cell-cycle block and growth inhibition in mouse embryonic palatal mesenchymal (MEPM). In the current study, gestation day (GD) 13 MEPM cells were used to test the hypothesis that the growth inhibition by atRA is due to apoptosis. The effects of atRA on apoptosis were assessed by performing MTT assay, Cell Death Detection ELISA and flow cytometry, respectively. Data analysis confirmed that atRA treatment induced apoptosis-like cell death, as shown by decreased cell viability and increased fragmented DNA and sub-G1 fraction. atRA-induced apoptosis was associated with upregulation of bcl-2, translocation of bax protein to the mitochondria from the cytosol, activation of caspase-3 and cytochrome c release into cytosol. atRA-induced apoptosis was abrogated by z-DEVD-fmk, a caspase-3 specific inhibitor, and z-VAD-fmk, a general caspase inhibitor, suggesting that the atRA-induced cell death of MEPM cells occurs through the cytochrome c- and caspase-3-dependent pathways. In addition, atRA treatment caused a strong and sustained activation of c-Jun N-terminal kinase (JNK) and p38 kinase (p38), as well as an early but transient activation of extracellular signal-regulated kinase (ERK). Importantly, atRA-induced DNA fragmentation and capase-3 activation were prevented by pretreatment with the JNK inhibitor (SP600125) and the p38 MAPK inhibitor (SB202190), but not by pretreatment with MEK inhibitor (U0126). From these results, we suggest that mitogen-activated protein kinase-dependent pathways is involved in the atRA-induced apoptosis of MEPM cells.

  11. Transition to turbulent thermal convection beyond Ra = 10(10) detected in numerical simulations

    PubMed

    Vincent; Yuen

    2000-05-01

    We have conducted high-resolution two-dimensional calculations for a Boussinesq convection model with a Prandtl number of unity in an aspect-ratio 3 box, going from Rayleigh numbers between 10(8) to 10(14). A grid of 1024 x 3076 grid points consisting of a cosine-sine basis set has been employed for free-slip boundary conditions. We have found evidence for a transition involving the branching of plumes at a Rayleigh number of 10(10). Inside the core of these "superplumes," the structure is extremely complex. There may be another transition at Ra of 10(12), where a secondary instability may develop in regions of the local Rayleigh number which becomes supercritical inside the core of the complex "superplumes." For Ra of 10(8) to 10(10), Ra follows a 1/3 power law in the Nusselt-Rayleigh number relationship. From Ra of 10(10) to 10(12), Ra follows a 1/2 power law. Above this value the Nusselt number becomes insensitive to the variation in the global Rayleigh number and this is due to the development of small-scale convection cells vertically aligned in the interior of the extremely high Ra number flow. The global Reynolds number scales as Re approximately Ra1/4 up to Ra of 10(14). Scaling relationships based on global properties would not work in extremely high Ra situations beyond Ra of 10(12) because of the complex turbulent layered convection in the core of the flow and the severe degradation of the boundary layers. PMID:11031571

  12. The CpxRA Two-Component System Is Essential for Citrobacter rodentium Virulence

    PubMed Central

    Thomassin, Jenny-Lee; Giannakopoulou, Natalia; Zhu, Lei; Gross, Jeremy; Salmon, Kristiana; Leclerc, Jean-Mathieu; Daigle, France; Le Moual, Hervé

    2015-01-01

    Citrobacter rodentium is a murine intestinal pathogen used as a model for the foodborne human pathogens enterohemorrhagic Escherichia coli and enteropathogenic E. coli. During infection, these pathogens use two-component signal transduction systems to detect and adapt to changing environmental conditions. In E. coli, the CpxRA two-component signal transduction system responds to envelope stress by modulating the expression of a myriad of genes. Quantitative real-time PCR showed that cpxRA was expressed in the colon of C57BL/6J mice infected with C. rodentium. To determine whether CpxRA plays a role during C. rodentium infection, a cpxRA deletion strain was generated and found to have a colonization defect during infection. This defect was independent of an altered growth rate or a defective type III secretion system, and single-copy chromosomal complementation of cpxRA restored virulence. The C. rodentium strains were then tested in C3H/HeJ mice, a lethal intestinal infection model. Mice infected with the ΔcpxRA strain survived infection, whereas mice infected with the wild-type or complemented strains succumbed to infection. Furthermore, we found that the cpxRA expression level was higher during early infection than at a later time point. Taken together, these data demonstrate that the CpxRA two-component signal transduction system is essential for the in vivo virulence of C. rodentium. In addition, these data suggest that fine-tuned cpxRA expression is important for infection. This is the first study that identifies a C. rodentium two-component transduction system required for pathogenesis. This study further indicates that CpxRA is an interesting target for therapeutics against enteric pathogens. PMID:25712925

  13. Synthesis and characterization of lanthanum phosphate nanoparticles as carriers for 223Ra and 225Ra for targeted alpha therapy

    SciTech Connect

    Rojas, J. V.; Woodward, J. D.; Chen, N.; Rondinone, A. J.; Castano, C. H.; Mirzadeh, S.

    2015-03-19

    Targeted alpha therapy (TAT) has the potential for killing specific tumor cells with minimum collateral damage to surrounding healthy tissue. Radionuclides such as 223Ra, 225Ra, and 225Ac are of special interest for radiotherapeutic applications as they emit multiple -particles during their decay. Utilizing appropriate carriers capable of retaining both the parent radioisotope as well as daughter products is important for the effective delivery of the radioisotope to the tumor site while mitigating global in vivo radiotoxicity. Methods. In this work, core and core+2 shells (NPs with 2 additional layers of cold LaPO4 deposited on the core surfaces) LaPO4 nanoparticles (NPs) were synthesized containing either 223Ra or 225Ra/225Ac and the retention of the parents and daughters within the NPs in vitro was investigated. Results. The NPs crystallized in rhabdophane phase with mean diameters of 3.4 and 6.3 nm for core and core+2 shells, respectively. The core LaPO 4 NPs retained up to 88% of 223Ra over 35 days. However, in the core+2 shell NPs, the retention of 223Ra and its daughter, 211Pb, was improved to > 99.9% over 27 days. Additionally, the retention of 225Ra/225Ac parents was > 99.98% and ~80% for the 221Fr and 213Bi daughters over 35 days for the core+2 shell NPs. Conclusions. These results suggest that LaPO4 NPs are potentially effective carriers of radium isotopes.

  14. Performance Characterization of RaPToRS Systems

    NASA Astrophysics Data System (ADS)

    Shibata, K.; Krieger, M.; Fallica, J.; Henchen, R.; Pogozelski, E.; Padalino, S.; SUNY Geneseo Collaboration; LaboratoryLaser Energetics at University of Rochester Collaboration

    2011-10-01

    The Rapid Pneumatic Transport of Radioactive Samples (RaPToRS) system can quickly and efficiently move radioactive materials from their activation site to a counting station. Facilities such as the NIF and LLE are considering these systems while NRL is currently using one. The system is essentially a 10 cm diameter pneumatic tube with a cylindrical sample carrier. The performance of the system depends on many factors, including the mass of the carrier, length of the tube, angle and difference in height of the tube's endpoints, the carrier's physical design, and the number, type, and distribution of blowers attached to the tube. These factors have been systematically examined to develop the fastest and most reliable system. The most significant factors are the mass and the vertical travel of the carrier. When the carrier mass is low, moving air supports the carrier in the tube, resulting in low friction. The terminal velocity ranges from 13.5 to 2.5 m/s for masses varying from 1 kg to 3 kg. Using a single 1100 W blower, the initial force exerted on the carrier was 11.3 N. This work was supported in part by the US Department of Energy through the LLE.

  15. Rapid Pneumatic Transport of Radioactive Samples - RaPToRS

    NASA Astrophysics Data System (ADS)

    Padalino, S.; Barrios, M.; Sangster, C.

    2005-10-01

    Some ICF neutron activation diagnostics require quick retrieval of the activated sample. Minimizing retrieval times is particularly important when the half-life of the activated material is on the order of the transport time or the degree of radioactivity is close to the background counting level. These restrictions exist in current experiments performed at the Laboratory for Laser Energetics, thus motivating the development of the RaPToRS system. The system has been designed to minimize transportation time while requiring no human intervention during transport or counting. These factors will be important if the system is to be used at the NIF where radiological hazards will be present during post activation. The sample carrier is pneumatically transported via a 4 inch ID PVC pipe to a remote location in excess of 100 meters from the activation site at a speed of approximately 7 m/s. It arrives at an end station where it is dismounted robotically from the carrier and removed from its hermetic package. The sample is then placed by the robot in a counting station. This system is currently being developed to measure back-to-back gamma rays produced by positron annihilation which were emitted by activated graphite. Funded in part by the U.S. DOE under sub contract with LLE at the University of Rochester.

  16. Exogenous Carbon Applications Enhance the Simultaneous Occurrence of Growth, Morphogenesis and Rosmarinic Acid Levels in Spearmint Plantelets In Vitro

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The caffeoyl ester rosmarinic acid (RA) synthesized in the phenylpropanoid pathway exhibits several proven medicinal properties. RA is constitutively synthesized in spearmint (Mentha spicata L.) plantlets grown in vitro and its content can be manipulated by nutritional and physical treatments. Car...

  17. Determination of (210)Pb and (226)Ra/(228)Ra in continental water using HIDEX 300SL LS-spectrometer with TDCR efficiency tracing and optimized α/β-discrimination.

    PubMed

    Eikenberg, J; Beer, H; Jäggi, M

    2014-11-01

    An analytical method for determination of (210)Pb, (226)Ra and (228)Ra is presented based on adsorption on 3M Empore RadDiscs, and measurement applying liquid scintillation spectrometry (LSC) after elution. The LSC measurement was performed with optimized α/β-discrimination and isotope standardization using the triple to double coincidence ratio (TDCR). The consistency of measurement results between radioactive parent-daughter pairs (210)Pb/(210)Bi, (226)Ra/(222)Rn and (228)Ra/(228)Ac was checked in long-term counting experiments and the influence ofinterference of in-growing daughters from (226)Ra into the β-spectrum of (228)Ra+(228)Ac was studied as well. Recommendations for optimized LSC (228)Ra measurement besides presence of (226)Ra are given. PMID:24637085

  18. Combination therapies improve the anticancer activities of retinoids in neuroblastoma

    PubMed Central

    Cheung, Belamy B

    2015-01-01

    Most therapeutic protocols for child cancers use cytotoxic agents which have a narrow therapeutic index, and resulting in severe acute and chronic toxicities to normal tissues. Despite the fact that most child cancer patients achieve complete remission after chemotherapy, death still occurs due to relapse of persistent minimal residual disease (MRD) which remaining after initial cytotoxic chemotherapy. Advanced neuroblastoma (NB) is a leading cause of cancer deaths in young children. Retinoids are an important component of advanced NB therapy at the stage of MRD, yet half of all patients treated with 13-cis-retinoic acid still relapse and die. More effective combination therapies, with a lower side-effect profile, are required to improve outcomes for NB. Fenretinide or N-4-hydroxyphenyl retinamide is a synthetic derivative of retinoic acid which works on cancer cells through nuclear receptor-dependent and -independent signalling mechanisms. Moreover, several histone deacetylase inhibitors have entered early phase trials, and, suberoylanilide hydroxamic acid has been approved for use in adult cutaneous T cell lymphoma. A number of studies suggest that retinoid signal activation is necessary for histone deacetylase inhibitor activity. A better understanding of their mechanism of actions will lead to more evidence-based retinoid combination therapies. PMID:26677433

  19. Retinoic acid stimulates interstitial collagenase messenger ribonucleic acid in osteosarcoma cells

    NASA Technical Reports Server (NTRS)

    Connolly, T. J.; Clohisy, J. C.; Shilt, J. S.; Bergman, K. D.; Partridge, N. C.; Quinn, C. O.

    1994-01-01

    The rat osteoblastic osteosarcoma cell line UMR 106-01 secretes interstitial collagenase in response to retinoic acid (RA). The present study demonstrates by Northern blot analysis that RA causes an increase in collagenase messenger RNA (mRNA) at 6 h, which is maximal at 24 h (20.5 times basal) and declines toward basal level by 72 h. This stimulation is dose dependent, with a maximal response at 5 x 10(-7) M RA. Nuclear run-on assays show a greater than 20-fold increase in the rate of collagenase mRNA transcription between 12-24 h after RA treatment. Cycloheximide blocks RA stimulation of collagenase mRNA, demonstrating the need for de novo protein synthesis. RA not only causes an increase in collagenase secretion, but is known to decrease collagen synthesis in UMR 106-01 cells. In this study, the increase in collagenase mRNA is accompanied by a concomitant decrease in the level of alpha 1(I) procollagen mRNA, which is maximal at 24 h (70% decrease), with a return to near-control levels by 72 h. Nuclear run-on assays demonstrated that the decrease in alpha 1 (I) procollagen expression does not have a statistically significant transcriptional component. RA did not statistically decrease the stability of alpha 1 (I) procollagen mRNA (calculated t1/2 = 8.06 +/- 0.30 and 9.01 +/- 0.62 h in the presence and absence of RA, respectively). However, transcription and stability together probably contribute to the major decrease in stable alpha 1 (I) procollagen mRNA observed. Cycloheximide treatment inhibits basal level alpha 1 (I) procollagen mRNA accumulation, demonstrating the need for on-going protein synthesis to maintain basal expression of this gene.

  20. Metrological Determination of Natural Radioactive Isotopes {sup 226}Ra, {sup 228}Ra and {sup 210}Pb by Means of Ge Detector

    SciTech Connect

    Almeida, Maria Candida M. de; Delgado, Jose U.; Poledna, Roberto; Oliveira, Estela Maria de; Silva, Ronaldo L. da

    2008-08-07

    A metrological method to determine the activity per mass unity (activity concentration) of {sup 226}Ra and {sup 210}Pb ({sup 238}U decay series) and {sup 228}Ra ({sup 232}Th series) by gamma-ray spectrometers based on hyper-pure coaxial germanium detector was developed. In the soil the {sup 22}Ra (half-life = 1600 years) exhibits the same level of radioactivity as {sup 238}U (half-life 4.5x10{sup 9} years) because of a natural phenomenon called secular equilibrium. {sup 226}Ra decays into {sup 222}Rn (half-life = 3.8 days), a radioactive inert gas. After several days, the {sup 222}Rn naturally decays to {sup 218}Po (half-life = 3 minutes), where finally {sup 210}Pb (half-life = 22 years) is produced. The metrological capability of high-resolution gamma-ray spectrometry for naturally occurring radionuclides at environmental levels is showed, with emphasis on the use of 2 mL standard sources volume in a glass ampoule. Source preparation and calibration procedures are described. Radionuclide standards in an activity range of 10 to 250 Bq/g were produced which can be applied in a variety of environmental sample analysis (water, plant material, sediment, etc.). Uncertainties for {sup 226}Ra and {sup 210}Pb around 3% (k = 1) were obtained.

  1. Substrate Specificity and Ligand Interactions of CYP26A1, the Human Liver Retinoic Acid Hydroxylase

    PubMed Central

    Thatcher, Jayne E.; Buttrick, Brian; Shaffer, Scott A.; Shimshoni, Jakob A.; Goodlett, David R.; Nelson, Wendel L.

    2011-01-01

    All-trans-retinoic acid (atRA) is the active metabolite of vitamin A. atRA is also used as a drug, and synthetic atRA analogs and inhibitors of retinoic acid (RA) metabolism have been developed. The hepatic clearance of atRA is mediated primarily by CYP26A1, but design of CYP26A1 inhibitors is hindered by lack of information on CYP26A1 structure and structure-activity relationships of its ligands. The aim of this study was to identify the primary metabolites of atRA formed by CYP26A1 and to characterize the ligand selectivity and ligand interactions of CYP26A1. On the basis of high-resolution tandem mass spectrometry data, four metabolites formed from atRA by CYP26A1 were identified as 4-OH-RA, 4-oxo-RA, 16-OH-RA and 18-OH-RA. 9-cis-RA and 13-cis-RA were also substrates of CYP26A1. Forty-two compounds with diverse structural properties were tested for CYP26A1 inhibition using 9-cis-RA as a probe, and IC50 values for 10 inhibitors were determined. The imidazole- and triazole-containing inhibitors [S-(R*,R*)]-N-[4-[2-(dimethylamino)-1-(1H-imidazole-1-yl)propyl]-phenyl]2-benzothiazolamine (R116010) and (R)-N-[4-[2-ethyl-1-(1H-1,2,4-triazol-1-yl)butyl]phenyl]-2-benzothiazolamine (R115866) were the most potent inhibitors of CYP26A1 with IC50 values of 4.3 and 5.1 nM, respectively. Liarozole and ketoconazole were significantly less potent with IC50 values of 2100 and 550 nM, respectively. The retinoic acid receptor (RAR) γ agonist CD1530 was as potent an inhibitor of CYP26A1 as ketoconazole with an IC50 of 530 nM, whereas the RARα and RARβ agonists tested did not significantly inhibit CYP26A1. The pan-RAR agonist 4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl]benzoic acid and the peroxisome proliferator-activated receptor ligands rosiglitazone and pioglitazone inhibited CYP26A1 with IC50 values of 3.7, 4.2, and 8.6 μM, respectively. These data demonstrate that CYP26A1 has high ligand selectivity but accepts structurally related nuclear

  2. Effects of retinoic acid on the differentiation of chondrogenic progenitor cells, ATDC5.

    PubMed

    Kirimoto, Akiko; Takagi, Yuzo; Ohya, Keiichi; Shimokawa, Hitoyata

    2005-09-01

    Chondrocyte differentiation is a fundamental process during endochondral ossification. Retinoic acid (RA) has been shown to regulate this process, however, the mechanisms underlying RA regulation of chondrogenesis are not clearly understood. Chondroprogenitor cells, ATDC5 have been shown to be a useful in vitro model for examining the multiple step differentiation of chondrocytes. The present study investigated the mechanisms underlying RA regulation of chondrogenesis using ATDC5 cell culture. In this study, we show that RA suppresses the cell growth, cartilage nodule formation, accumulation of proteoglycan, alkaline phosphatase (ALPase) activity and mineralization and that RA dose dependently upregulates the levels of type X collagen and matrix metalloproteinase-13 (MMP-13) mRNA which are marker proteins of hypertrophic chondrocytes, in ATDC5 cells. The addition of protein synthesis inhibitor, cycloheximide (CHX), partially inhibits the induction of type X collagen and MMP-13 mRNA by RA. In this system, RA upregulates the mRNA level of Runx2/Cbfa1 (type II), a positive regulator for mineralization, and downregulates the mRNA of Indian hedgehog (Ihh), parathyroid hormone related protein (PTHrP), negative regulators for terminal differentiation. However, RA downregulates ALPase, bone gla protein (BGP) mRNAs and mineralization. These data indicate that RA stimulates cartilage differentiation, however, cell condensation and cartilage nodule formation may be candidates of primary importance in the terminal differentiation of chondrocytes. PMID:16350840

  3. Regulation by retinoic acid of acylation-stimulating protein and complement C3 in human adipocytes.

    PubMed Central

    Scantlebury, T; Sniderman, A D; Cianflone, K

    2001-01-01

    Acylation-stimulating protein (ASP), a product of complement C3, stimulates triacylglycerol synthesis in adipocytes. Previous studies have identified transthyretin, associated with chylomicrons, as a stimulator of C3 and ASP production. Since both transthyretin and chylomicrons transport retinyl ester/retinol, our goal was to investigate whether retinoic acid (RA) could be a potential hormonal mediator of the effect. Inhibitors of protein synthesis and protein secretion eliminated the stimulatory effects of chylomicrons on both C3 and ASP production in human differentiated adipocytes, suggesting that de novo protein synthesis and secretion are both required. Incubation with chylomicrons increased C3 mRNA levels (37+/-1.5%). RA alone or with chylomicrons had a stimulatory effect on C3 production (29-fold at 16.6 nM RA) and ASP production. An RA receptor antagonist blocked stimulation of C3 mRNA and C3 secretion by both RA and chylomicrons. Finally, RA and chylomicrons activated a 1.8 kb C3-promoter-luciferase construct transfected into 3T3-F442 and 3T3-L1 cells (by 41+/-0.2% and 69+/-0.3% respectively), possibly via RA receptor half-sites identified by sequence analysis. This is the first evidence documenting stimulation by RA of the C3 gene. Thus we propose RA as a novel cellular trigger in chylomicrons that subsequently results in increased ASP production by adipocytes after a meal. PMID:11368771

  4. The CpxRA two-component system contributes to Legionella pneumophila virulence.

    PubMed

    Tanner, Jennifer R; Li, Laam; Faucher, Sébastien P; Brassinga, Ann Karen C

    2016-06-01

    The bacterium Legionella pneumophila is capable of intracellular replication within freshwater protozoa as well as human macrophages, the latter of which results in the serious pneumonia Legionnaires' disease. A primary factor involved in these host cell interactions is the Dot/Icm Type IV secretion system responsible for translocating effector proteins needed to establish and maintain the bacterial replicative niche. Several regulatory factors have been identified to control the expression of the Dot/Icm system and effectors, one of which is the CpxRA two-component system, suggesting essentiality for virulence. In this study, we generated cpxR, cpxA and cpxRA in-frame null mutant strains to further delineate the role of the CpxRA system in bacterial survival and virulence. We found that cpxR is essential for intracellular replication within Acanthamoeba castellanii, but not in U937-derived macrophages. Transcriptome analysis revealed that CpxRA regulates a large number of virulence-associated proteins including Dot/Icm effectors as well as Type II secreted substrates. Furthermore, the cpxR and cpxRA mutant strains were more sodium resistant than the parental strain Lp02, and cpxRA expression reaches maximal levels during postexponential phase. Taken together, our findings suggest the CpxRA system is a key contributor to L. pneumophila virulence in protozoa via virulence factor regulation. PMID:26934669

  5. Carbachol-Induced Reduction in the Activity of Adult Male Zebra Finch RA Projection Neurons

    PubMed Central

    Meng, Wei; Wang, Song-Hua; Li, Dong-Feng

    2016-01-01

    Cholinergic mechanism is involved in motor behavior. In songbirds, the robust nucleus of the arcopallium (RA) is a song premotor nucleus in the pallium and receives cholinergic inputs from the basal forebrain. The activity of projection neurons in RA determines song motor behavior. Although many evidences suggest that cholinergic system is implicated in song production, the cholinergic modulation of RA is not clear until now. In the present study, the electrophysiological effects of carbachol, a nonselective cholinergic receptor agonist, were investigated on the RA projection neurons of adult male zebra finches through whole-cell patch-clamp techniques in vitro. Our results show that carbachol produced a significant decrease in the spontaneous and evoked action potential (AP) firing frequency of RA projection neurons, accompanying a hyperpolarization of the membrane potential, an increase in the evoked AP latency, afterhyperpolarization (AHP) peak amplitude, and AHP time to peak, and a decrease in the membrane input resistance, membrane time constant, and membrane capacitance. These results indicate that carbachol reduces the activity of RA projection neurons by hyperpolarizing the resting membrane potential and increasing the AHP and the membrane conductance, suggesting that the cholinergic modulation of RA may play an important role in song production. PMID:26904300

  6. 228Ra flux in the northwestern Pacific marginal seas: Implications for disproportionally large submarine groundwater discharge

    NASA Astrophysics Data System (ADS)

    Kim, Jeonghyun; Cho, Hyung-Mi; Kim, Guebuem

    2015-06-01

    To determine the fluxes of 228Ra (half life: 5.75 years) to the northwestern Pacific marginal seas, 228Ra data were compiled for the East China Sea, Yellow Sea, South Sea, and East/Japan Sea. Most of the 228Ra data in the East Sea were newly obtained through the onboard surveys in July 2012, October 2012, and March 2013. A 228Ra mass balance model was established by considering the input fluxes from the Pacific Ocean, river, atmosphere, sediments, and submarine groundwater discharge (SGD) and the output fluxes by radioactive decay and to the Pacific Ocean and the deep East Sea through vertical mixing. Using this model, the 228Ra flux through SGD was estimated to be at least 2.3 × 1015 dpm yr-1 in the entire area of these marginal seas, which is about 20% of the total 228Ra input flux to this region. This SGD-driven 228Ra flux to this region accounts for about 2% of that to the global oceans. This result implies that the magnitude of SGD in this region could be disproportionally larger than those in general oceanic margins. We suggest that SGD may play a critical role in the delivery of terrestrial materials to these large marginal seas, perhaps due to large tidal pumping.

  7. Chronic retinoic acid treatment suppresses adult hippocampal neurogenesis, in close correlation with depressive-like behavior.

    PubMed

    Hu, Pu; Wang, Yu; Liu, Ji; Meng, Fan-Tao; Qi, Xin-Rui; Chen, Lin; van Dam, Anne-Marie; Joëls, Marian; Lucassen, Paul J; Zhou, Jiang-Ning

    2016-07-01

    Clinical studies have highlighted an association between retinoid treatment and depressive symptoms. As we had shown before that chronic application of all-trans retinoic acid (RA) potently activated the hypothalamus-pituitary-adrenal (HPA) stress axis, we here questioned whether RA also induced changes in adult hippocampal neurogenesis, a form of structural plasticity sensitive to stress and implicated in aspects of depression and hippocampal function. RA was applied intracerebroventricularly (i.c.v.) to adult rats for 19 days after which animals were subjected to tests for depressive-like behavior (sucrose preference) and spatial learning and memory (water maze) performance. On day 27, adult hippocampal neurogenesis and astrogliosis was quantified using BrdU (newborn cell survival), PCNA (proliferation), doublecortin (DCX; neuronal differentiation), and GFAP (astrocytes) as markers. RA was found to increase retinoic acid receptor-α (RAR-α) protein expression in the hippocampus, suggesting an activation of RA-induced signaling mechanisms. RA further potently suppressed cell proliferation, newborn cell survival as well as neurogenesis, but not astrogliosis. These structural plasticity changes were significantly correlated with scores for anhedonia, a core symptom of depression, but not with water maze performance. Our results suggest that RA-induced impairments in hippocampal neurogenesis correlate with depression-like symptoms but not with spatial learning and memory in this design. Thus, manipulations aimed to enhance neurogenesis may help ameliorate emotional aspects of RA-associated mood disorders. © 2016 Wiley Periodicals, Inc. PMID:26860546

  8. QM/MM Refinement and Analysis of Protein Bound Retinoic Acid

    PubMed Central

    Li, Xue; Fu, Zheng; Merz, Kenneth M.

    2011-01-01

    Retinoic acid (RA) is a vitamin A derivative, which modifies the appearance of fine wrinkles and roughness of facial skin and treats acne and activates gene transcription by binding to heterodimers of the retinoic acid receptor (RAR) and the retinoic X receptor (RXR). There are series of protein bound RA complexes available in the protein databank (PDB), which provides a broad range of information about the different bioactive conformations of RA. In order to gain further insights into the observed bioactive RA conformations we applied quantum mechanic (QM)/molecular mechanic (MM) approaches to re-refine the available RA protein-ligand complexes. MP2 complete basis set (CBS) extrapolations single energy calculations are also carried out for both the experimental conformations and QM optimized geometries of RA in the gas as well as solution phase. The results demonstrate that the re-refined structures show better geometries for RA than seen in the originally deposited PDB structures through the use of quantum mechanics for the ligand in the X-ray refinement procedure. QM/MM re-refined conformations also reduced the computed strain energies found in the deposited crystal conformations for RA. Finally, the dependence of ligand strain on resolution is analyzed. It is shown that ligand strain is not converged in our calculations and is likely an artifact of the typical resolutions employed to study protein-ligand complexes. PMID:22108894

  9. Transcriptional Factors Mediating Retinoic Acid Signals in the Control of Energy Metabolism.

    PubMed

    Zhang, Rui; Wang, Yueqiao; Li, Rui; Chen, Guoxun

    2015-01-01

    Retinoic acid (RA), an active metabolite of vitamin A (VA), is important for many physiological processes including energy metabolism. This is mainly achieved through RA-regulated gene expression in metabolically active cells. RA regulates gene expression mainly through the activation of two subfamilies in the nuclear receptor superfamily, retinoic acid receptors (RARs) and retinoid X receptors (RXRs). RAR/RXR heterodimers or RXR/RXR homodimers bind to RA response element in the promoters of RA target genes and regulate their expressions upon ligand binding. The development of metabolic diseases such as obesity and type 2 diabetes is often associated with profound changes in the expressions of genes involved in glucose and lipid metabolism in metabolically active cells. RA regulates some of these gene expressions. Recently, in vivo and in vitro studies have demonstrated that status and metabolism of VA regulate macronutrient metabolism. Some studies have shown that, in addition to RARs and RXRs, hepatocyte nuclear factor 4α, chicken ovalbumin upstream promoter-transcription factor II, and peroxisome proliferator activated receptor β/δ may function as transcriptional factors mediating RA response. Herein, we summarize current progresses regarding the VA metabolism and the role of nuclear receptors in mediating RA signals, with an emphasis on their implication in energy metabolism. PMID:26110391

  10. Transcriptional Factors Mediating Retinoic Acid Signals in the Control of Energy Metabolism

    PubMed Central

    Zhang, Rui; Wang, Yueqiao; Li, Rui; Chen, Guoxun

    2015-01-01

    Retinoic acid (RA), an active metabolite of vitamin A (VA), is important for many physiological processes including energy metabolism. This is mainly achieved through RA-regulated gene expression in metabolically active cells. RA regulates gene expression mainly through the activation of two subfamilies in the nuclear receptor superfamily, retinoic acid receptors (RARs) and retinoid X receptors (RXRs). RAR/RXR heterodimers or RXR/RXR homodimers bind to RA response element in the promoters of RA target genes and regulate their expressions upon ligand binding. The development of metabolic diseases such as obesity and type 2 diabetes is often associated with profound changes in the expressions of genes involved in glucose and lipid metabolism in metabolically active cells. RA regulates some of these gene expressions. Recently, in vivo and in vitro studies have demonstrated that status and metabolism of VA regulate macronutrient metabolism. Some studies have shown that, in addition to RARs and RXRs, hepatocyte nuclear factor 4α, chicken ovalbumin upstream promoter-transcription factor II, and peroxisome proliferator activated receptor β/δ may function as transcriptional factors mediating RA response. Herein, we summarize current progresses regarding the VA metabolism and the role of nuclear receptors in mediating RA signals, with an emphasis on their implication in energy metabolism. PMID:26110391

  11. Behavior of /sup 226/Ra in the Mississippi River mixing zone

    SciTech Connect

    Moore, D.G.; Scott, M.R.

    1986-12-15

    The behavior of /sup 226/Ra in the Mississippi River mixing zone is strongy nonconservative and includes desorption similar to that for the Hudson, Pee Dee, and Amazon rivers. However, dissolved and desorbed /sup 226/Ra concentrations in the Mississippi are 2 to 5 times greater than in the other rivers at the same salinity. Radium concentrations vary inversely with the water discharge rate. The /sup 226/Ra desorption maximum occurs at a salinity of 5.0, much lower than the 18 to 28 salinity values for the maxima of the other three rivers. High concentrations of dissolved /sup 226/Ra (up to 82 dpm per 100 L) and the low salinity values for the desorption maximum in the Mississippi River result from three major factors. Suspended sediments include a large fraction of montmorillonite, which gives the sediment a high cation exchange capacity. 0.54 meq/g. The average suspended sediment load is large, about 510 mg/L, and contains 1.9 dpm g desorbable /sup 226/Ra. The dissolved /sup 226/Ra river water end-member (9.6 dpm per 100 L) is higher than in surface seawater. The annual contribution of /sup 226/Ra to the ocean from the Mississippi River is 3.7 x 10/sup 14/ dmp/yr based on data from three cruises. Evidence of flux of /sup 226/Ra from estuarine and shelf sediments is common in vertical profile sampling of the deltaic waters but is not reflected in calculations made with an ''apparent'' river water Ra value extrapolated to zero salinity.

  12. Molecular mechanism of 9-cis-retinoic acid inhibition of adipogenesis in 3T3-L1 cells

    SciTech Connect

    Sagara, Chiaki; Takahashi, Katsuhiko; Kagechika, Hiroyuki; Takahashi, Noriko

    2013-03-29

    Highlights: ► We examined the effects of 9-cis-RA on adipogenesis in mouse preadipocyte 3T3-L1. ► 9-cis-RA inhibited lipid accumulation in adipogenetically-induced 3T3-L1 cells. ► A RXR pan-antagonist suppressed the inhibitory effects of 9-cis-RA on adipogenesis. ► This antagonist had no effects on RXRα and PPARγ levels in 9-cis-RA-treated cells. ► 9-cis-RA-induced decrease in both RXRα and PPARγ was independent of RXR activation. -- Abstract: Retinoic acid (RA) signaling is mediated by specific nuclear hormone receptors. Here we examined the effects of 9-cis-RA on adipogenesis in mouse preadipocyte 3T3-L1 cells. 9-cis-RA inhibits the lipid accumulation of adipogenetically induced 3T3-L1 cells. The complex of retinoid X receptor α (RXRα) with peroxisome proliferator-activated receptor γ (PPARγ) is a major transcription factor in the process of adipogenesis, and the levels of these molecules were decreased by 9-cis-RA treatment. A RXR pan-antagonist suppressed 9-cis-RA’s inhibitory effects on adipogenesis, but not on the intracellular levels of both RXRα and PPARγ. These results suggest that 9-cis-RA could inhibit adipogenesis by activating RXR, and decrease both RXR and PPARγs levels in a RXR activation-independent manner.

  13. Retinoic acid triggers meiosis initiation via stra8-dependent pathway in Southern catfish, Silurus meridionalis.

    PubMed

    Li, Minghui; Feng, Ruijuan; Ma, He; Dong, Ranran; Liu, Zhilong; Jiang, Wentao; Tao, Wenjing; Wang, Deshou

    2016-06-01

    Existing studies demonstrated that retinoic acid (RA) regulates meiotic initiation via stra8-independent pathway in teleosts which lack stra8 in their genomes. However, stra8 was recently identified from several fish species including Southern catfish (Silurus meridionalis). To explore the existence of stra8-dependent pathway in RA mediated meiotic initiation in fishes, in the present study, the genes encoding RA synthase aldh1a2 and catabolic enzyme cyp26a1 and cyp26b1 were cloned from the Southern catfish. By immunohistochemistry, Aldh1a2 signal was observed in gonads of both sexes during the meiotic initiation period. By real-time PCR, differentially expressed gene was observed for cyp26a1, but not for cyp26b1, in gonads during the meiotic initiation. Administration of exogenous RA or inhibition of endogenous RA degradation by either KET (RA catabolic enzyme inhibitor) or cyp26a1 knockdown using CRISPR/Cas9 induced advanced meiotic initiation in the ovaries as demonstrated by increased Stra8/stra8 expression and appearance of oocytes. In contrast, treatment with RA synthase inhibitor DEAB resulted in delayed meiotic initiation and Stra8/stra8 expression in the ovaries, which was rescued by exogenous RA administration. These results indicated that (1) RA triggers the onset of meiosis via stra8-dependent pathway in stra8 existing teleosts, as it does in tetrapods; (2) exogenous RA can rescue the endogenous RA deficiency; (3) Cyp26a1, instead of Cyp26b1, is the key catabolic enzyme involved in meiosis initiation in teleosts. Taken together, RA might trigger meiotic initiation via stra8-dependent and -independent pathway in different teleosts. PMID:26764212

  14. Abscisic-acid-induced cellular apoptosis and differentiation in glioma via the retinoid acid signaling pathway.

    PubMed

    Zhou, Nan; Yao, Yu; Ye, Hongxing; Zhu, Wei; Chen, Liang; Mao, Ying

    2016-04-15

    Retinoid acid (RA) plays critical roles in regulating differentiation and apoptosis in a variety of cancer cells. Abscisic acid (ABA) and RA are direct derivatives of carotenoids and share structural similarities. Here we proposed that ABA may also play a role in cellular differentiation and apoptosis by sharing a similar signaling pathway with RA that may be involved in glioma pathogenesis. We reported for the first time that the ABA levels were twofold higher in low-grade gliomas compared with high-grade gliomas. In glioma tissues, there was a positive correlation between the ABA levels and the transcription of cellular retinoic acid-binding protein 2 (CRABP2) and a negative correlation between the ABA levels and transcription of fatty acid-binding protein 5 (FABP5). ABA treatment induced a significant increase in the expression of CRABP2 and a decrease in the expression of peroxisome proliferator-activated receptor (PPAR) in glioblastoma cells. Remarkably, both cellular apoptosis and differentiation were increased in the glioblastoma cells after ABA treatment. ABA-induced cellular apoptosis and differentiation were significantly reduced by selectively silencing RAR-α, while RAR-α overexpression exaggerated the ABA-induced effects. These results suggest that ABA may play a role in the pathogenesis of glioma by promoting cellular apoptosis and differentiation through the RA signaling pathway. PMID:26594836

  15. Effects of retinoids on differentiation, lipid metabolism, epidermal growth factor, and low-density lipoprotein binding in squamous carcinoma cells

    SciTech Connect

    Ponec, M.; Weerheim, A. ); Havekes, L. ); Boonstra, J. )

    1987-08-01

    The relationship among keratinocyte differentiation capacity, lipid synthesis, low-density lipoprotein (LDL) metabolism, plasma membrane composition, and epidermal growth factor (EGF) binding has been studied in SCC-12F2 cells. The differentiation capacity of the cells, i.e., ionophore-induced cornified envelope formation, was inhibited by various retinoids and stimulated by hydrocortisone. Retinoids that caused a significant reduction of cornified envelope formation, i.e., retinoic acid and 13-cis-retinoic acid, caused only minor changes in lipid synthesis and plasma membrane composition. Arotinoid ethylsulfone, having a minor effect on cornified envelope formation, caused a drastic inhibition of cholesterol synthesis resulting in changes in the plasma membrane composition. Hydrocortisone stimulated cornified envelope formation but had only minor effects on lipid synthesis and plasma membrane composition. Of all retinoids tested, only arotinoid ethylsulfone caused a drastic increase in EGF binding, while hydrocortisone had no effect. These results clearly demonstrate that the plasma membrane composition is not related to keratinocyte differentiation capacity, but most likely does determine EGF binding. Furthermore, EGF binding does not determine keratinocyte differentiation capacity.

  16. Evaluation of 224Ra as a tracer for submarine groundwater discharge in Long Island Sound (NY)

    NASA Astrophysics Data System (ADS)

    Garcia-Orellana, J.; Cochran, J. K.; Bokuniewicz, H.; Daniel, J. W. R.; Rodellas, V.; Heilbrun, C.

    2014-09-01

    The approach to quantify submarine groundwater discharge using Ra isotopes generally involves developing a Ra mass balance in an estuary, bay or lagoon. In this work we present a 224Ra mass balance used to evaluate the importance of the submarine groundwater discharge (SGD) in Long Island Sound (NY, US), the third most important estuary in US, located between Long Island and Connecticut that is usually affected by summertime hypoxia in the western basin. Three surveys were conducted between April 2009 and August 2010 where 25 water stations were sampled for Ra isotopes, oxygen and Mn. Stations were oriented along 4 transects: one axial extending from the western to the eastern Sound and three longitudinal transects in the western, central and eastern Sound. The inventory of 224Ra in the water column in summer was circa 2 times greater than in winter, suggesting an increased 224Ra flux to the Sound in summer. A mass balance for 224Ra was constructed considering tidal exchange, inputs from rivers, desorption from resuspended particles, diffusive fluxes (including bioirrigation) from bottom sediments and radioactive decay in the water column. Fluxes of 224Ra from bottom sediments were measured by incubating cores under oxic conditions in a continuous flow mode such that the overlying water was circulated through a Mn-oxide fiber to maintain a constant activity of 224Ra. Fluxes from muddy sediments (comprising ∼67% of the Sound bottom) ranged from 127 to 312 dpm m-2 d-1 and were ∼60 dpm m-2 d-1 in sandy sediments (33% of the Sound). Incubations under hypoxic conditions showed variable fluxes depending on reduction and mobilization of Mn. The 224Ra mass balance shows a net input of Ra to the Sound of 106 ± 50 × 1012 dpm y-1 in spring and 244 ± 112 × 1012 dpm y-1 in the summer that is attributed to SGD. Elevated 224Ra values were observed near shore and in the pore fluids of the coarse beach sands along the Long Island and Connecticut coasts, suggesting that SGD

  17. Measurement of non-steady-state free fatty acid turnover

    SciTech Connect

    Jensen, M.D.; Heiling, V.; Miles, J.M. )

    1990-01-01

    The accuracy of non-steady-state equations for measuring changes in free fatty acid rate of appearance (Ra) is unknown. In the present study, endogenous lipolysis (traced with ({sup 14}C)-linoleate) was pharmacologically suppressed in six conscious mongrel dogs. A computer-responsive infusion pump was then used to deliver an intravenous oleic acid emulsion in both constant and linear gradient infusion modes. Both non-steady-state equations with various effective volumes of distribution (V) and steady-state equations were used to measure oleate Ra (({sup 14}C)oleate). Endogenous lipolysis did not change during the experiment. When oleate Ra increased in a linear gradient fashion, only non-steady-state equations with a large (150 ml/kg) V resulted in erroneous values (9% overestimate, P less than 0.05). In contrast, when oleate Ra decreased in a similar fashion, steady-state and standard non-steady-state equations (V = plasma volume = 50 ml/kg) overestimated total oleate Ra (18 and 7%, P less than 0.001 and P less than 0.05, respectively). Overall, non-steady-state equations with an effective V of 90 ml/kg (1.8 x plasma volume) allowed the most accurate estimates of oleate Ra.

  18. Induction of carnitine palmitoyl transferase 1 and fatty acid oxidation by retinoic acid in HepG2 cells.

    PubMed

    Amengual, Jaume; Petrov, Petar; Bonet, M Luisa; Ribot, Joan; Palou, Andreu

    2012-11-01

    The vitamin A derivative retinoic acid (RA) is an important regulator of mammalian adiposity and lipid metabolism, primarily acting at the gene expression level through nuclear receptors of the RA receptor (RAR) and retinoid X receptor (RXR) subfamilies. Here, we studied cell-autonomous effects of RA on fatty acid metabolism, particularly fatty acid oxidation, in human hepatoma HepG2 cells. Exposure to all-trans RA (ATRA) up-regulated the expression of carnitine palmitoyl transferase-1 (CPT1-L) in HepG2 cells in a dose- and time-dependent manner, and increased cellular oxidation rate of exogenously added radiolabeled palmitate. The effect of ATRA on gene expression of CPT1-L was: dependent on ongoing transcription, reproduced by both 9-cis RA and a pan-RXR agonist (but not a pan-RAR agonist) and abolished following RXRα partial siRNA-mediated silencing. CPT1-L gene expression was synergistically induced in HepG2 cells simultaneously exposed to ATRA and a selective peroxisome proliferator-activated receptor α agonist. We conclude that ATRA treatment enhances fatty acid catabolism in hepatocytes through RXR-mediated mechanisms that likely involve the transactivation of the PPARα:RXR heterodimer. Knowledge of agents and nutrient-derivatives capable of enhancing substrate oxidation systemically and specifically in liver, and their mechanisms of action, may contribute to new avenues of prevention and treatment of fatty liver, obesity and other metabolic syndrome-related disorders. PMID:22871568

  19. Retinoic acid induces nuclear FAK translocation and reduces breast cancer cell adhesion through Moesin, FAK, and Paxillin.

    PubMed

    Sanchez, Angel Matías; Shortrede, Jorge Eduardo; Vargas-Roig, Laura María; Flamini, Marina Inés

    2016-07-15

    Breast cancer is the most common malignancy in women, with metastases being the cause of death in 98%. In previous works we have demonstrated that retinoic acid (RA), the main retinoic acid receptor (RAR) ligand, is involved in the metastatic process by inhibiting migration through a reduced expression of the specific migration-related proteins Moesin, c-Src, and FAK. At present, our hypothesis is that RA also acts for short periods in a non-genomic action to cooperate with motility reduction and morphology of breast cancer cells. Here we identify that the administration of 10(-6) M RA (10-20 min) induces the activation of the migration-related proteins Moesin, FAK, and Paxillin in T-47D breast cancer cells. The phosphorylation exerted by the selective agonists for RARα and RARβ, on Moesin, FAK, and Paxillin was comparable to the activation exerted by RA. The RARγ agonist only led to a weak activation, suggesting the involvement of RARα and RARβ in this pathway. We then treated the cells with different inhibitors that are involved in cell signaling to regulate the mechanisms of cell motility. RA failed to activate Moesin, FAK, and Paxillin in cells treated with Src inhibitor (PP2) and PI3K inhibitor (WM), suggesting the participation of Src-PI3K in this pathway. Treatment with 10(-6) M RA for 20 min significantly decreased cell adhesion. However, when cells were treated with 10(-6) M RA and FAK inhibitor, the RA did not significantly inhibit adhesion, suggesting a role of FAK in the adhesion inhibited by RA. By immunofluorescence and immunoblotting analysis we demonstrated that RA induced nuclear FAK translocation leading to a reduced cellular adhesion. These findings provide new information on the actions of RA for short periods. RA participates in cell adhesion and subsequent migration, modulating the relocation and activation of proteins involved in cell migration. PMID:27130522

  20. Permeability of Rosmarinic acid in Prunella vulgaris and Ursolic acid in Salvia officinalis Extracts across Caco-2 Cell Monolayers

    PubMed Central

    Qiang, Zhiyi; Ye, Zhong; Hauck, Cathy; Murphy, Patricia A.; McCoy, Joe-Ann; Widrlechner, Mark P.; Reddy, Manju B.; Hendrich, Suzanne

    2011-01-01

    Ethnopharmacological relevance Rosmarinic acid (RA), a caffeic acid-related compound found in high concentrations in Prunella vulgaris (self-heal), and ursolic acid (UA), a pentacyclic triterpene acid concentrated in Salvia officinalis (sage), have been traditionally used to treat inflammation in the mouth, and may also be beneficial for gastrointestinal health in general. Aim of the study To investigate the permeabilities of RA and UA as pure compounds and in P. vulgaris and S. officinalis ethanol extracts across human intestinal epithelial Caco-2 cell monolayers. Materials and methods The permeabilities and Phase II biotransformation of RA and UA as pure compounds and in herbal extracts were compared using Caco-2 cells with HPLC detection. Results The apparent permeability coefficient (Papp) for RA and RA in P. vulgaris extracts was 0.2 ± 0.05 × 10−6 cm/s, significantly increased to 0.9 ± 0.2 × 10−6 cm/s after β-glucuronidase/sulfatase treatment. Papp for UA and UA in S. officinalis extract was 2.7 ± 0.3 × 10−6 cm/s and 2.3 ± 0.5 × 10−6 cm/s before and after β-glucuronidase/sulfatase treatment, respectively. Neither compound was affected in permeability by the herbal extract matrix. Conclusion RA and UA in herbal extracts had similar uptake as that found using the pure compounds, which may simplify the prediction of compound efficacy, but the apparent lack of intestinal glucuronidation/sulfation of UA is likely to further enhance the bioavailability of that compound compared with RA. PMID:21798330

  1. Altered retinoic acid signalling underpins dentition evolution.

    PubMed

    Gibert, Yann; Samarut, Eric; Pasco-Viel, Emmanuel; Bernard, Laure; Borday-Birraux, Véronique; Sadier, Alexa; Labbé, Catherine; Viriot, Laurent; Laudet, Vincent

    2015-03-01

    Small variations in signalling pathways have been linked to phenotypic diversity and speciation. In vertebrates, teeth represent a reservoir of adaptive morphological structures that are prone to evolutionary change. Cyprinid fish display an impressive diversity in tooth number, but the signals that generate such diversity are unknown. Here, we show that retinoic acid (RA) availability influences tooth number size in Cyprinids. Heterozygous adult zebrafish heterozygous for the cyp26b1 mutant that encodes an enzyme able to degrade RA possess an extra tooth in the ventral row. Expression analysis of pharyngeal mesenchyme markers such as dlx2a and lhx6 shows lateral, anterior and dorsal expansion of these markers in RA-treated embryos, whereas the expression of the dental epithelium markers dlx2b and dlx3b is unchanged. Our analysis suggests that changes in RA signalling play an important role in the diversification of teeth in Cyprinids. Our work illustrates that through subtle changes in the expression of rate-limiting enzymes, the RA pathway is an active player of tooth evolution in fish. PMID:25652838

  2. Altered retinoic acid signalling underpins dentition evolution

    PubMed Central

    Gibert, Yann; Samarut, Eric; Pasco-Viel, Emmanuel; Bernard, Laure; Borday-Birraux, Véronique; Sadier, Alexa; Labbé, Catherine; Viriot, Laurent; Laudet, Vincent

    2015-01-01

    Small variations in signalling pathways have been linked to phenotypic diversity and speciation. In vertebrates, teeth represent a reservoir of adaptive morphological structures that are prone to evolutionary change. Cyprinid fish display an impressive diversity in tooth number, but the signals that generate such diversity are unknown. Here, we show that retinoic acid (RA) availability influences tooth number size in Cyprinids. Heterozygous adult zebrafish heterozygous for the cyp26b1 mutant that encodes an enzyme able to degrade RA possess an extra tooth in the ventral row. Expression analysis of pharyngeal mesenchyme markers such as dlx2a and lhx6 shows lateral, anterior and dorsal expansion of these markers in RA-treated embryos, whereas the expression of the dental epithelium markers dlx2b and dlx3b is unchanged. Our analysis suggests that changes in RA signalling play an important role in the diversification of teeth in Cyprinids. Our work illustrates that through subtle changes in the expression of rate-limiting enzymes, the RA pathway is an active player of tooth evolution in fish. PMID:25652838

  3. Expression of the retinoic acid catabolic enzyme CYP26B1 in the human brain to maintain signaling homeostasis.

    PubMed

    Stoney, Patrick N; Fragoso, Yara D; Saeed, Reem Bu; Ashton, Anna; Goodman, Timothy; Simons, Claire; Gomaa, Mohamed S; Sementilli, Angelo; Sementilli, Leonardo; Ross, Alexander W; Morgan, Peter J; McCaffery, Peter J

    2016-07-01

    Retinoic acid (RA) is a potent regulator of gene transcription via its activation of a set of nuclear receptors controlling transcriptional activation. Precise maintenance of where and when RA is generated is essential and achieved by local expression of synthetic and catabolic enzymes. The catabolic enzymes Cyp26a1 and Cyp26b1 have been studied in detail in the embryo, where they limit gradients of RA that form patterns of gene expression, crucial for morphogenesis. This paracrine role of RA has been assumed to occur in most tissues and that the RA synthetic enzymes release RA at a site distant from the catabolic enzymes. In contrast to the embryonic CNS, relatively little is known about RA metabolism in the adult brain. This study investigated the distribution of Cyp26a1 and Cyp26b1 transcripts in the rat brain, identifying several novel regions of expression, including the cerebral cortex for both enzymes and striatum for Cyp26b1. In vivo use of a new and potent inhibitor of the Cyp26 enzymes, ser 2-7, demonstrated a function for endogenous Cyp26 in the brain and that hippocampal RA levels can be raised by ser 2-7, altering the effect of RA on differential patterning of cell proliferation in the hippocampal region of neurogenesis, the subgranular zone. The expression of CYP26A1 and CYP26B1 was also investigated in the adult human brain and colocalization of CYP26A1 and the RA synthetic enzyme RALDH2 indicated a different, autocrine role for RA in human hippocampal neurons. Studies with the SH-SY5Y human neuroblastoma cell line implied that the co-expression of RA synthetic and catabolic enzymes maintains retinoid homeostasis within neurons. This presents a novel view of RA in human neurons as part of an autocrine, intracellular signaling system. PMID:26374207

  4. 112. HISTORIC AMERICAN BUILDINGS SURVEY R.A. Waugh, Photographer October 1936 ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    112. HISTORIC AMERICAN BUILDINGS SURVEY R.A. Waugh, Photographer October 1936 NOTCHING in STUDS for OLD WINDOW FRAMES, NORTH WALL, ORIGINAL KITCHEN, LOOKING NORTH - Colonel Paul Wentworth House, Dover Street (moved to MA, Dover), Dover, Strafford County, NH

  5. 100. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    100. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 STUDS & SLOTS for FORMER WINDOW, SOUTH WALL, WEST BAY, 2nd FLOOR LOOKING SOUTH - Colonel Paul Wentworth House, Dover Street (moved to MA, Dover), Dover, Strafford County, NH

  6. 79. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    79. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ATTIC FLOOR TIMBER in LEAN-TO INVERTED - Colonel Paul Wentworth House, Dover Street (moved to MA, Dover), Dover, Strafford County, NH

  7. 73. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    73. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 SOUTH END of WEST PLATE (INVERTED) - Colonel Paul Wentworth House, Dover Street (moved to MA, Dover), Dover, Strafford County, NH

  8. First Measurement of the Atomic Electric Dipole Moment of (225)Ra.

    PubMed

    Parker, R H; Dietrich, M R; Kalita, M R; Lemke, N D; Bailey, K G; Bishof, M; Greene, J P; Holt, R J; Korsch, W; Lu, Z-T; Mueller, P; O'Connor, T P; Singh, J T

    2015-06-12

    The radioactive radium-225 ((225)Ra) atom is a favorable case to search for a permanent electric dipole moment. Because of its strong nuclear octupole deformation and large atomic mass, (225)Ra is particularly sensitive to interactions in the nuclear medium that violate both time-reversal symmetry and parity. We have developed a cold-atom technique to study the spin precession of (225)Ra atoms held in an optical dipole trap, and demonstrated the principle of this method by completing the first measurement of its atomic electric dipole moment, reaching an upper limit of |d((225)Ra)|<5.0×10(-22)  e cm (95% confidence). PMID:26196797

  9. Release of 226Ra from uranium mill tailings by microbial Fe(III) reduction

    USGS Publications Warehouse

    Landa, E.R.; Phillips, E.J.P.; Lovley, D.R.

    1991-01-01

    Uranium mill tailings were anaerobically incubated in the presence of H2 with Alteromonas putrefaciens, a bacterium known to couple the oxidation of H2 and organic compounds to the reduction of Fe(III) oxides. There was a direct correlation between the extent of Fe(III) reduction and the accumulation of dissolved 226Ra. In sterile tailings in which Fe(III) was not reduced, there was negligible leaching of 226Ra. The behavior of Ba was similar to that of Ra in inoculated and sterile systems. These results demonstrate that under anaerobic conditions, microbial reduction of Fe(III) may result in the release of dissolved 226Ra from uranium mill tailings. ?? 1991.

  10. 45. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    45. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 FRAMING of WEST END LOOKING SOUTH EAST - Colonel Paul Wentworth House, Dover Street (moved to MA, Dover), Dover, Strafford County, NH

  11. 43. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    43. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 FRAMING of WEST ELEVATION LOOKING NORTH EAST - Colonel Paul Wentworth House, Dover Street (moved to MA, Dover), Dover, Strafford County, NH

  12. 62. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    62. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 WEST END of 2nd FLOOR EAST SUMMER BEAM - Colonel Paul Wentworth House, Dover Street (moved to MA, Dover), Dover, Strafford County, NH

  13. 59. Historic American Buildings Survey R.A. WAUGH, Photographer October 1936 ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    59. Historic American Buildings Survey R.A. WAUGH, Photographer October 1936 POST SHOWING CUT & TENON SLOT for GIRTS - Colonel Paul Wentworth House, Dover Street (moved to MA, Dover), Dover, Strafford County, NH

  14. 44. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    44. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 FRAMING of WEST END LOOKING SOUTH EAST - Colonel Paul Wentworth House, Dover Street (moved to MA, Dover), Dover, Strafford County, NH

  15. 80. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    80. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 FRAMING of PURLIN onto RAFTER, EAST BAY LOOKING NORTH WEST - Colonel Paul Wentworth House, Dover Street (moved to MA, Dover), Dover, Strafford County, NH

  16. 74. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    74. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ELEVATION RAFTER & PLATES SOUTH WEST CORNER of MAIN HOUSE - Colonel Paul Wentworth House, Dover Street (moved to MA, Dover), Dover, Strafford County, NH

  17. 42. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    42. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 FRAMING of WEST ELEVATION LOOKING NORTH EAST - Colonel Paul Wentworth House, Dover Street (moved to MA, Dover), Dover, Strafford County, NH

  18. 83. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    83. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 SPLICING of PURLINS over INTERMEDIATE RAFTER in LEAN-TO LOOKING SOUTH EAST - Colonel Paul Wentworth House, Dover Street (moved to MA, Dover), Dover, Strafford County, NH

  19. 66. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    66. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 INTERIOR CENTER BAY REAR WALL of MAIN HOUSE 2nd FLOOR LOOKING NORTH EAST - Colonel Paul Wentworth House, Dover Street (moved to MA, Dover), Dover, Strafford County, NH

  20. 75. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    75. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 INTERMEDIATE RAFTER & PLATES LOOKING NORTH EAST, REAR RAFTER MAIN HOUSE - Colonel Paul Wentworth House, Dover Street (moved to MA, Dover), Dover, Strafford County, NH

  1. 57. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    57. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 2nd FLOOR EAST CHIMNEY GIRT, NORTH END FRAMING INTO POST - Colonel Paul Wentworth House, Dover Street (moved to MA, Dover), Dover, Strafford County, NH

  2. 84. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    84. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 END GIRT & POST, NORTH WEST CORNER MAIN HOUSE LOOKING NORTH WEST - Colonel Paul Wentworth House, Dover Street (moved to MA, Dover), Dover, Strafford County, NH

  3. 53. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    53. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 SOUTH WEST POST Last of Structure to be taken down. Looking East - Colonel Paul Wentworth House, Dover Street (moved to MA, Dover), Dover, Strafford County, NH

  4. 96. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    96. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 NORTH & WEST SILLS of MAIN HOUSE - LOOKING NORTH WEST - Colonel Paul Wentworth House, Dover Street (moved to MA, Dover), Dover, Strafford County, NH

  5. 40. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    40. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 FRAMING of SOUTH & EAST ELEVATIONS LOOKING NORTH WEST - Colonel Paul Wentworth House, Dover Street (moved to MA, Dover), Dover, Strafford County, NH

  6. 49. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    49. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 STRUCTURE of WEST BAY of MAIN HOUSE, PLATES & RAFTERS REMOVED LOOKING NORTH WEST - Colonel Paul Wentworth House, Dover Street (moved to MA, Dover), Dover, Strafford County, NH

  7. 95. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    95. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 NORTH & WEST SILLS of MAIN HOUSE-LOOKING SOUTH EAST - Colonel Paul Wentworth House, Dover Street (moved to MA, Dover), Dover, Strafford County, NH

  8. 101. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    101. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 DADO & PLASTER in SOUTH EAST CORNER of KITCHEN SHOWING HORIZONTAL BOARDING UNDER PLASTER & LATHS - Colonel Paul Wentworth House, Dover Street (moved to MA, Dover), Dover, Strafford County, NH

  9. 65. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    65. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 EAST CHIMNEY GIRT & FLOOR FRAMING 2nd FLOOR LOOKING EAST - Colonel Paul Wentworth House, Dover Street (moved to MA, Dover), Dover, Strafford County, NH

  10. 51. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    51. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 STRUCTURE MAIN HOUSE LOOKING NORTH EAST, ATTIC FLOOR FRAMING & ROOF FRAMING REMOVED - Colonel Paul Wentworth House, Dover Street (moved to MA, Dover), Dover, Strafford County, NH

  11. 81. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    81. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 FRAMING JOINT PURLIN over RAFTER, EAST BAY LOOKING SOUTH - Colonel Paul Wentworth House, Dover Street (moved to MA, Dover), Dover, Strafford County, NH

  12. 60. Historic American Buildings Survey R.A. WAUGH, Photographer October 1936 ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    60. Historic American Buildings Survey R.A. WAUGH, Photographer October 1936 SOUTH WEST CORNER POST & GIRT SHOWING TENON ON GIRT LOOKING SOUTH EAST - Colonel Paul Wentworth House, Dover Street (moved to MA, Dover), Dover, Strafford County, NH

  13. 55. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    55. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 REAR WEST INTERMEDIATE POST LOOKING SOUTH EAST, 2nd FLOOR - Colonel Paul Wentworth House, Dover Street (moved to MA, Dover), Dover, Strafford County, NH

  14. 41. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    41. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 FRAMING of SOUTH & EAST ELEVATIONS LOOKING NORTH WEST - Colonel Paul Wentworth House, Dover Street (moved to MA, Dover), Dover, Strafford County, NH

  15. 50. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    50. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 REAR POST & CHIMNEY GIRT, WEST BAY LOOKING WEST - Colonel Paul Wentworth House, Dover Street (moved to MA, Dover), Dover, Strafford County, NH

  16. 64. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    64. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 WEST END of WEST SUMMER BEAM - Colonel Paul Wentworth House, Dover Street (moved to MA, Dover), Dover, Strafford County, NH

  17. 54. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    54. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 POST & GIRT NORTH WEST CORNER LOOKING EAST - Colonel Paul Wentworth House, Dover Street (moved to MA, Dover), Dover, Strafford County, NH

  18. 63. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    63. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 TENON & PINS on WEST END of EAST SUMMER BEAM - Colonel Paul Wentworth House, Dover Street (moved to MA, Dover), Dover, Strafford County, NH

  19. 98. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    98. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 FRAMING of SUMMER BEAM INTO SILL ALSO NUMERALS ON SILL - Colonel Paul Wentworth House, Dover Street (moved to MA, Dover), Dover, Strafford County, NH

  20. 70. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    70. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ELEVATION FRAMING of NORTH WEST CORNER LEAN-TO LOOKING SOUTH WEST - Colonel Paul Wentworth House, Dover Street (moved to MA, Dover), Dover, Strafford County, NH

  1. 39. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    39. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 FRAMING of EAST END LOOKING SOUTH WEST - Colonel Paul Wentworth House, Dover Street (moved to MA, Dover), Dover, Strafford County, NH

  2. 99. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    99. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 NORTH & SOUTH RAFTERS & RIDGE ON WEST END LOOKING WEST - Colonel Paul Wentworth House, Dover Street (moved to MA, Dover), Dover, Strafford County, NH

  3. 71. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    71. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 RAFTER on REAR PLATE (INTERMEDIATE RAFTER LEAN-TO) - Colonel Paul Wentworth House, Dover Street (moved to MA, Dover), Dover, Strafford County, NH

  4. 56. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    56. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 REAR WEST INTERMEDIATE POST LOOKING WEST, 2nd FLOOR - Colonel Paul Wentworth House, Dover Street (moved to MA, Dover), Dover, Strafford County, NH

  5. 37. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    37. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 WEST ROOM, 2nd. FLOOR, NORTH WALL - Colonel Paul Wentworth House, Dover Street (moved to MA, Dover), Dover, Strafford County, NH

  6. 78. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    78. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 REAR PLATE, LEAN-TO SHOWING NOTCHING for ATTIC FLOOR BEAM - Colonel Paul Wentworth House, Dover Street (moved to MA, Dover), Dover, Strafford County, NH

  7. 77. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    77. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 PLAN of PLATES & CORNER POST, SOUTH WEST CORNER, MAIN HOUSE - Colonel Paul Wentworth House, Dover Street (moved to MA, Dover), Dover, Strafford County, NH

  8. 46. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    46. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ELEVATION of STRUCTURE LOOKING NORTH WEST - Colonel Paul Wentworth House, Dover Street (moved to MA, Dover), Dover, Strafford County, NH

  9. 58. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    58. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 East INTERMEDIATE POST on FRONT of MAIN HOUSE LOOKING SOUTH EAST - Colonel Paul Wentworth House, Dover Street (moved to MA, Dover), Dover, Strafford County, NH

  10. 69. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    69. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 CORNER POST & RAFTER LOOOKING SOUTH WEST (NORTH WEST CORNER LEAN-TO) - Colonel Paul Wentworth House, Dover Street (moved to MA, Dover), Dover, Strafford County, NH

  11. 52. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    52. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 PHOTOGRAPH SHOWING CUT IN FRONT SILL - Colonel Paul Wentworth House, Dover Street (moved to MA, Dover), Dover, Strafford County, NH

  12. 72. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    72. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 SOUTH END of WEST PLATE AFTER REMOVAL from BUILDING MAIN HOUSE - Colonel Paul Wentworth House, Dover Street (moved to MA, Dover), Dover, Strafford County, NH

  13. 47. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    47. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 Structure of MAIN HOUSE LOOKING NORTH WEST, ATTIC FLOOR FRAMING & ROOF FRAMING REMOVED - Colonel Paul Wentworth House, Dover Street (moved to MA, Dover), Dover, Strafford County, NH

  14. 76. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    76. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ELEVATION of INTERMEDIATE RAFTER in LEAN-TO - Colonel Paul Wentworth House, Dover Street (moved to MA, Dover), Dover, Strafford County, NH

  15. 48. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    48. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 FRAMING of EAST END MAIN HOUSE LOOKING NORTH WEST - Colonel Paul Wentworth House, Dover Street (moved to MA, Dover), Dover, Strafford County, NH

  16. 134. Historic American Buildings Survey R.A. WAUGH, Photographer October 1936 ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    134. Historic American Buildings Survey R.A. WAUGH, Photographer October 1936 ELEVATION 1st. FLOOR WEST FIREPLACE AS IT WAS BEING TORN OUT - Colonel Paul Wentworth House, Dover Street (moved to MA, Dover), Dover, Strafford County, NH

  17. 124. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    124. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 CHAIR RAIL FOUND AS HOUSE WAS BEING TORN DOWN - Colonel Paul Wentworth House, Dover Street (moved to MA, Dover), Dover, Strafford County, NH

  18. 142. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    142. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 LEAN-TO OVENS-SECTION WITH FRONT WALL TORN DOWN - Colonel Paul Wentworth House, Dover Street (moved to MA, Dover), Dover, Strafford County, NH

  19. 123. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    123. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 LOOM STRETCHER FOUND AS HOUSE WAS BEING TORN DOWN - Colonel Paul Wentworth House, Dover Street (moved to MA, Dover), Dover, Strafford County, NH

  20. 132. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    132. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ELEVATION, 1st. FLOOR WEST FIREPLACE LATEST - Colonel Paul Wentworth House, Dover Street (moved to MA, Dover), Dover, Strafford County, NH

  1. 128. HISTORIC AMERICAN BUILDINGS SURVEY R.A. Waugh, Photographer October 1936 ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    128. HISTORIC AMERICAN BUILDINGS SURVEY R.A. Waugh, Photographer October 1936 ELEVATION, 1st FLOOR, EAST FIREPLACE LATEST - Colonel Paul Wentworth House, Dover Street (moved to MA, Dover), Dover, Strafford County, NH

  2. 146. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    146. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ELEVATION, 2nd. FLOOR FIREPLACE, EAST ROOM LATEST WITH PLASTER FACE - Colonel Paul Wentworth House, Dover Street (moved to MA, Dover), Dover, Strafford County, NH

  3. 97. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    97. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 FRAMING of SUMMER BEAM INTO SILL ALSO FLOOR TIMBERS INTO SUMMER BEAM - Colonel Paul Wentworth House, Dover Street (moved to MA, Dover), Dover, Strafford County, NH

  4. Further optimization of SeDDaRA blind image deconvolution algorithm and its DSP implementation

    NASA Astrophysics Data System (ADS)

    Wen, Bo; Zhang, Qiheng; Zhang, Jianlin

    2011-11-01

    Efficient algorithm for blind image deconvolution and its high-speed implementation is of great value in practice. Further optimization of SeDDaRA is developed, from algorithm structure to numerical calculation methods. The main optimization covers that, the structure's modularization for good implementation feasibility, reducing the data computation and dependency of 2D-FFT/IFFT, and acceleration of power operation by segmented look-up table. Then the Fast SeDDaRA is proposed and specialized for low complexity. As the final implementation, a hardware system of image restoration is conducted by using the multi-DSP parallel processing. Experimental results show that, the processing time and memory demand of Fast SeDDaRA decreases 50% at least; the data throughput of image restoration system is over 7.8Msps. The optimization is proved efficient and feasible, and the Fast SeDDaRA is able to support the real-time application.

  5. 107. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    107. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 DIAGONAL LATHING AROUND WINDOWS, WEST ROOM, 1st. FLOOR, MAIN HOUSE on NORTH WALL - Colonel Paul Wentworth House, Dover Street (moved to MA, Dover), Dover, Strafford County, NH

  6. A Study on Sorption of (226)Ra on Different Clay Matrices.

    PubMed

    Alhajji, E; Al-Masri, M S; Khalily, H; Naoum, B E; Khalil, H S; Nashawati, A

    2016-08-01

    The sorption of radium 226 ((226)Ra) on different clay materials (bentonite, illite and a mixture of bentonite-illite) was studied. Clay materials are used in the construction of disposal pits for technically enhanced naturally occurring radioactive materials (TENORM) wastes (i.e., contaminated soil and sludge) generated by the oil and gas industry operations. Experimental conditions (pH, clay materials quantity, and activity concentrations of (226)Ra) were changed in order to determine the optimal state for adsorption of (226)Ra. The results showed that the concentration of adsorbed (226)Ra on clay materials increased with time to reach an equilibrium state after approximately 5 h. More than 95 % of the radium was adsorbed. The mixture of bentonite-illite (1/9) exhibited the greatest adsorption of radium under all experimental conditions. PMID:27329110

  7. Laser-cooled RaF as a promising candidate to measure molecular parity violation

    SciTech Connect

    Isaev, T. A.; Berger, R.; Hoekstra, S.

    2010-11-15

    The parameter W{sub a}, which characterizes nuclear-spin-dependent parity violation (PV) in the molecular spin-rotational Hamiltonian, was computed with a quasirelativistic Hartree-Fock approach for radium fluoride (RaF) and found to be one of the largest absolute values predicted so far. The peculiar electronic structure of RaF leads to highly diagonal Franck-Condon matrices between the energetically lowest two electronic states, which qualifies RaF for direct laser cooling. A subset of diatomic molecules with a wide range of internal structures suitable for this cooling technique is also indicated. As trapped cold molecules offer superior coherence times, RaF can be considered promising for high-precision experiments aimed at molecular PV.

  8. Retinoic acid receptors: from molecular mechanisms to cancer therapy.

    PubMed

    di Masi, Alessandra; Leboffe, Loris; De Marinis, Elisabetta; Pagano, Francesca; Cicconi, Laura; Rochette-Egly, Cécile; Lo-Coco, Francesco; Ascenzi, Paolo; Nervi, Clara

    2015-02-01

    Retinoic acid (RA), the major bioactive metabolite of retinol or vitamin A, induces a spectrum of pleiotropic effects in cell growth and differentiation that are relevant for embryonic development and adult physiology. The RA activity is mediated primarily by members of the retinoic acid receptor (RAR) subfamily, namely RARα, RARβ and RARγ, which belong to the nuclear receptor (NR) superfamily of transcription factors. RARs form heterodimers with members of the retinoid X receptor (RXR) subfamily and act as ligand-regulated transcription factors through binding specific RA response elements (RAREs) located in target genes promoters. RARs also have non-genomic effects and activate kinase signaling pathways, which fine-tune the transcription of the RA target genes. The disruption of RA signaling pathways is thought to underlie the etiology of a number of hematological and non-hematological malignancies, including leukemias, skin cancer, head/neck cancer, lung cancer, breast cancer, ovarian cancer, prostate cancer, renal cell carcinoma, pancreatic cancer, liver cancer, glioblastoma and neuroblastoma. Of note, RA and its derivatives (retinoids) are employed as potential chemotherapeutic or chemopreventive agents because of their differentiation, anti-proliferative, pro-apoptotic, and anti-oxidant effects. In humans, retinoids reverse premalignant epithelial lesions, induce the differentiation of myeloid normal and leukemic cells, and prevent lung, liver, and breast cancer. Here, we provide an overview of the biochemical and molecular mechanisms that regulate the RA and retinoid signaling pathways. Moreover, mechanisms through which deregulation of RA signaling pathways ultimately impact on cancer are examined. Finally, the therapeutic effects of retinoids are reported. PMID:25543955

  9. Rapid determination of 226Ra and uranium isotopes in solid samples by fusion with lithium metaborate and alpha spectrometry.

    PubMed

    Bojanowski, R; Radecki, Z; Piekoś, R

    2002-07-01

    A simple and rapid method has been developed to determine 226Ra in rocks, soils, and sediments. Samples are decomposed by fusion with lithium metaborate and the melt is dissolved in a solution containing sulfates and citric acid. During the dissolution, a fine suspension of mixed barium and radium sulfates is formed. The microcrystals are collected on a membrane filter (pore size 0.1 microm) and analysed in an alpha spectrometer. Application of a 133Ba tracer enables us to assess the loss of the analyte, which only rarely exceeds 10%. All analytical operations, beginning from sample decomposition to source preparation for alpha spectrometry, can be accomplished within 1 or 2 h. With uranium determination, the filtrate is spiked with a 232U tracer and passed through a column loaded with a Dowex AG (1 x 4) anion-exchange resin in the sulfate form. Interfering elements are eluted with dilute sulfuric acid followed by concentrated hydrochloric acid. Uranium is eluted with water, electrodeposited on silver discs, and analysed in the alpha spectrometer. The method was tested on reference soil and sediment materials and was found to be accurate within the estimated uncertainties. PMID:12920318

  10. Retinoic acid affects calcium signaling in adult molluscan neurons.

    PubMed

    Vesprini, Nicholas D; Dawson, Taylor F; Yuan, Ye; Bruce, Doug; Spencer, Gaynor E

    2015-01-01

    Retinoic acid, the active metabolite of vitamin A, is important for nervous system development, regeneration, as well as cognitive functions of the adult central nervous system. These central nervous system functions are all highly dependent on neuronal activity. Retinoic acid has previously been shown to induce changes in the firing properties and action potential waveforms of adult molluscan neurons in a dose- and isomer-dependent manner. In this study, we aimed to determine the cellular pathways by which retinoic acid might exert such effects, by testing the involvement of pathways previously shown to be affected by retinoic acid. We demonstrated that the ability of all-trans retinoic acid (atRA) to induce electrophysiological changes in cultured molluscan neurons was not prevented by inhibitors of protein synthesis, protein kinase A or phospholipase C. However, we showed that atRA was capable of rapidly reducing intracellular calcium levels in the same dose- and isomer-dependent manner as shown previously for changes in neuronal firing. Moreover, we also demonstrated that the transmembrane ion flux through voltage-gated calcium channels was rapidly modulated by retinoic acid. In particular, the peak current density was reduced and the inactivation rate was increased in the presence of atRA, over a similar time course as the changes in cell firing and reductions in intracellular calcium. These studies provide further evidence for the ability of atRA to induce rapid effects in mature neurons. PMID:25343782

  11. Rapid determination of 226Ra in emergency urine samples

    SciTech Connect

    Maxwell, Sherrod L.; Culligan, Brian K.; Hutchison, Jay B.; Utsey, Robin C.; McAlister, Daniel R.

    2014-02-27

    A new method has been developed at the Savannah River National Laboratory (SRNL) that can be used for the rapid determination of 226Ra in emergency urine samples following a radiological incident. If a radiological dispersive device event or a nuclear accident occurs, there will be an urgent need for rapid analyses of radionuclides in urine samples to ensure the safety of the public. Large numbers of urine samples will have to be analyzed very quickly. This new SRNL method was applied to 100 mL urine aliquots, however this method can be applied to smaller or larger sample aliquots as needed. The method was optimized for rapid turnaround times; urine samples may be prepared for counting in <3 h. A rapid calcium phosphate precipitation method was used to pre-concentrate 226Ra from the urine sample matrix, followed by removal of calcium by cation exchange separation. A stacked elution method using DGA Resin was used to purify the 226Ra during the cation exchange elution step. This approach combines the cation resin elution step with the simultaneous purification of 226Ra with DGA Resin, saving time. 133Ba was used instead of 225Ra as tracer to allow immediate counting; however, 225Ra can still be used as an option. The rapid purification of 226Ra to remove interferences using DGA Resin was compared with a slightly longer Ln Resin approach. A final barium sulfate micro-precipitation step was used with isopropanol present to reduce solubility; producing alpha spectrometry sources with peaks typically <40 keV FWHM (full width half max). This new rapid method is fast, has very high tracer yield (>90 %), and removes interferences effectively. The sample preparation method can also be adapted to ICP-MS measurement of 226Ra, with rapid removal of isobaric interferences.

  12. 226Ra bioavailability to plants at the Urgeiriça uranium mill tailings site.

    PubMed

    Madruga, M J; Brogueira, A; Alberto, G; Cardoso, F

    2001-01-01

    Large amounts of solid wastes (tailings) resulting from the exploitation and treatment of uranium ore at the Urgeiriça mine (north of Portugal) have been accumulated in dams (tailing ponds). To reduce the dispersion of natural radionuclides into the environment, some dams were revegetated with eucalyptus (Eucalyptus globolus) and pines (Pinus pinea). Besides these plants, some shrubs (Cytisus spp.) are growing in some of the dams. The objective of this study is to determine the 226Ra bioavailability from uranium mill tailings by quantifying the total and available fraction of radium in the tailings and to estimate its transfer to plants growing on the tailing piles. Plant and tailing samples were randomly collected and the activity concentration of 226Ra in plants (aerial part and roots) and tailings was measured by gamma-spectrometry. The exchangeable fraction of radium in tailings was quantified using one single step extraction with 1 mol dm-3 ammonium acetate (pH = 7) or 1 mol dm-3 calcium chloride solutions. The results obtained for 226Ra uptake by plants show that 226Ra concentration ratios for eucalyptus and pines decrease at low 226Ra concentrations in the tailings and appear relatively constant at higher radium concentrations. For shrubs, the concentration ratios increase at higher 226Ra solid waste concentrations approaching a saturation value. Percentage values of 16.0 +/- 8.3 and 12.9 +/- 8.9, for the fraction of radium extracted from the tailings, using 1 mol dm-3 ammonium acetate or calcium chloride solutions, respectively, were obtained. The 226Ra concentration ratios determined on the basis of exchangeable radium are one order of magnitude higher than those based on total radium. It can be concluded that, at a 95% confidence level, more consistent 226Ra concentration ratios were obtained when calculated on the basis of available radium than when total radium was considered, for all the dams. PMID:11379070

  13. Reversible effect of all-trans-retinoic acid on AML12 hepatocyte proliferation and cell cycle progression

    EPA Science Inventory

    The role of all-trans-retinoic acid (atRA) in the regulation of cellular proliferation and differentiation is well documented. Numerous studies have established the cancer preventive propertiesofatRAwhichfunctionstoregulate levels ofcellcycleproteinsessentialfortheGliS transition...

  14. First In Vivo Evaluation of Liposome-encapsulated 223Ra as a Potential Alpha-particle-emitting Cancer Therapeutic Agent

    SciTech Connect

    Jonasdottir, Thora J.; Fisher, Darrell R.; Borrebaek, Jorgen; Bruland, Oyvind S.; Larsen, Roy H.

    2006-09-13

    Liposomes carrying chemotherapeutics have had some success in cancer treatment and may be suitable carriers for therapeutic radionuclides. This study was designed to evaluate the biodistribution of and to estimate the radiation doses from the alpha emitter 223Ra loaded into pegylated liposomes in selected tissues. 223Ra was encapsulated in pegylated liposomal doxorubicin by ionophore-mediated loading. The biodistribution of liposomal 223Ra was compared to free cationic 223Ra in Balb/C mice. We showed that liposomal 223 Ra circulated in the blood with an initial half-time in excess of 24 hours, which agreed well with that reported for liposomal doxorubicin in rodents, while the blood half-time of cationic 223Ra was considerably less than one hour. When liposomal 223 Ra was catabolized, the released 223Ra was either excreted or taken up in the skeleton. This skeletal uptake increased up to 14 days after treatment, but did not reach the level seen with free 223Ra. Pre-treatment with non-radioactive liposomal doxorubicin 4 days in advance lessened the liver uptake of liposomal 223 Ra. Dose estimates showed that the spleen, followed by bone surfaces, received the highest absorbed doses. Liposomal 223 Ra was relatively stable in vivo and may have potential for radionuclide therapy and combination therapy with chemotherapeutic agents.

  15. Anti-Citrullinated Protein Antibodies Induce Macrophage Subset Disequilibrium in RA Patients.

    PubMed

    Zhu, Wei; Li, Xiu; Fang, Shaohong; Zhang, Xiaoli; Wang, Ying; Zhang, Tongshuai; Li, Zhaoying; Xu, Yanwen; Qu, Siying; Liu, Chuanliang; Gao, Fei; Pan, Haile; Wang, Guangyou; Li, Hulun; Sun, Bo

    2015-12-01

    We used samples from rheumatoid arthritis (RA) patients to examine whether Anti-citrullinated protein antibodies (ACPAs) alter macrophage subset distribution and promote RA development. Macrophage subset distributions and interferon regulatory factor 4 (IRF4) and IRF5 expressions were analyzed. ACPAs were purified by affinity column. After RA and osteoarthritis (OA) patients' macrophages were cocultured with ACPAs, macrophage subsets and IRF4 and IRF5 expressions were measured. Small interfering RNAs (siRNAs) were transfected into ACPA-activated cells to suppress IRF4 or IRF5. Fluorescence-activated cell sorting (FACS), Western blot, and immunohistochemistry were performed. Macrophage subset disequilibrium occurred in RA patient synovial fluids. IRF4 and IRF5 were all expressed in the synovial fluid and synovium. ACPAs (40 IU/ml) could induce macrophages to polarize to M1 subsets, and the percentage of increased M1/M2 ratio of RA patients was higher than that of the OA patients. ACPAs also induce IRF4 and IRF5 protein expressions. IRF5 siRNA transfection impaired ACPA activity significantly. We demonstrated that macrophage subset disequilibrium occurred in RA patients. ACPAs induced IRF5 activity and led to M1 macrophage polarization. PMID:26063186

  16. Distribution and retention in bone of /sup 226/Ra and comparison with the ICRP 20 model

    SciTech Connect

    Holtzman, R.B.; Rundo, J.; Sha, J.Y.; Spaletto, M.I.

    1981-01-01

    Analyses are presented of the ratios of /sup 226/Ra to calcium in over 650 samples of compact and cancellous bone from 66 female and 26 male subjects who had died from less than one to 60 years after first exposure to radium. The /sup 226/Ra/Ca ratios were normalized to the terminal /sup 226/Ra skeletal content. The /sup 226/Ra/Ca ratios for vertebrae were essentialy identical to those for other cancellous bone for a given subject. Comparisons of the data with predictions of the ICRP model of alkaline earth metabolism show that for female cancellous bone the normalized /sup 226/Ra/Ca ratios tended to be greater than predicted, while those for female cortical bone (femoral and tibial shaft) tended to be less. The data for males were fitted better by the model. A modification of the model to reduce the amount of radium deposited in soft tissue fitted the data better in some respects. A straight line linear least squares fit to the data appeared to fit as well as, or better than, the models. A radiation effect was suggested in that the normalized /sup 226/Ra/Ca ratio for vertebrae relative to the ratio expected increased with skeletal absorbed dose for vertebra. However, no such effect was apparent for compact bone or for the cancellous bone as a whole.

  17. Argonne-Utah studies of /sup 224/Ra endosteal surface dosimetry

    SciTech Connect

    Schlenker, R.A.; Smith, J.M.

    1984-01-01

    The activities of /sup 212/Pb relative to /sup 224/Ra and of /sup 222/Rn relative to /sup 226/Ra were measured in bone surface deposits 24 h after radium injection into beagles. The fractional retention of /sup 220/Rn atoms was measured in vitro with hydrated and dehydrated bone samples to determine the effect of water content on the escape of radon from bone surfaces. The experimental data suggest that substantial /sup 224/Ra daughter product disequilibrium exists in bone surface deposits. Estimates for the lower and upper limits on the fractional retention of /sup 220/Rn in vivo are 0.05 and 0.25, respectively. The average bone surface activity of /sup 212/Pb relative to /sup 224/Ra ranged from 0.34 to 0.71 for four dogs, with the majority of the values toward the low end of the range. Only a small portion of the deposited /sup 212/Pb came from lead in the injection solution despite near equilibrium between /sup 224/Ra and its daughters at the time of injection. The retention data indicate that the endosteal tissue dose rate in the dogs at one day was actually one-third to about one-half that which would be calculated assuming equilibrium of /sup 224/Ra daughter products in bone surface deposits. 11 references, 2 figures, 7 tables.

  18. Opium Addiction Increases Interleukin 1 Receptor Antagonist (IL-1Ra) in the Coronary Artery Disease Patients

    PubMed Central

    Saadat, Habibollah; Ziai, Seyed Ali; Ghanemnia, Maryam; Namazi, Mohammad Hasan; Safi, Morteza; Vakili, Hosein; Dabbagh, Ali; Gholami, Omid

    2012-01-01

    Background There is evidence that opium addiction has immunosuppressant effects. Coronary artery disease (CAD) is a condition resulted from atherosclerosis which is dependent on the immune response. Purpose To evaluate plasma levels of interleukin-6 and interleukin-1Ra in 30 patients with three-vessel coronary artery disease, ejection fraction of more than 35% and to evaluate their changes after prognostic treadmill test in 15 opium addicted and 15 non-addicted patients. Methods The participants underwent prognostic treadmill test and plasma levels of interleukin-6 (IL-6) and interleukin-1Ra (IL-1Ra) were evaluated with ELISA method before, just after and 4 hours after the test. Results IL-1Ra (2183 pg/ml) tended to decrease over time in the opium addicted group (1372 pg/ml after prognostic treadmill test and 1034 pg/ml 4 hours after that), although such decrease did not reach the statistical significance. IL-1Ra levels were significantly higher in opium addicted than in non addicted patients. Opium addiction had no significant effect on IL-6 changes. Conclusion Consumption of opium in CAD patients is associated with higher IL-1Ra levels. PMID:23028694

  19. Determination of (226)Ra in produced water by liquid scintillation counting.

    PubMed

    Godoy, José Marcus; Vianna, Lucas M; Godoy, Maria Luiza D P; Almeida, Ana Cristina

    2016-08-01

    It is proposed a method for the determination of (226)Ra in offshore platform liquid effluent samples (produced water). The method is based on a two-phase liquid scintillation counting system and allows for the direct and simple determination of (226)Ra content. Samples with high barium content may also have high (226)Ra concentration. Therefore, the sample volume is based on the barium concentration and ranges from 10 mL to 100 mL. Our new method was tested using multiple real samples and was compared with the BaSO4 precipitation method. The results based on the LSC were 30% higher than the precipitation method, which is attributed to the self-absorption of alpha particles in the BaSO4 precipitate. The determination of both (226)Ra and (228)Ra in the liquid effluent of offshore oil platforms is mandatory in Brazil. Thus, a second method of accurately assessing (228)Ra content remains necessary. PMID:27116402

  20. Retinoic acid modulates RAR alpha and RAR beta receptors in human glioma cell lines.

    PubMed

    Carpentier, A F; Leonard, N; Lacombe, J; Zassadowski, F; Padua, R A; Degos, L; Daumas-Duport, C; Chomienne, C

    1999-01-01

    To identify retinoic acid (RA) signalling pathways involved in growth and differentiation in cells of the glial lineage, two human glioma ceh lines were studied. The three RA receptors (RARs) mRNAs were constitutively expressed, and of the three RXRs, RXR beta appeared predominant. Western blotting analysis confirmed the constitutive expression of RAR alpha and RAR beta. Treatment with all-trans-RA induced morphological changes in the two cell lines, which progressed from their normal pattern of randomly oriented spindle-shaped cells to fibroblast-like glial cells. RA up-regulated RAR alpha and RAR beta mRNAs in both cell lines. Interestingly, RA treatment up-regulated RAR beta proteins but not RAR alpha proteins, suggesting post-transcriptional regulations of RAR transcripts in glioma cells. PMID:10652610

  1. From carrot to clinic: an overview of the retinoic acid signaling pathway.

    PubMed

    Theodosiou, Maria; Laudet, Vincent; Schubert, Michael

    2010-05-01

    Vitamin A is essential for the formation and maintenance of many body tissues. It is also important for embryonic growth and development and can act as a teratogen at critical periods of development. Retinoic acid (RA) is the biologically active form of vitamin A and its signaling is mediated by the RA and retinoid X receptors. In addition to its role as an important molecule during development, RA has also been implicated in clinical applications, both as a potential anti-tumor agent as well as for the treatment of skin diseases. This review presents an overview of how dietary retinoids are converted to RA, hence presenting the major players in RA metabolism and signaling, and highlights examples of treatment applications of retinoids. Moreover, we discuss the origin and diversification of the retinoid pathway, which are important factors for understanding the evolution of ligand-specificity among retinoid receptors. PMID:20140749

  2. Cullin 3 mediates SRC-3 ubiquitination and degradation to control the retinoic acid response

    PubMed Central

    Ferry, Christine; Gaouar, Samia; Fischer, Benoit; Boeglin, Marcel; Paul, Nicodeme; Samarut, Eric; Piskunov, Aleksandr; Pankotai-Bodo, Gabriella; Brino, Laurent; Rochette-Egly, Cecile

    2011-01-01

    SRC-3 is an important coactivator of nuclear receptors including the retinoic acid (RA) receptor α. Most of SRC-3 functions are facilitated by changes in the posttranslational code of the protein that involves mainly phosphorylation and ubiquitination. We recently reported that SRC-3 is degraded by the proteasome in response to RA. Here, by using an RNAi E3-ubiquitin ligase entry screen, we identified CUL-3 and RBX1 as components of the E3 ubiquitin ligase involved in the RA-induced ubiquitination and subsequent degradation of SRC-3. We also show that the RA-induced ubiquitination of SRC-3 depends on its prior phosphorylation at serine 860 that promotes binding of the CUL-3–based E3 ligase in the nucleus. Finally, phosphorylation, ubiquitination, and degradation of SRC-3 cooperate to control the dynamics of transcription. In all, this process participates to the antiproliferative effect of RA. PMID:22147914

  3. Retinoic acid as a survival factor in neuronal development of the grasshopper, Locusta migratoria.

    PubMed

    Sukiban, Jeyathevy; Bräunig, Peter; Mey, Jörg; Bui-Göbbels, Katrin

    2014-11-01

    Based on experience with cell cultures of adult insect neurons, we develop a serum-free culture system for embryonic locust neurons. Influences of trophic substances on survival and neurite outgrowth of developing neurons are investigated. For the first time, a positive trophic effect of 9-cis retinoic acid (9-cis RA) was shown in vitro on embryonic neurons of an insect. We observed longer cell survival of 50 % developmental stage neurons in cultures supplemented with 0.3 nM 9-cis RA. Furthermore, an influence on neuron morphology was revealed, as the addition of 9-cis RA to cell culture medium led to an increase in the number of neurites per cell. Although an RA receptor gene, LmRXR (Locusta migratoria retinoid X receptor), was expressed in the central nervous system throughout development, the influence of 9-cis RA on neuronal survival and outgrowth was restricted to 50 % stage embryonic cells. PMID:25107605

  4. A Novel Method for the Preparation of Retinoic Acid-Loaded Nanoparticles

    PubMed Central

    Errico, Cesare; Gazzarri, Matteo; Chiellini, Federica

    2009-01-01

    The goal of present work was to investigate the use of bioerodible polymeric nanoparticles as carriers of retinoic acid (RA), which is known to induce differentiation of several cell lines into neurons. A novel method, named “Colloidal-Coating”, has been developed for the preparation of nanoparticles based on a copolymer of maleic anhydride and butyl vinyl ether (VAM41) loaded with RA. Nanoparticles with an average diameter size of 70 nm and good morphology were prepared. The activity of the encapsulated RA was evaluated on SK-N-SH human neuroblastoma cells, which are known to undergo inhibition of proliferation and neuronal differentiation upon treatment with RA. The activity of RA was not affected by the encapsulation and purification processes. PMID:19564952

  5. Retinoid protection against x-ray-induced chromatid damage in human peripheral blood lymphocytes.

    PubMed Central

    Sanford, K K; Parshad, R; Price, F M; Tarone, R E; Kraemer, K H

    1992-01-01

    Oral administration of isotretinoin (13-cis retinoic acid) was shown previously (Kraemer, K. H., J. J. DiGiovanna, A. N. Moshell, R. E. Tarone, and G. L. Peck. 1988. N. Engl. J. Med. 318:1633-1637) to reduce the frequency of skin cancers in xeroderma pigmentosum (XP) patients. The mechanism of protection was unclear. In the present study, x-ray-induced chromatid damage in PHA-stimulated blood lymphocytes from five XP patients receiving isotretinoin was approximately half that in blood samples from the same patients before or subsequent to treatment. The x-ray-induced chromatid damage in blood lymphocytes from a normal control was reduced significantly by cocultivation with blood or plasma from an XP patient receiving isotretinoin or by addition of 10(-6) M isotretinoin to cultures 1 h before x-irradiation. A similar reduction in x-ray-induced chromatid damage was reported previously by adding to the culture medium, mannitol, a scavenger of the free hydroxyl radical, or catalase, which decomposes hydrogen peroxide; both of these products are generated during ionizing radiation. The present observations suggest that isotretinoin acts as a scavenger of such radiation products, thereby providing protection against x-ray-induced chromatid damage. PMID:1430230

  6. Dinutuximab: first global approval.

    PubMed

    Dhillon, Sohita

    2015-05-01

    United Therapeutics Corporation and the National Cancer Institute are developing dinutuximab (Unituxin™; ch14.18), a monoclonal antibody targeting GD2, for the treatment of neuroblastoma. GD2 is a glycolipid found on the surface of tumour cells, which is overexpressed in neuroblastoma. Dinutuximab, an IgG1 human/mouse chimeric switch variant of murine monoclonal antibody 14G2a, binds to GD2 and induces antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity. The US FDA has recently approved the use of dinutuximab combination therapy for the treatment of high-risk neuroblastoma in paediatric patients. The marketing authorization application for dinutuximab is under regulatory review in the EU, and phase I-III development is underway in several other countries. This article summarizes the milestones in the development of dinutuximab leading to this first approval for use (in combination with granulocyte macrophage colony-stimulating factor, interleukin-2 and 13-cis retinoic acid) in the treatment of paediatric patients with high-risk neuroblastoma who achieve at least partial response to prior first-line multiagent, multimodality therapy. PMID:25940913

  7. Pituitary specific retinoid-X receptor ligand interactions with thyroid hormone receptor signaling revealed by high throughput reporter and endogenous gene responses.

    PubMed

    Mengeling, Brenda J; Furlow, J David

    2015-10-01

    Disruption of thyroid hormone (TH) signaling can compromise vital processes both during development and in the adult. We previously reported on high-throughput screening experiments for man-made TH disruptors using a stably integrated line of rat pituitary cells, GH3.TRE-Luc, in which a thyroid hormone receptor (TR) response element drives luciferase (Luc) expression. In these experiments, several retinoid/rexinoid compounds activated the reporter. Here we show that all-trans and 13-cis retinoic acid appear to function through the heterodimer partners of TRs, retinoid-X receptors (RXRs), as RXR antagonists abrogated retinoid-induced activation. The retinoids also induced known endogenous TR target genes, showing good correlation with Luc activity. Synthetic RXR-specific agonists significantly activated all tested TR target genes, but interestingly, retinoid/rexinoid activation was more consistent between genes than the extent of T3-induced activation. In contrast, the retinoids neither activated the Luc reporter construct in transient transfection assays in the human hepatocarcinoma cell line HuH7, nor two of the same T3-induced genes examined in pituitary cells. These data demonstrate the suitability and sensitivity of GH3.TRE-Luc cells for screening chemical compound libraries for TH disruption and suggest that the extent of disruption can vary on a cell type and gene-specific bases, including an underappreciated contribution by RXRs. PMID:26096596

  8. The Role of Isotretinoin Therapy for Cushing's Disease: Results of a Prospective Study

    PubMed Central

    Vilar, Lucio; Albuquerque, José Luciano; Lyra, Ruy; Trovão Diniz, Erik; Rangel Filho, Frederico; Gadelha, Patrícia; Thé, Ana Carolina; Ibiapina, George Robson; Gomes, Barbara Sales; Santos, Vera; Melo da Fonseca, Maíra; Frasão Viana, Karoline; Lopes, Isis Gabriella; Araújo, Douglas; Naves, Luciana

    2016-01-01

    Objective. This prospective open trial aimed to evaluate the efficacy and safety of isotretinoin (13-cis-retinoic acid) in patients with Cushing's disease (CD). Methods. Sixteen patients with CD and persistent or recurrent hypercortisolism after transsphenoidal surgery were given isotretinoin orally for 6–12 months. The drug was started on 20 mg daily and the dosage was increased up to 80 mg daily if needed and tolerated. Clinical, biochemical, and hormonal parameters were evaluated at baseline and monthly for 6–12 months. Results. Of the 16 subjects, 4% (25%) persisted with normal urinary free cortisol (UFC) levels at the end of the study. UFC reductions of up to 52.1% were found in the rest. Only patients with UFC levels below 2.5-fold of the upper limit of normal achieved sustained UFC normalization. Improvements of clinical and biochemical parameters were also noted mostly in responsive patients. Typical isotretinoin side-effects were experienced by 7 patients (43.7%), though they were mild and mostly transient. We also observed that the combination of isotretinoin with cabergoline, in relatively low doses, may occasionally be more effective than either drug alone. Conclusions. Isotretinoin may be an effective and safe therapy for some CD patients, particularly those with mild hypercortisolism. PMID:27034666

  9. Induced differentiation inhibits sphere formation in neuroblastoma.

    PubMed

    Craig, Brian T; Rellinger, Eric J; Alvarez, Alexandra L; Dusek, Haley L; Qiao, Jingbo; Chung, Dai H

    2016-08-19

    Neuroblastoma arises from the neural crest, the precursor cells of the sympathoadrenal axis, and differentiation status is a key prognostic factor used for clinical risk group stratification and treatment strategies. Neuroblastoma tumor-initiating cells have been successfully isolated from patient tumor samples and bone marrow using sphere culture, which is well established to promote growth of neural crest stem cells. However, accurate quantification of sphere-forming frequency of commonly used neuroblastoma cell lines has not been reported. Here, we show that MYCN-amplified neuroblastoma cell lines form spheres more frequently than non-MYCN-amplified cell lines. We also show that sphere formation is directly sensitive to cellular differentiation status. 13-cis-retinoic acid is a clinically used differentiating agent that induces a neuronal phenotype in neuroblastoma cells. Induced differentiation nearly completely blocked sphere formation. Furthermore, sphere formation was specifically FGF-responsive and did not respond to increasing doses of EGF. Taken together, these data suggest that sphere formation is an accurate method of quantifying the stemness phenotype in neuroblastoma. PMID:27297102

  10. CONTROL OF ALKALINE PHOSPHATASE ACTIVITY IN C3H10T1/2 CELLS: ROLE OF RETINOIC ACID AND CELL DENSITY

    EPA Science Inventory

    The enzyme alkaline phosphatase (AP) has been shown to be lost or inappropriately expressed during carcinogenesis in some tissues. ecause retinoic acid (RA) appears to play a role in the normal regulation of the enzyme (RA up-regulates AP in a variety of cell types) we have sugge...

  11. SB-RA-2001 Inhibits Bacterial Proliferation by Targeting FtsZ Assembly

    PubMed Central

    2015-01-01

    FtsZ has been recognized as a promising antimicrobial drug target because of its vital role in bacterial cell division. In this work, we found that a taxane SB-RA-2001 inhibited the proliferation of Bacillus subtilis 168 and Mycobacterium smegmatis cells with minimal inhibitory concentrations of 38 and 60 μM, respectively. Cell lengths of these microorganisms increased remarkably in the presence of SB-RA-2001, indicating that it inhibits bacterial cytokinesis. SB-RA-2001 perturbed the formation of the FtsZ ring in B. subtilis 168 cells and also affected the localization of the late cell division protein, DivIVA, at the midcell position. Flow cytometric analysis of the SB-RA-2001-treated cells indicated that the compound did not affect the duplication of DNA in B. subtilis 168 cells. Further, SB-RA-2001 treatment did not affect the localization of the chromosomal partitioning protein, Spo0J, along the two ends of the nucleoids and also had no discernible effect on the nucleoid segregation in B. subtilis 168 cells. The agent also did not appear to perturb the membrane potential of B. subtilis 168 cells. In vitro, SB-RA-2001 bound to FtsZ with modest affinity, promoted the assembly and bundling of FtsZ protofilaments, and reduced the GTPase activity of FtsZ. GTP did not inhibit the binding of SB-RA-2001 to FtsZ, suggesting that it does not bind to the GTP binding site on FtsZ. A computational analysis indicated that SB-RA-2001 binds to FtsZ in the cleft region between the C-terminal domain and helix H7, and the binding site of SB-RA-2001 on FtsZ resembled that of PC190723, a well-characterized inhibitor of FtsZ. The findings collectively suggested that SB-RA-2001 inhibits bacterial proliferation by targeting the assembly dynamics of FtsZ, and this can be exploited further to develop potent FtsZ-targeted antimicrobials. PMID:24749867

  12. Molecular cloning and characterization of tyrosine aminotransferase and hydroxyphenylpyruvate reductase, and rosmarinic acid accumulation in Scutellaria baicalensis.

    PubMed

    Kim, Yeon Bok; Uddina, Md Romij; Kim, YeJi; Park, Chun Geon; Park, Sang Un

    2014-09-01

    Rosmarinic acid (a-O-caffeoyl-3,4-dihydroxyphenylacetic acid, RA) is a caffeoyl ester widely distributed in plants. cDNA clones encoding tyrosine aminotransferase (TAT1 and 2) and hydroxyphenylpyruvate reductase (HPPR) have been isolated from Scutellaria baicalensis. The open reading frames (ORFs) of SbTAT1 and 2 were 1230 and 1272 bp long and encoded 409 and 423 amino acid residues, respectively. HPPR corresponded to a 942-bp ORF and 313 amino acid residues of translated protein. To study the molecular mechanisms of TAT and HPPR and investigate RA accumulation in S. baicalensis, we examined the transcript levels of TAT isoforms and HPPR with quantitative real-time PCR and analyzed the RA content in different organs by using high-performance liquid chromatography. The transcript levels of SbTATI SbTAT2, and SbHPPR in the flowers were higher than those in other organs. RA was also highly accumulated in the flowers and with a trace amount in the roots. No RA was detected in the leaves and stems of S. baicalensis. The amount of accumulated RA in the flowers was 28.7 times higher than that in the roots. Our results will be helpful in elucidating the mechanisms of RA biosynthesis in S. baicalensis. PMID:25918800

  13. Suppression of ricinoleic acid toxicity by ptl2 overexpression in fission yeast Schizosaccharomyces pombe.

    PubMed

    Yazawa, Hisashi; Ogiso, Masayo; Kumagai, Hiromichi; Uemura, Hiroshi

    2014-11-01

    We previously succeeded to obtain a high content of ricinoleic acid (RA), a hydroxylated fatty acid with great values as a petrochemical replacement, in fission yeast Schizosaccharomyces pombe by introducing Claviceps purpurea oleate Δ12-hydroxylase gene (CpFAH12). Although the production was toxic to S. pombe cells, we identified plg7, encoding phospholipase A2, as a multicopy suppressor that restored the growth defect by removing RA from phospholipids and induced secretion of a part of the released free RA into culture media. In this study, we extended our analysis and examined the effect of triglyceride (TG) lipase overexpression on the tolerance to RA toxicity and RA productivity. S. pombe has three TG lipase genes, ptl1, ptl2, and ptl3, which have high protein sequence similarities to each other and to Saccharomyces cerevisiae counterparts TGL3, TGL4, and TGL5, but only ptl2 overexpression suppressed the growth defect induced by RA production, and the culture grown at 20 °C secreted free RA into media like plg7 overexpression. Suppression by ptl2 was independent of plg7, and a large amount of free RA was accumulated in the cells concomitant with the decrease in RA moieties in phospholipids. Furthermore, the suppression by ptl2 was attenuated by bromoenol lactone (BEL), a phospholipase A2 specific inhibitor, suggesting that Ptl2p may have phospholipase activity. Simultaneous overexpression of ptl2 and plg7 in the FAH12 integrant increased secretion and intracellular accumulation of RA 1.2- and 1.3-fold, respectively, compared to those with single overexpression of plg7 on day 10 at 20 °C. PMID:25109267

  14. Evolution of rosmarinic acid biosynthesis.

    PubMed

    Petersen, Maike; Abdullah, Yana; Benner, Johannes; Eberle, David; Gehlen, Katja; Hücherig, Stephanie; Janiak, Verena; Kim, Kyung Hee; Sander, Marion; Weitzel, Corinna; Wolters, Stefan

    2009-01-01

    Rosmarinic acid and chlorogenic acid are caffeic acid esters widely found in the plant kingdom and presumably accumulated as defense compounds. In a survey, more than 240 plant species have been screened for the presence of rosmarinic and chlorogenic acids. Several rosmarinic acid-containing species have been detected. The rosmarinic acid accumulation in species of the Marantaceae has not been known before. Rosmarinic acid is found in hornworts, in the fern family Blechnaceae and in species of several orders of mono- and dicotyledonous angiosperms. The biosyntheses of caffeoylshikimate, chlorogenic acid and rosmarinic acid use 4-coumaroyl-CoA from the general phenylpropanoid pathway as hydroxycinnamoyl donor. The hydroxycinnamoyl acceptor substrate comes from the shikimate pathway: shikimic acid, quinic acid and hydroxyphenyllactic acid derived from l-tyrosine. Similar steps are involved in the biosyntheses of rosmarinic, chlorogenic and caffeoylshikimic acids: the transfer of the 4-coumaroyl moiety to an acceptor molecule by a hydroxycinnamoyltransferase from the BAHD acyltransferase family and the meta-hydroxylation of the 4-coumaroyl moiety in the ester by a cytochrome P450 monooxygenase from the CYP98A family. The hydroxycinnamoyltransferases as well as the meta-hydroxylases show high sequence similarities and thus seem to be closely related. The hydroxycinnamoyltransferase and CYP98A14 from Coleus blumei (Lamiaceae) are nevertheless specific for substrates involved in RA biosynthesis showing an evolutionary diversification in phenolic ester metabolism. Our current view is that only a few enzymes had to be "invented" for rosmarinic acid biosynthesis probably on the basis of genes needed for the formation of chlorogenic and caffeoylshikimic acid while further biosynthetic steps might have been recruited from phenylpropanoid metabolism, tocopherol/plastoquinone biosynthesis and photorespiration. PMID:19560175

  15. A Novel Bidirectional Interaction between endothelin-3 and Retinoic Acid in Rat Enteric Nervous System Precursors

    PubMed Central

    Gisser, Jonathan M.; Cohen, Ariella R.; Yin, Han; Gariepy, Cheryl E.

    2013-01-01

    Background Signaling through the endothelin receptor B (EDNRB) is critical for the development of the enteric nervous system (ENS) and mutations in endothelin system genes cause Hirschsprung’s aganglionosis in humans. Penetrance of the disease is modulated by other genetic factors. Mutations affecting retinoic acid (RA) signaling also produce aganglionosis in mice. Thus, we hypothesized that RA and endothelin signaling pathways may interact in controlling development of the ENS. Methods Rat immunoselected ENS precursor cells were cultured with the EDNRB ligand endothelin-3, an EDNRB-selective antagonist (BQ-788), and/or RA for 3 or 14 days. mRNA levels of genes related to ENS development, RA- and EDNRB-signaling were measured at 3 days. Proliferating cells and cells expressing neuronal, glial, and myofibroblast markers were quantified. Results Culture of isolated ENS precursors for 3 days with RA decreases expression of the endothelin-3 gene and that of its activation enzyme. These changes are associated with glial proliferation, a higher percentage of glia, and a lower percentage of neurons compared to cultures without RA. These changes are independent of EDNRB signaling. Conversely, EDNRB activation in these cultures decreases expression of RA receptors β and γ mRNA and affects the expression of the RA synthetic and degradative enzymes. These gene expression changes are associated with reduced glial proliferation and a lower percentage of glia in the culture. Over 14 days in the absence of EDNRB signaling, RA induces the formation of a heterocellular plexus replete with ganglia, glia and myofibroblasts. Conclusions A complex endothelin-RA interaction exists that coordinately regulates the development of rat ENS precursors in vitro. These results suggest that environmental RA may modulate the expression of aganglionosis in individuals with endothelin mutations. PMID:24040226

  16. Evaluation of 9-cis retinoic acid and mitotane as antitumoral agents in an adrenocortical xenograft model

    PubMed Central

    Nagy, Zoltán; Baghy, Kornélia; Hunyadi-Gulyás, Éva; Micsik, Tamás; Nyírő, Gábor; Rácz, Gergely; Butz, Henriett; Perge, Pál; Kovalszky, Ilona; Medzihradszky, Katalin F; Rácz, Károly; Patócs, Attila; Igaz, Peter

    2015-01-01

    The available drug treatment options for adrenocortical carcinoma (ACC) are limited. In our previous studies, the in vitro activity of 9-cis retinoic acid (9-cisRA) on adrenocortical NCI-H295R cells was shown along with its antitumoral effects in a small pilot xenograft study. Our aim was to dissect the antitumoral effects of 9-cisRA on ACC in a large-scale xenograft study involving mitotane, 9-cisRA and their combination. 43 male SCID mice inoculated with NCI-H295R cells were treated in four groups (i. control, ii. 9-cisRA, iii. mitotane, iv. 9-cisRA + mitotane) for 28 days. Tumor size follow-up, histological and immunohistochemical (Ki-67) analysis, tissue gene expression microarray, quantitative real-time-PCR for the validation of microarray results and to detect circulating microRNAs were performed. Protein expression was studied by proteomics and Western-blot validation. Only mitotane alone and the combination of 9-cisRA and mitotane resulted in significant tumor size reduction. The Ki-67 index was significantly reduced in both 9-cisRA and 9-cisRA+mitotane groups. Only modest changes at the mRNA level were found: the 9-cisRA-induced overexpression of apolipoprotein A4 and down-regulation of phosphodiesterase 4A was validated. The expression of circulating hsa-miR-483-5p was significantly reduced in the combined treatment group. The SET protein was validated as being significantly down-regulated in the combined mitotane+9-cisRA group. 9-cisRA might be a helpful additive agent in the treatment of ACC in combination with mitotane. Circulating hsa-miR-483-5p could be utilized for monitoring the treatment efficacy in ACC patients, and the treatment-induced reduction in protein SET expression might raise its relevance in ACC biology. PMID:26885453

  17. Simultaneous determination of 226Ra, 233U and 237Np by liquid scintillation spectrometry.

    PubMed

    Nebelung, Cordula; Baraniak, Lutz

    2007-02-01

    A method has been developed for the simultaneous determination of 226Ra, 233U and 237Np by liquid-scintillation (LS) spectrometry. This method consists of the evaluation of the alpha-spectrum that is composed of the strongly overlapping peaks of 226Ra, 233U, 237Np, 222Rn and 218Po in the energy range of 4.60-6.00 MeV and the single 214Po peak at 7.69 MeV. The alpha-peaks are analysed by a special peak fit function that considers the deviation of the alpha-peak at the low energy side from the pure Gaussian shape. First 237Np is determined using its daughter 233Pa by analysing the beta-spectrum in the range 150-570 keV. 226Ra follows from the alpha-spectrum that is measured 6 weeks after sample preparation, i.e., 226Ra is determined from the radioactive equilibrium with its short-lived daughters 222Rn, 218Po and 214Po. Finally the 233U activity results from the fitted spectrum in the range of 4.4-4.8 MeV by subtracting the activity of 226Ra and 237Np. Knowing the exact energy position of the LS-peaks an alternative evaluation consists in the accurate deconvolution of the first three peaks that are formed by 226Ra and 233U (maximum of both at channel 700), 237Np (maxima at channels 700 and 725) and 222Rn (maximum at channel 737). In these two ways 226Ra, 233U and 237Np can be determined in mutual activity ratios of 1:50 with a relative standard deviation of less than 4% for the major activity and 9% for the minor activity. PMID:17142052

  18. Competition of IL-1 and IL-1ra determines lymphocyte response to delayed stimulation with PHA.

    PubMed Central

    Dabrowski, M P; Stankiewicz, W; Płusa, T; Chciałowski, A; Szmigielski, S

    2001-01-01

    BACKGROUND: Human peripheral blood mononuclear cells (PBMC) left in microcultures for 24h without mitogen do not respond to subsequent stimulation with PHA. They regain reactivity if the native culture medium is absorbed with other party lymphocytes or partially replaced with the medium from a PHA-stimulated culture. The observations suggest that, during the incubation, some inhibitory agent had accumulated in the culture medium. AIM: The study was performed to determine the nature of the observed phenomenon in respect of the possible role of monocytes and their products IL-1 and IL-1 receptor antagonist (IL-1ra), and to test for immunodiagnostic purposes the significance of quantifying the lymphocyte response to delayed stimulation with PHA in patients suffering from inflammatory prosesses. METHODS: Lymphocyte response to delayed stimulation with PHA, calculated as the lymphocyte-monokine interaction (LM) index, was determined in the microcultures of PBMC isolated from the blood of healthy donors or of patients with acute tonsilitis. The values of LM indices were compared with the ratios of IL-1ra/IL-1beta concentration estimated by enzyme-linked immunosorbent assay method in the culture supernatants. The influences of exogenous IL-1beta, IL-1ra, anti-IL1ra antibodies and antibiotic cefaclor on the monokine concentrations and on the values of LM index were tested. RESULTS AND CONCLUSIONS: The results show that the level of lymphocyte response to delayed stimulation with PHA (LM index) is inversely proportional to the ratio of IL-1ra/IL-1beta concentration in the culture. The low LM values at high IL-1ra/IL-1beta ratios in PBMC cultures from healthy donors, reversed proportions found in patients' PBMC (acute tonsilitis), and the cefaclor-induced reduction of LM value with correlated increase of the IL-1ra/IL-1beta ratio suggest that the LM assay may prove to be useful for immunodiagnostic purposes. PMID:11545246

  19. Transcription factor TLX1 controls retinoic acid signaling to ensure spleen development.

    PubMed

    Lenti, Elisa; Farinello, Diego; Yokoyama, Kazunari K; Penkov, Dmitry; Castagnaro, Laura; Lavorgna, Giovanni; Wuputra, Kenly; Sandell, Lisa L; Tjaden, Naomi E Butler; Bernassola, Francesca; Caridi, Nicoletta; De Antoni, Anna; Wagner, Michael; Kozinc, Katja; Niederreither, Karen; Blasi, Francesco; Pasini, Diego; Majdic, Gregor; Tonon, Giovanni; Trainor, Paul A; Brendolan, Andrea

    2016-07-01

    The molecular mechanisms that underlie spleen development and congenital asplenia, a condition linked to increased risk of overwhelming infections, remain largely unknown. The transcription factor TLX1 controls cell fate specification and organ expansion during spleen development, and Tlx1 deletion causes asplenia in mice. Deregulation of TLX1 expression has recently been proposed in the pathogenesis of congenital asplenia in patients carrying mutations of the gene-encoding transcription factor SF-1. Herein, we have shown that TLX1-dependent regulation of retinoic acid (RA) metabolism is critical for spleen organogenesis. In a murine model, loss of Tlx1 during formation of the splenic anlage increased RA signaling by regulating several genes involved in RA metabolism. Uncontrolled RA activity resulted in premature differentiation of mesenchymal cells and reduced vasculogenesis of the splenic primordium. Pharmacological inhibition of RA signaling in Tlx1-deficient animals partially rescued the spleen defect. Finally, spleen growth was impaired in mice lacking either cytochrome P450 26B1 (Cyp26b1), which results in excess RA, or retinol dehydrogenase 10 (Rdh10), which results in RA deficiency. Together, these findings establish TLX1 as a critical regulator of RA metabolism and provide mechanistic insights into the molecular determinants of human congenital asplenia. PMID:27214556

  20. Retinoic acid acts as a selective human IgA switch factor.

    PubMed

    Seo, Goo-Young; Jang, Young-Saeng; Kim, Jini; Choe, Jongseon; Han, Hye-Ju; Lee, Jeong-Min; Kang, Seong-Ho; Rhee, Ki-Jong; Park, Seok-Rae; Kim, Woan-Sub; Kim, Pyeung-Hyeun

    2014-08-01

    Retinoic acid (RA) is known to have several functions that lead to a potent mucosal IgA response. Nevertheless, its exact role in human IgA synthesis has yet to be elucidated. Thus, we investigated the role of RA in promoting IgA isotype switching in human B cells. We found that RA increased IgA production and the expression of germ-line IgA1 and IgA2 transcripts (GLTα1 and GLTα2). This induction occurred alongside an increase in the frequency of IgA1-secreting B cell clones, as assessed by limiting dilution analysis. Under the same conditions, RA did not increase IgM and IgG production. Am80, an agonist of RA receptor α (RARα), increased IgA production. In addition, RA activity was abrogated by LE540, an antagonist of RAR, suggesting that the RAR pathway is involved in RA-induced IgA production. Taken together, these results indicate that RA induces IgA isotype switching mainly through RARα in human B cells. PMID:24994461

  1. Formation of oral and pharyngeal dentition in teleosts depends on differential recruitment of retinoic acid signaling.

    PubMed

    Gibert, Yann; Bernard, Laure; Debiais-Thibaud, Melanie; Bourrat, Franck; Joly, Jean-Stephane; Pottin, Karen; Meyer, Axel; Retaux, Sylvie; Stock, David W; Jackman, William R; Seritrakul, Pawat; Begemann, Gerrit; Laudet, Vincent

    2010-09-01

    One of the goals of evolutionary developmental biology is to link specific adaptations to changes in developmental pathways. The dentition of cypriniform fishes, which in contrast to many other teleost fish species possess pharyngeal teeth but lack oral teeth, provides a suitable model to study the development of feeding adaptations. Here, we have examined the involvement of retinoic acid (RA) in tooth development and show that RA is specifically required to induce the pharyngeal tooth developmental program in zebrafish. Perturbation of RA signaling at this stage abolished tooth induction without affecting the development of tooth-associated ceratobranchial bones. We show that this inductive event is dependent on RA synthesis from aldh1a2 in the ventral posterior pharynx. Fibroblast growth factor (FGF) signaling has been shown to be critical for tooth induction in zebrafish, and its loss has been associated with oral tooth loss in cypriniform fishes. Pharmacological treatments targeting the RA and FGF pathways revealed that both pathways act independently during tooth induction. In contrast, we find that in Mexican tetra and medaka, species that also possess oral teeth, both oral and pharyngeal teeth are induced independently of RA. Our analyses suggest an evolutionary scenario in which the gene network controlling tooth development obtained RA dependency in the lineage leading to the cypriniforms. The loss of pharyngeal teeth in this group was cancelled out through a shift in aldh1a2 expression, while oral teeth might have been lost ultimately due to deficient RA signaling in the oral cavity. PMID:20445074

  2. Evidence for the presence of a retinoic acid receptor in rat osteosarcoma cells

    SciTech Connect

    Atkins, K.B.; Beitz, D.C. ); Horst, R.L.; Reinhardt, T.A. )

    1990-02-26

    Research has shown that ROS 17/2.8 cells respond to retinoic acid (RA) and do not express the cellular binding protein (CRABP) for RA. Initial experiments indicated the presence of a cytosolic and nuclear RA-binding activity. Both cytosolic and nuclear extracts were centrifuged (230,000g), and the supernatants labeled with ({sup 3}H)-RA{plus minus}100-fold excess RA. Sucrose gradient analysis of the nuclear extract showed a specific RA-binding activity sedimenting at 3.3S. Scatchard analysis of the nuclear extract showed a single binding component with an apparent K{sub d} of 10{sup {minus}9}M and an estimate of 1,700-3,000 copies/cell. The molecular weight of putative RAR was estimated to be 51KD by gel filtration. The cytosolic RA-binding activity co-sediments (2.0S) on a sucrose gradient with the cytosolic RA-binding activity from rat testis. Scatchard analysis resulted in an apparent Kd of 10{sup {minus}8}M with an estimated 60,000 copies of CRABP/cell. These data indicate ROS 17/2.8 cells express both RAR and CRABP.

  3. UV-A emission from fluorescent energy-saving light bulbs alters local retinoic acid homeostasis.

    PubMed

    Hellmann-Regen, Julian; Heuser, Isabella; Regen, Francesca

    2013-12-01

    Worldwide bans on incandescent light bulbs (ILBs) drive the use of compact fluorescent light (CFL) bulbs, which emit ultraviolet (UV) radiation. Potential health issues of these light sources have already been discussed, including speculation about the putative biological effects on light exposed tissues, yet the underlying mechanisms remain unclear. We hypothesized photoisomerization of all-trans retinoic acid (at-RA), a highly light sensitive morphogen, into biologically less active isomers, as a mechanism mediating biological effects of CFLs. Local at-RA is anti-carcinogenic, entrains molecular rhythms and is crucial for skin homeostasis. Therefore, we quantified the impact of CFL irradiation on extra- and intracellular levels of RA isomers using an epidermal cell culture model. Moreover, a biologically relevant impact of CFL irradiation was assessed using highly at-RA-sensitive human neuroblastoma cells. Dose-dependent conversion of extra- and intracellular at-RA into the biologically less active 13-cis-isomer was significantly higher in CFL vs. ILB exposure and completely preventable by employing a UV-filter. Moreover, pre-irradiation of culture media by CFL attenuated at-RA-specific effects on cell viability in human at-RA-sensitive cells in a dose-dependent manner. These findings point towards a biological relevance of CFL-induced at-RA decomposition, providing a mechanism for CFL-mediated effects on environmental health. PMID:24135972

  4. Cutting Edge: Retinoic Acid Signaling in B Cells Is Essential for Oral Immunization and Microflora Composition.

    PubMed

    Pantazi, Eirini; Marks, Ellen; Stolarczyk, Emilie; Lycke, Nils; Noelle, Randolph J; Elgueta, Raul

    2015-08-15

    Retinoic acid (RA) is a critical regulator of the intestinal adaptive immune response. However, the intrinsic impact of RA on B cell differentiation in the regulation of gut humoral immunity in vivo has never been directly shown. To address this issue, we have been able to generate a mouse model where B cells specifically express a dominant-negative receptor α for RA. In this study, we show that the silencing of RA signaling in B cells reduces the numbers of IgA(+) Ab-secreting cells both in vitro and in vivo, suggesting that RA has a direct effect on IgA plasma cell differentiation. Moreover, the lack of RA signaling in B cells abrogates Ag-specific IgA responses after oral immunization and affects the microbiota composition. In conclusion, these results suggest that RA signaling in B cells through the RA receptor α is important to generate an effective gut humoral response and to maintain a normal microbiota composition. PMID:26163586

  5. Rosmarinic Acid Attenuates Airway Inflammation and Hyperresponsiveness in a Murine Model of Asthma.

    PubMed

    Liang, Zhengmin; Xu, Yangfeng; Wen, Xuemei; Nie, Haiying; Hu, Tingjun; Yang, Xiaofeng; Chu, Xiao; Yang, Jian; Deng, Xuming; He, Jiakang

    2016-01-01

    Rosmarinic acid (RA) has numerous pharmacologic effects, including anti-oxidant, anti-inflammatory, and analgesic effects. This study aimed to evaluate the preventive activity of RA in a murine model of asthma and to investigate its possible molecular mechanisms. Female BALB/c mice sensitized and challenged with ovalbumin (Ova) were pretreated with RA (5, 10 or 20 mg/kg) at 1 h before Ova challenge. The results demonstrated that RA markedly inhibited increases in inflammatory cells and Th2 cytokines in the bronchoalveolar lavage fluid (BALF), significantly reduced the total IgE and Ova-specific IgE concentrations, and greatly ameliorated airway hyperresponsiveness (AHR) compared with the control Ova-induced mice. Histological analyses showed that RA substantially decreased the number of inflammatory cells and mucus hypersecretion in the airway. In addition, our results suggested that the protective effects of RA might be mediated by the suppression of ERK, JNK and p38 phosphorylation and activation of nuclear factor-κB (NF-κB). Furthermore, RA pretreatment resulted in a noticeable reduction in AMCase, CCL11, CCR3, Ym2 and E-selectin mRNA expression in lung tissues. These findings suggest that RA may effectively delay the progression of airway inflammation. PMID:27304950

  6. All-Trans Retinoic Acid Activity in Acute Myeloid Leukemia: Role of Cytochrome P450 Enzyme Expression by the Microenvironment

    PubMed Central

    Su, Meng; Alonso, Salvador; Jones, Jace W.; Yu, Jianshi; Kane, Maureen A.; Jones, Richard J.; Ghiaur, Gabriel

    2015-01-01

    Differentiation therapy with all-trans retinoic acid (atRA) has markedly improved outcome in acute promyelocytic leukemia (APL) but has had little clinical impact in other AML sub-types. Cell intrinsic mechanisms of resistance have been previously reported, yet the majority of AML blasts are sensitive to atRA in vitro. Even in APL, single agent atRA induces remission without cure. The microenvironment expression of cytochrome P450 (CYP)26, a retinoid-metabolizing enzyme was shown to determine normal hematopoietic stem cell fate. Accordingly, we hypothesized that the bone marrow (BM) microenvironment is responsible for difference between in vitro sensitivity and in vivo resistance of AML to atRA-induced differentiation. We observed that the pro-differentiation effects of atRA on APL and non-APL AML cells as well as on leukemia stem cells from clinical specimens were blocked by BM stroma. In addition, BM stroma produced a precipitous drop in atRA levels. Inhibition of CYP26 rescued atRA levels and AML cell sensitivity in the presence of stroma. Our data suggest that stromal CYP26 activity creates retinoid low sanctuaries in the BM that protect AML cells from systemic atRA therapy. Inhibition of CYP26 provides new opportunities to expand the clinical activity of atRA in both APL and non-APL AML. PMID:26047326

  7. Retinoic Acid Prevents Disruption of Blood-Spinal Cord Barrier by Inducing Autophagic Flux After Spinal Cord Injury.

    PubMed

    Zhou, Yulong; Zheng, Binbin; Ye, Libing; Zhang, Hongyu; Zhu, Sipin; Zheng, Xiaomeng; Xia, Qinghai; He, Zili; Wang, Qingqing; Xiao, Jian; Xu, Huazi

    2016-04-01

    Spinal cord injury (SCI) induces the disruption of the blood-spinal cord barrier (BSCB), which leads to infiltration of blood cells, inflammatory responses and neuronal cell death, with subsequent development of spinal cord secondary damage. Recent reports pointed to an important role of retinoic acid (RA), the active metabolite of the vitamin A, in the induction of the blood-brain barrier (BBB) during human and mouse development, however, it is unknown whether RA plays a role in maintaining BSCB integrity under the pathological conditions such as SCI. In this study, we investigated the BSCB protective role of RA both in vivo and in vitro and demonstrated that autophagy are involved in the BSCB protective effect of RA. Our data show that RA attenuated BSCB permeability and also attenuated the loss of tight junction molecules such as P120, β-catenin, Occludin and Claudin5 after injury in vivo as well as in brain microvascular endothelial cells. In addition, RA administration improved functional recovery of the rat model of trauma. We also found that RA could significantly increase the expression of LC3-II and decrease the expression of p62 both in vivo and in vitro. Furthermore, combining RA with the autophagy inhibitor chloroquine (CQ) partially abolished its protective effect on the BSCB and exacerbated the loss of tight junctions. Together, our studies indicate that RA improved functional recovery in part by the prevention of BSCB disruption via the activation of autophagic flux after SCI. PMID:26582233

  8. Lipid Abundance in Zebrafish Embryos Is Regulated by Complementary Actions of the Endocannabinoid System and Retinoic Acid Pathway.

    PubMed

    Fraher, Daniel; Ellis, Megan K; Morrison, Shona; McGee, Sean L; Ward, Alister C; Walder, Ken; Gibert, Yann

    2015-10-01

    The endocannabinoid system (ECS) and retinoic acid (RA) signaling have been associated with influencing lipid metabolism. We hypothesized that modulation of these pathways could modify lipid abundance in developing vertebrates and that these pathways could have a combinatorial effect on lipid levels. Zebrafish embryos were exposed to chemical treatments altering the activity of the ECS and RA pathway. Embryos were stained with the neutral lipid dye Oil-Red-O (ORO) and underwent whole-mount in situ hybridization (WISH). Mouse 3T3-L1 fibroblasts were differentiated under exposure to RA-modulating chemicals and subsequently stained with ORO and analyzed for gene expression by qRT-PCR. ECS activation and RA exposure increased lipid abundance and the expression of lipoprotein lipase. In addition, RA treatment increased expression of CCAAT/enhancer-binding protein alpha. Both ECS receptors and RA receptor subtypes were separately involved in modulating lipid abundance. Finally, increased ECS or RA activity ameliorated the reduced lipid abundance caused by peroxisome proliferator-activated receptor gamma (PPARγ) inhibition. Therefore, the ECS and RA pathway influence lipid abundance in zebrafish embryos and have an additive effect when treated simultaneously. Furthermore, we demonstrated that these pathways act downstream or independently of PPARγ to influence lipid levels. Our study shows for the first time that the RA and ECS pathways have additive function in lipid abundance during vertebrate development. PMID:26181105

  9. All-Trans Retinoic Acid Activity in Acute Myeloid Leukemia: Role of Cytochrome P450 Enzyme Expression by the Microenvironment.

    PubMed

    Su, Meng; Alonso, Salvador; Jones, Jace W; Yu, Jianshi; Kane, Maureen A; Jones, Richard J; Ghiaur, Gabriel

    2015-01-01

    Differentiation therapy with all-trans retinoic acid (atRA) has markedly improved outcome in acute promyelocytic leukemia (APL) but has had little clinical impact in other AML sub-types. Cell intrinsic mechanisms of resistance have been previously reported, yet the majority of AML blasts are sensitive to atRA in vitro. Even in APL, single agent atRA induces remission without cure. The microenvironment expression of cytochrome P450 (CYP)26, a retinoid-metabolizing enzyme was shown to determine normal hematopoietic stem cell fate. Accordingly, we hypothesized that the bone marrow (BM) microenvironment is responsible for difference between in vitro sensitivity and in vivo resistance of AML to atRA-induced differentiation. We observed that the pro-differentiation effects of atRA on APL and non-APL AML cells as well as on leukemia stem cells from clinical specimens were blocked by BM stroma. In addition, BM stroma produced a precipitous drop in atRA levels. Inhibition of CYP26 rescued atRA levels and AML cell sensitivity in the presence of stroma. Our data suggest that stromal CYP26 activity creates retinoid low sanctuaries in the BM that protect AML cells from systemic atRA therapy. Inhibition of CYP26 provides new opportunities to expand the clinical activity of atRA in both APL and non-APL AML. PMID:26047326

  10. A retinoic acid receptor-specific element controls the retinoic acid receptor-beta promoter.

    PubMed

    Hoffmann, B; Lehmann, J M; Zhang, X K; Hermann, T; Husmann, M; Graupner, G; Pfahl, M

    1990-11-01

    The morphogen retinoic acid (RA) regulates gene transcription by interacting with specific nuclear receptors that recognize DNA sequences near responsive promoters. While much has recently been learned about the nuclear receptor proteins, little is known about the genes that are directly regulated by RA and their cis-acting response elements recognized by these receptors. Here we have analyzed the RA receptor-beta (RAR beta) gene promoter that is controlled by RA. We find that a RA-responsive element (RARE) is located adjacent to the TATA box. The RARE shows a direct repeat symmetry which is essential for its function. While thyroid hormone-responsive elements can also function as RAR response elements, we show here that this RARE is activated by endogenous RARs and RAR beta, but cannot be regulated by thyroid hormone receptors and other known nuclear receptors. In addition, we find that RAR gamma is a poor activator of this RARE. However, the response element is bound with high affinity by both RAR beta and RAR gamma as well as by thyroid hormone receptors. Thus, interaction between specific response elements and receptors is insufficient for gene activation. PMID:2177841

  11. Safety profile of solid lipid nanoparticles loaded with rosmarinic acid for oral use: in vitro and animal approaches

    PubMed Central

    Madureira, Ana Raquel; Nunes, Sara; Campos, Débora A; Fernandes, João C; Marques, Cláudia; Zuzarte, Monica; Gullón, Beatriz; Rodríguez-Alcalá, Luís M; Calhau, Conceição; Sarmento, Bruno; Gomes, Ana Maria; Pintado, Maria Manuela; Reis, Flávio

    2016-01-01

    Rosmarinic acid (RA) possesses several protective bioactivities that have attracted increasing interest by nutraceutical/pharmaceutical industries. Considering the reduced bioavailability after oral use, effective (and safe) delivery systems are crucial to protect RA from gastrointestinal degradation. This study aims to characterize the safety profile of solid lipid nanoparticles produced with Witepsol and Carnauba waxes and loaded with RA, using in vitro and in vivo approaches, focused on genotoxicity and cytotoxicity assays, redox status markers, hematological and biochemical profile, liver and kidney function, gut bacterial microbiota, and fecal fatty acids composition. Free RA and sage extract, empty nanoparticles, or nanoparticles loaded with RA or sage extract (0.15 and 1.5 mg/mL) were evaluated for cell (lymphocytes) viability, necrosis and apoptosis, and antioxidant/prooxidant effects upon DNA. Wistar rats were orally treated for 14 days with vehicle (control) and with Witepsol or Carnauba nanoparticles loaded with RA at 1 and 10 mg/kg body weight/d. Blood, urine, feces, and several tissues were collected for analysis. Free and loaded RA, at 0.15 mg/mL, presented a safe profile, while genotoxic potential was found for the higher dose (1.5 mg/mL), mainly by necrosis. Our data suggest that both types of nanoparticles are safe when loaded with moderate concentrations of RA, without in vitro genotoxicity and cytotoxicity and with an in vivo safety profile in rats orally treated, thus opening new avenues for use in nutraceutical applications. PMID:27536103

  12. Safety profile of solid lipid nanoparticles loaded with rosmarinic acid for oral use: in vitro and animal approaches.

    PubMed

    Madureira, Ana Raquel; Nunes, Sara; Campos, Débora A; Fernandes, João C; Marques, Cláudia; Zuzarte, Monica; Gullón, Beatriz; Rodríguez-Alcalá, Luís M; Calhau, Conceição; Sarmento, Bruno; Gomes, Ana Maria; Pintado, Maria Manuela; Reis, Flávio

    2016-01-01

    Rosmarinic acid (RA) possesses several protective bioactivities that have attracted increasing interest by nutraceutical/pharmaceutical industries. Considering the reduced bioavailability after oral use, effective (and safe) delivery systems are crucial to protect RA from gastrointestinal degradation. This study aims to characterize the safety profile of solid lipid nanoparticles produced with Witepsol and Carnauba waxes and loaded with RA, using in vitro and in vivo approaches, focused on genotoxicity and cytotoxicity assays, redox status markers, hematological and biochemical profile, liver and kidney function, gut bacterial microbiota, and fecal fatty acids composition. Free RA and sage extract, empty nanoparticles, or nanoparticles loaded with RA or sage extract (0.15 and 1.5 mg/mL) were evaluated for cell (lymphocytes) viability, necrosis and apoptosis, and antioxidant/prooxidant effects upon DNA. Wistar rats were orally treated for 14 days with vehicle (control) and with Witepsol or Carnauba nanoparticles loaded with RA at 1 and 10 mg/kg body weight/d. Blood, urine, feces, and several tissues were collected for analysis. Free and loaded RA, at 0.15 mg/mL, presented a safe profile, while genotoxic potential was found for the higher dose (1.5 mg/mL), mainly by necrosis. Our data suggest that both types of nanoparticles are safe when loaded with moderate concentrations of RA, without in vitro genotoxicity and cytotoxicity and with an in vivo safety profile in rats orally treated, thus opening new avenues for use in nutraceutical applications. PMID:27536103

  13. Retinoic acid signaling targets Hox genes during the amphioxus gastrula stage: insights into early anterior-posterior patterning of the chordate body plan.

    PubMed

    Koop, Demian; Holland, Nicholas D; Sémon, Marie; Alvarez, Susana; de Lera, Angel Rodriguez; Laudet, Vincent; Holland, Linda Z; Schubert, Michael

    2010-02-01

    Previous studies of vertebrate development have shown that retinoic acid (RA) signaling at the gastrula stage strongly influences anterior-posterior (A-P) patterning of the neurula and later stages. However, much less is known about the more immediate effects of RA signaling on gene transcription and developmental patterning at the gastrula stage. To investigate the targets of RA signaling during the gastrula stage, we used the basal chordate amphioxus, in which gastrulation involves very minimal tissue movements. First, we determined the effect of altered RA signaling on expression of 42 genes (encoding transcription factors and components of major signaling cascades) known to be expressed in restricted domains along the A-P axis during the gastrula and early neurula stage. Of these 42 genes, the expression domains during gastrulation of only four (Hox1, Hox3, HNF3-1 and Wnt3) were spatially altered by exposure of the embryos to excess RA or to the RA antagonist BMS009. Moreover, blocking protein synthesis with puromycin before adding RA or BMS009 showed that only three of these genes (Hox1, Hox3 and HNF3-1) are direct RA targets at the gastrula stage. From these results we conclude that in the amphioxus gastrula RA signaling primarily acts via regulation of Hox transcription to establish positional identities along the A-P axis and that Hox1, Hox3, HNF3-1 and Wnt3 constitute a basal module of RA action during chordate gastrulation. PMID:19914237

  14. Retinoic acid expression associates with enhanced IL-22 production by γδ T cells and innate lymphoid cells and attenuation of intestinal inflammation

    PubMed Central

    Mielke, Lisa A.; Jones, Sarah A.; Raverdeau, Mathilde; Higgs, Rowan; Stefanska, Anna; Groom, Joanna R.; Misiak, Alicja; Dungan, Lara S.; Sutton, Caroline E.; Streubel, Gundula; Bracken, Adrian P.

    2013-01-01

    Retinoic acid (RA), a vitamin A metabolite, modulates mucosal T helper cell responses. Here we examined the role of RA in regulating IL-22 production by γδ T cells and innate lymphoid cells in intestinal inflammation. RA significantly enhanced IL-22 production by γδ T cells stimulated in vitro with IL-1β or IL-18 and IL-23. In vivo RA attenuated colon inflammation induced by dextran sodium sulfate treatment or Citrobacter rodentium infection. This was associated with a significant increase in IL-22 secretion by γδ T cells and innate lymphoid cells. In addition, RA treatment enhanced production of the IL-22–responsive antimicrobial peptides Reg3β and Reg3γ in the colon. The attenuating effects of RA on colitis were reversed by treatment with an anti–IL-22 neutralizing antibody, demonstrating that RA mediates protection by enhancing IL-22 production. To define the molecular events involved, we used chromatin immunoprecipitation assays and found that RA promoted binding of RA receptor to the IL-22 promoter in γδ T cells. Our findings provide novel insights into the molecular events controlling IL-22 transcription and suggest that one key outcome of RA signaling may be to shape early intestinal immune responses by promoting IL-22 synthesis by γδ T cells and innate lymphoid cells. PMID:23690441

  15. Retinoic Acid Induced-Autophagic Flux Inhibits ER-Stress Dependent Apoptosis and Prevents Disruption of Blood-Spinal Cord Barrier after Spinal Cord Injury

    PubMed Central

    Zhou, Yulong; Zhang, Hongyu; Zheng, Binbin; Ye, Libing; Zhu, Sipin; Johnson, Noah R; Wang, Zhouguang; Wei, Xiaojie; Chen, Daqing; Cao, Guodong; Fu, Xiaobing; Li, Xiaokun; Xu, Hua-Zi; Xiao, Jian

    2016-01-01

    Spinal cord injury (SCI) induces the disruption of the blood-spinal cord barrier (BSCB) which leads to infiltration of blood cells, an inflammatory response, and neuronal cell death, resulting spinal cord secondary damage. Retinoic acid (RA) has a neuroprotective effect in both ischemic brain injury and SCI, however the relationship between BSCB disruption and RA in SCI is still unclear. In this study, we demonstrated that autophagy and ER stress are involved in the protective effect of RA on the BSCB. RA attenuated BSCB permeability and decreased the loss of tight junction (TJ) molecules such as P120, β-catenin, Occludin and Claudin5 after injury in vivo as well as in Brain Microvascular Endothelial Cells (BMECs). Moreover, RA administration improved functional recovery in the rat model of SCI. RA inhibited the expression of CHOP and caspase-12 by induction of autophagic flux. However, RA had no significant effect on protein expression of GRP78 and PDI. Furthermore, combining RA with the autophagy inhibitor chloroquine (CQ) partially abolished its protective effect on the BSCB via exacerbated ER stress and subsequent loss of tight junctions. Taken together, the neuroprotective role of RA in recovery from SCI is related to prevention of of BSCB disruption via the activation of autophagic flux and the inhibition of ER stress-induced cell apoptosis. These findings lay the groundwork for future translational studies of RA for CNS diseases, especially those related to BSCB disruption. PMID:26722220

  16. Retinoic Acid Induces Ubiquitination-Resistant RIP140/LSD1 Complex to Fine-Tune Pax6 Gene in Neuronal Differentiation.

    PubMed

    Wu, Cheng-Ying; Persaud, Shawna D; Wei, Li-Na

    2016-01-01

    Receptor-interacting protein 140 (RIP140) is a wide-spectrum coregulator for hormonal regulation of gene expression, but its activity in development/stem cell differentiation is unknown. Here, we identify RIP140 as an immediate retinoic acid (RA)-induced dual-function chaperone for LSD1 (lysine-specific demethylase 1). RIP140 protects LSD1's catalytic domain and antagonizes its Jade-2-mediated ubiquitination and degradation. In RA-induced neuronal differentiation, the increased RIP140/LSD1 complex is recruited by RA-elevated Pit-1 to specifically reduce H3K4me2 modification on the Pax6 promoter, thereby repressing RA-induction of Pax6. This study reveals a new RA-induced gene repressive mechanism that modulates the abundance, enzyme quality, and recruitment of histone modifier LSD1 to neuronal regulator Pax6, which provides a homeostatic control for RA induction of neuronal differentiation. PMID:26372689

  17. Signaling through retinoic acid receptors in cardiac development: Doing the right things at the right times.

    PubMed

    Xavier-Neto, José; Sousa Costa, Ângela M; Figueira, Ana Carolina M; Caiaffa, Carlo Donato; Amaral, Fabio Neves do; Peres, Lara Maldanis Cerqueira; da Silva, Bárbara Santos Pires; Santos, Luana Nunes; Moise, Alexander R; Castillo, Hozana Andrade

    2015-02-01

    Retinoic acid (RA) is a terpenoid that is synthesized from vitamin A/retinol (ROL) and binds to the nuclear receptors retinoic acid receptor (RAR)/retinoid X receptor (RXR) to control multiple developmental processes in vertebrates. The available clinical and experimental data provide uncontested evidence for the pleiotropic roles of RA signaling in development of multiple embryonic structures and organs such eyes, central nervous system, gonads, lungs and heart. The development of any of these above-mentioned embryonic organ systems can be effectively utilized to showcase the many strategies utilized by RA signaling. However, it is very likely that the strategies employed to transfer RA signals during cardiac development comprise the majority of the relevant and sophisticated ways through which retinoid signals can be conveyed in a complex biological system. Here, we provide the reader with arguments indicating that RA signaling is exquisitely regulated according to specific phases of cardiac development and that RA signaling itself is one of the major regulators of the timing of cardiac morphogenesis and differentiation. We will focus on the role of signaling by RA receptors (RARs) in early phases of heart development. This article is part of a Special Issue entitled: Nuclear receptors in animal development. PMID:25134739

  18. SIGNALLING THROUGH RETINOIC ACID RECEPTORS IN CARDIAC DEVELOPMENT: DOING THE RIGHT THINGS AT THE RIGHT TIMES

    PubMed Central

    Xavier-Neto, José; Costa, Ângela M. Sousa; Figueira, Ana Carolina M.; Caiaffa, Carlo Donato; do Amaral, Fabio Neves; Peres, Lara Maldanis Cerqueira; da Silva, Bárbara Santos Pires; Santos, Luana Nunes; Moise, Alexander R.; Castillo, Hozana Andrade

    2015-01-01

    Retinoic acid (RA) is a terpenoid that is synthesized from Vitamin A/retinol (ROL) and binds to the nuclear receptors retinoic acid receptor (RAR)/retinoid X receptor (RXR) to control multiple developmental processes in vertebrates. The available clinic and experimental data provide uncontested evidence for the pleiotropic roles of RA signalling in development of multiple embryonic structures and organs such eyes, central nervous system, gonads, lungs and heart. The development of any of these above-mentioned embryonic organ systems can be effectively utilized to showcase the many strategies utilized by RA signalling. However, it is very likely that the strategies employed to transfer RA signals during cardiac development comprise the majority of the relevant and sophisticated ways through which retinoid signals can be conveyed in a complex biological system. Here, we provide the reader with arguments indicating that RA signalling is exquisitely regulated according to specific phases of cardiac development and that RA signalling itself is one of the major regulators of the timing of cardiac morphogenesis and differentiation. We will focus on the role of signalling by RA receptors (RARs) in early phases of heart development. PMID:25134739

  19. RDH10 Oxidation of Vitamin A Is a Critical Control Step in Synthesis of Retinoic Acid during Mouse Embryogenesis

    PubMed Central

    Sandell, Lisa L.; Lynn, Megan L.; Inman, Kimberly E.; McDowell, William; Trainor, Paul A.

    2012-01-01

    Retinoic Acid (RA) is a small lipophilic signaling molecule essential for embryonic development and adult tissue maintenance. Both an excess of RA and a deficiency of RA can cause pathogenic anomalies, hence it is critical to understand the mechanisms controlling the spatial and temporal distribution of RA. However, our current understanding of these processes remains incomplete. Vitamin A is metabolized to RA via two sequential enzymatic reactions. The first requires retinol dehydrogenase (RDH) activity to oxidize Vitamin A (retinol) to retinal, and the second requires retinaldehyde activity (RALDH) to oxidize retinal into RA. The first reaction has previously been attributed to the alcohol dehydrogenase (ADH) family, whose genes are ubiquitously or redundantly expressed. Consequently, the specificity of RA synthesis was thought to reside exclusively at the level of the second reaction. To better understand the metabolism of Vitamin A into RA during embryogenesis, we generated new mouse models that disrupt this process. Here we describe a new targeted knockout of Rdh10 in which RA synthesis is severely impaired, particularly at critical early embryonic stages. We also introduce a new mutant allele of Aldh1a2. Both mutations produce similar developmental defects resulting in lethality around embryonic day 10.5 (E10.5). The severity of the Rdh10 null phenotype demonstrates that embryonic oxidation of retinol is carried out primarily by RDH10 and that neither ADHs nor other enzymes contribute significantly to this reaction. We also show that reduced RA production results in upregulation of Rdh10. These data demonstrate that RDH10 plays a critical role in mediating the rate limiting RDH step of Vitamin A metabolism and functions as a nodal point in feedback regulation of RA synthesis. Moreover, RDH10-mediated oxidation of retinol plays as important a role in the control and regulation of RA production during embryogenesis as does the subsequent RALDH-mediated reaction

  20. Retinoic acid isomers facilitate apolipoprotein E production and lipidation in astrocytes through the retinoid X receptor/retinoic acid receptor pathway.

    PubMed

    Zhao, Jing; Fu, Yuan; Liu, Chia-Chen; Shinohara, Mitsuru; Nielsen, Henrietta M; Dong, Qiang; Kanekiyo, Takahisa; Bu, Guojun

    2014-04-18

    Apolipoprotein E (apoE) is the major cholesterol transport protein in the brain. Among the three human APOE alleles (APOE2, APOE3, and APOE4), APOE4 is the strongest genetic risk factor for late-onset Alzheimer disease (AD). The accumulation of amyloid-β (Aβ) is a central event in AD pathogenesis. Increasing evidence demonstrates that apoE isoforms differentially regulate AD-related pathways through both Aβ-dependent and -independent mechanisms; therefore, modulating apoE secretion, lipidation, and function might be an attractive approach for AD therapy. We performed a drug screen for compounds that modulate apoE production in immortalized astrocytes derived from apoE3-targeted replacement mice. Here, we report that retinoic acid (RA) isomers, including all-trans-RA, 9-cis-RA, and 13-cis-RA, significantly increase apoE secretion to ~4-fold of control through retinoid X receptor (RXR) and RA receptor. These effects on modulating apoE are comparable with the effects recently reported for the RXR agonist bexarotene. Furthermore, all of these compounds increased the expression of the cholesterol transporter ABCA1 and ABCG1 levels and decreased cellular uptake of Aβ in an apoE-dependent manner. Both bexarotene and 9-cis-RA promote the lipidation status of apoE, in which 9-cis-RA promotes a stronger effect and exhibits less cytotoxicity compared with bexarotene. Importantly, we showed that oral administration of bexarotene and 9-cis-RA significantly increases apoE, ABCA1, and ABCG1 levels in mouse brains. Taken together, our results demonstrate that RXR/RA receptor agonists, including several RA isomers, are effective modulators of apoE secretion and lipidation and may be explored as potential drugs for AD therapy. PMID:24599963

  1. Direct inhibition of retinoic acid catabolism by fluoxetine.

    PubMed

    Hellmann-Regen, Julian; Uhlemann, Ria; Regen, Francesca; Heuser, Isabella; Otte, Christian; Endres, Matthias; Gertz, Karen; Kronenberg, Golo

    2015-09-01

    Recent evidence from animal and human studies suggests neuroprotective effects of the SSRI fluoxetine, e.g., in the aftermath of stroke. The underlying molecular mechanisms remain to be fully defined. Because of its effects on the cytochrome P450 system (CYP450), we hypothesized that neuroprotection by fluoxetine is related to altered metabolism of retinoic acid (RA), whose CYP450-mediated degradation in brain tissue constitutes an important step in the regulation of its site-specific auto- and paracrine actions. Using traditional pharmacological in vitro assays, the effects of fluoxetine on RA degradation were probed in crude synaptosomes from rat brain and human-derived SH-SY5Y cells, and in cultures of neuron-like SH-SY5Y cells. Furthermore, retinoid-dependent effects of fluoxetine on neuronal survival following glutamate exposure were investigated in rat primary neurons cells using specific retinoid receptor antagonists. Experiments revealed dose-dependent inhibition of synaptosomal RA degradation by fluoxetine along with dose-dependent increases in RA levels in cell cultures. Furthermore, fluoxetine's neuroprotective effects against glutamate excitotoxicity in rat primary neurons were demonstrated to partially depend on RA signaling. Taken together, these findings demonstrate for the first time that the potent, pleiotropic antidepressant fluoxetine directly interacts with RA homeostasis in brain tissue, thereby exerting its neuroprotective effects. PMID:25981674

  2. Genomic antagonism between retinoic acid and estrogen signaling in breast cancer.

    PubMed

    Hua, Sujun; Kittler, Ralf; White, Kevin P

    2009-06-26

    Retinoic acid (RA) triggers antiproliferative effects in tumor cells, and therefore RA and its synthetic analogs have great potential as anticarcinogenic agents. Retinoic acid receptors (RARs) mediate RA effects by directly regulating gene expression. To define the genetic network regulated by RARs in breast cancer, we identified RAR genomic targets using chromatin immunoprecipitation and expression analysis. We found that RAR binding throughout the genome is highly coincident with estrogen receptor alpha (ERalpha) binding, resulting in a widespread crosstalk of RA and estrogen signaling to antagonistically regulate breast cancer-associated genes. ERalpha- and RAR-binding sites appear to be coevolved on a large scale throughout the human genome, often resulting in competitive binding activity at nearby or overlapping cis-regulatory elements. The highly coordinated intersection between these two critical nuclear hormone receptor signaling pathways provides a global mechanism for balancing gene expression output via local regulatory interactions dispersed throughout the genome. PMID:19563758

  3. Immunization of cattle with Ra86 impedes Rhipicephalus appendiculatus nymphal-to-adult molting.

    PubMed

    Olds, Cassandra; Mwaura, Stephen; Crowder, David; Odongo, David; van Oers, Monique; Owen, Jeb; Bishop, Richard; Daubenberger, Claudia

    2012-06-01

    Commercial vaccines based on the tick gut protein Bm86 have been successful in controlling the one-host tick Rhipicephalus (Boophilus) microplus and provide heterologous protection against certain other non-target ixodid tick species. This cross protection, however, does not extend to the three-host tick R. appendiculatus, the vector of the protozoan parasite Theileria parva. When transmitted to cattle, T. parva causes the often fatal disease East Coast fever. Here, we used insect cell-expressed recombinant versions of the R. appendiculatus homologs of Bm86, named Ra86, to vaccinate cattle. We measured multiple fitness characteristics for ticks that were fed on cattle Ra86-vaccinated or unvaccinated. The Ra86 vaccination of cattle significantly decreased the molting success of nymphal ticks to the adult stage. Modeling simulations based on our empirical data suggest that repeated vaccinations using Ra86 could reduce tick populations over successive generations. Vaccination with Ra86 could thus form a component of integrated control strategies for R. appendiculatus leading to a reduction in use of environmentally damaging acaricides. PMID:22658857

  4. Ra isotopes as a tracer of sediment-water column exchange in the North Sea

    NASA Astrophysics Data System (ADS)

    Burt, William; Thomas, Helmuth; Pätsch, Johannnes; Omar, Abdirahman; Schrum, Corinna; Daewel, Ute

    2014-05-01

    Quantifying the benthic flux of short-lived radium isotopes (224Ra and 223Ra) provides information regarding the extent, and the dominant processes governing sediment-water column exchange in the North Sea. For this purpose we employed three independent measurement techniques including sediment incubation chambers, water column inventories, and a surface mass-balance. Incubation results from 11 stations indicate significant spatial variability in Radium efflux throughout the North Sea, as well as a strong dependence on the stirring rate of the overlying water column. Both inventory and mass-balance methods yield consistently higher benthic fluxes for the Southern North Sea than incubation-based estimates due to the inability of the laboratory incubations to recreate the in-situ mixing conditions present in the well-mixed Southern North Sea. Furthermore, fluxes in the Southern North Sea are higher than those previously reported in other regions, likely due to high rates of sediment irrigation induced by strong tidal and wind mixing near the interface of permeable sandy sediments. The seasonality of distributions and the magnitudes of both benthic and coastal Ra fluxes are further examined by applying Ra as a passive tracer in the 3-dimensional hydrodynamics of the ECOSMO model. Finally, flux estimates combined with direct measurements of porewater Ra activities yield volume fluxes [L m-2 d-1], which when further applied to porewater concentrations of carbon or nutrient species, can provide important information regarding the role of sediments in North Sea biogeochemistry.

  5. Phenotypic effects of an induced mutation of the ObRa isoform of the leptin receptor★

    PubMed Central

    Li, Zhiying; Ceccarini, Giovanni; Eisenstein, Michael; Tan, Keith; Friedman, Jeffrey Michael

    2013-01-01

    Leptin receptors play critical roles in mediating leptin's pleiotropic effects on mammalian physiology. To date, six splice variants of the leptin receptor gene have been identified [1–3]. These splice variants have identical extracellular leptin binding motifs but different intracellular C termini. The finding that mutations specifically ablating the function of ObRb cause obesity has established a critical role for this isoform in leptin signaling [1,7]. ObRa is the most abundant splicing isoform with a broad tissue distribution [5], and it has been proposed to play roles in regulating leptin bioavailability, CSF (cerebrospinal fluid) transport and function by forming heterodimers with ObRb and also activating signal transduction via JAK2 in-vitro [5–10]. To assess the in-vivo role of ObRa, we generated an ObRa KO mouse by deleting the ObRa-specific exon 19a. Homozygous mutant mice breed normally and are indistinguishable from wild-type mice on regular chow diet, but show a slightly increased basal plasma leptin, a slight improvement of their GTT and a slightly reduced response to systemic leptin administration. These mice also show a modest but statistically significant increase in weight when placed on a high fat diet with a slightly reduced CSF/plasma ratio of leptin. These data suggest that ObRa plays a role in mediating some of leptin's effects but that the phenotypic consequences are modest compared to a deletion of ObRb. PMID:24327953

  6. Longitudinal neuropsychological findings in amyloid beta-related angiitis (AβRA): a case report.

    PubMed

    Omisade, Antonina; Rigby, Heather; Easton, Alexander; Phillips, Stephen J; Carter, Sherri L

    2013-01-01

    Amyloid β-related angiitis (AβRA) is a clinicopathological diagnosis of primary central nervous system angiitis theoretically triggered by vascular deposition of amyloid β peptide. Deposits of Aβ are associated with degeneration of the vasculature, thereby increasing risks of a stroke and/or cognitive impairment. Despite this, no prior studies have presented a detailed neuropsychological profile associated with AβRA. We present longitudinal neuropsychological findings for the case of a 58-year-old man with biopsy-diagnosed AβRA. Neuropsychological test results and clinical presentation demonstrated a mild to moderate dysexecutive syndrome implicating dorsolateral frontal and orbitofrontal-subcortical systems involvement. Despite prior reports of cognitive decline following a diagnosis of AβRA, cognitive functioning remained relatively stable over a 15-month period after immunosuppressive treatment. For the most part, objective measures did not demonstrate a measurable change in cognitive functioning, except for a mild decline in memory. There were subjective reports of improvement in cognitive and adaptive functioning from the patient and his spouse over this time period. The clinical significance of these results is discussed in the context of theories of executive dysfunction, and with reference to previously-published cases of AβRA. PMID:23244572

  7. Epithelial IL-22RA1-Mediated Fucosylation Promotes Intestinal Colonization Resistance to an Opportunistic Pathogen

    PubMed Central

    Pham, Tu Anh N.; Clare, Simon; Goulding, David; Arasteh, Julia M.; Stares, Mark D.; Browne, Hilary P.; Keane, Jacqueline A.; Page, Andrew J.; Kumasaka, Natsuhiko; Kane, Leanne; Mottram, Lynda; Harcourt, Katherine; Hale, Christine; Arends, Mark J.; Gaffney, Daniel J.; Dougan, Gordon; Lawley, Trevor D.

    2014-01-01

    Summary Our intestinal microbiota harbors a diverse microbial community, often containing opportunistic bacteria with virulence potential. However, mutualistic host-microbial interactions prevent disease by opportunistic pathogens through poorly understood mechanisms. We show that the epithelial interleukin-22 receptor IL-22RA1 protects against lethal Citrobacter rodentium infection and chemical-induced colitis by promoting colonization resistance against an intestinal opportunistic bacterium, Enterococcus faecalis. Susceptibility of Il22ra1−/− mice to C. rodentium was associated with preferential expansion and epithelial translocation of pathogenic E. faecalis during severe microbial dysbiosis and was ameloriated with antibiotics active against E. faecalis. RNA sequencing analyses of primary colonic organoids showed that IL-22RA1 signaling promotes intestinal fucosylation via induction of the fucosyltransferase Fut2. Additionally, administration of fucosylated oligosaccharides to C. rodentium-challenged Il22ra1−/− mice attenuated infection and promoted E. faecalis colonization resistance by restoring the diversity of anaerobic commensal symbionts. These results support a model whereby IL-22RA1 enhances host-microbiota mutualism to limit detrimental overcolonization by opportunistic pathogens. PMID:25263220

  8. Measurement of 224Ra uptake in a fern actively accumulating radium.

    PubMed

    Chao, J H; Lee, H P; Chiu, C Y

    2006-03-01

    A method is proposed for determining the level of 224Ra in plant samples by measuring its descendant nuclide 212Pb at 239 keV by gamma-ray spectrometry. Variations of 224Ra and 212Pb over time during sample preparation and counting were delineated prior to gamma-ray measurement. The 224Ra concentrations in plant samples were measured by their direct uptake from soil, which could be determined and distinguished from that resulting from decay of 228Th inside the plants. We propose that a field-growing Dicranopteris linearis, which actively accumulates radium, can be used as an indicator of the nutritional transportation and metabolic rate of radium and other alkaline earth elements. We investigated the influence of rainfall on 224Ra concentrations in fronds of D. linearis and the corresponding uptake rates. 224Ra could serve as a natural tracer of growth in plants over a several days. Its presence and content in plants implies a temporal mineral metabolic rate, which can provide useful information for plant physiological and environmental investigations. PMID:16087212

  9. Comparative Analysis Of 226Ra Soil-To-Plant Transfer In Cabbage Grown In Various Regions

    NASA Astrophysics Data System (ADS)

    Madruga, M. J.; Carvalho, F. P.; Silva, L.; Gouveia, J.

    2008-08-01

    The transfer of 226Ra from soil to cabbage was compared amongst regions, namely the surroundings of Urgeiriça uranium milling tailings (GE), regions with past uranium mining activities (GN1), and regions with no uranium mining activities and no uranium deposits (GN2). Results show a slight increase of the concentration ratio values at low radium concentration in soils. Statistical analysis of the mean 226Ra activity concentrations in soil and cabbage for the three regions was carried out. The comparison of 226Ra activity concentrations in soils indicated no difference (p>0.05), between GE and GN2 and significant differences (p<0.05) between GE and GN1 and between GN1 and GN2. Similar statistical results were obtained for 226Ra activity concentrations in cabbage from the same regions. It was concluded that radium Concentration Ratio (CR) for cabbage grown in the region of the main uranium milling site (GE) is of the same order of magnitude of CR in cabagge grown in background regions (GN2). However, 226Ra CR was higher in cabagge from the region with past uranium mining activities (GN1).

  10. PADI4 Haplotypes in Association with RA Mexican Patients, a New Prospect for Antigen Modulation

    PubMed Central

    Gonzalez-Montoya, Norma Guadalupe; Gamez-Nava, Jorge I.; Moran-Moguel, Maria Cristina; Rosales-Gomez, Roberto Carlos; Gutierrez-Rubio, Susan Andrea; Sanchez-Corona, Jose; Davalos-Rodriguez, Ingrid Patricia; Salazar-Paramo, Mario

    2013-01-01

    Peptidyl arginine deiminase IV (PAD 4) is the responsible enzyme for a posttranslational modification called citrullination, originating the antigenic determinant recognized by anti-cyclic citrullinated peptide antibodies (ACPA). Four SNPs (single nucleotide polymorphisms) have been described in PADI4 gene to form a susceptibility haplotype for rheumatoid arthritis (RA); nevertheless, results in association studies appear contradictory in different populations. The aim of the study was to analyze if the presence of three SNPs in PADI4 gene susceptibility haplotype (GTG) is associated with ACPA positivity in patients with RA. This was a cross-sectional study that included 86 RA patients and 98 healthy controls. Polymorphisms PADI4_89, PADI4_90, and PADI4_92 in the PADI4 gene were genotyped. The susceptibility haplotype (GTG) was more frequent in RA patients; interestingly, we found a new haplotype associated with RA with a higher frequency (GTC). There were no associations between polymorphisms and high scores in Spanish HAQ-DI and DAS-28, but we did find an association between RARBIS index and PADI4_89, PADI4_90 polymorphisms. We could not confirm an association between susceptibility haplotype presence and ACPA positivity. Further evidence about proteomic expression of this gene will determine its participation in antigenic generation and autoimmunity. PMID:24454473

  11. PADI4 haplotypes in association with RA Mexican patients, a new prospect for antigen modulation.

    PubMed

    Zavala-Cerna, Maria Guadalupe; Gonzalez-Montoya, Norma Guadalupe; Nava, Arnulfo; Gamez-Nava, Jorge I; Moran-Moguel, Maria Cristina; Rosales-Gomez, Roberto Carlos; Gutierrez-Rubio, Susan Andrea; Sanchez-Corona, Jose; Gonzalez-Lopez, Laura; Davalos-Rodriguez, Ingrid Patricia; Salazar-Paramo, Mario

    2013-01-01

    Peptidyl arginine deiminase IV (PAD 4) is the responsible enzyme for a posttranslational modification called citrullination, originating the antigenic determinant recognized by anti-cyclic citrullinated peptide antibodies (ACPA). Four SNPs (single nucleotide polymorphisms) have been described in PADI4 gene to form a susceptibility haplotype for rheumatoid arthritis (RA); nevertheless, results in association studies appear contradictory in different populations. The aim of the study was to analyze if the presence of three SNPs in PADI4 gene susceptibility haplotype (GTG) is associated with ACPA positivity in patients with RA. This was a cross-sectional study that included 86 RA patients and 98 healthy controls. Polymorphisms PADI4_89, PADI4_90, and PADI4_92 in the PADI4 gene were genotyped. The susceptibility haplotype (GTG) was more frequent in RA patients; interestingly, we found a new haplotype associated with RA with a higher frequency (GTC). There were no associations between polymorphisms and high scores in Spanish HAQ-DI and DAS-28, but we did find an association between RARBIS index and PADI4_89, PADI4_90 polymorphisms. We could not confirm an association between susceptibility haplotype presence and ACPA positivity. Further evidence about proteomic expression of this gene will determine its participation in antigenic generation and autoimmunity. PMID:24454473

  12. Transfer coefficient of 226Ra from vegetation to meadow voles, Microtus pennsylvanicus, on U mill tailings

    SciTech Connect

    Cloutier, N.R.; Clulow, F.V.; Lim, T.P.; Dave, N.K.

    1986-06-01

    The 226Ra level in vegetation growing on U mine tailings in Elliot Lake, Ontario, Canada, was 211 + 22 mBq g-1 (dry weight) compared to less than 7 mBq g-1 (dry weight) in material from a control site. Skeletons of meadow voles (Microtus pennsylvanicus) established on the tailings had concentrations of 226Ra of 6083 +/- 673 mBq per animal in winter; 7163 +/- 1077 mBq per animal in spring; 1506 +/- 625 mBq per animal in summer; and 703 +/- 59 mBq per animal in fall, compared to less than 7 mBq per animal in controls. The /sup 226/Ra transfer coefficient from vegetation to voles (defined as total millibecquerels of /sup 226/Ra in adult vole per total millibecquerels of 226Ra consumed by the vole in its lifetime) was calculated as 4.6 +/- 2.9 X 10(-2) in summer and 2.8 +/- 0.6 X 10(-2) in fall.

  13. Simulated acid rain alters litter decomposition and enhances the allelopathic potential of the invasive plant Wedelia trilobata (Creeping Daisy)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Invasive species and acid rain cause global environmental problems. Limited information exists, however, concerning the effects of acid rain on the invasiveness of these plants. For example, creeping daisy, an invasive exotic allelopathic weed, has caused great damage in southern China where acid ra...

  14. Effects of ruminant trans fatty acids on cardiovascular disease and cancer: a comprehensive review of epidemiological, clinical, and mechanistic studies

    Technology Transfer Automated Retrieval System (TEKTRAN)

    There are two predominant sources of dietary trans fatty acids in the food supply, those formed during the industrial partial hydrogenation of vegetable oils (iTFA) and those formed by biohydrogenation in ruminants (rTFA), including vaccenic acid and (VA) and rumenic acid [RA, a conjugated linoleic ...

  15. Retinoic acid deficiency alters second heart field formation

    PubMed Central

    Ryckebusch, Lucile; Wang, Zengxin; Bertrand, Nicolas; Lin, Song-Chang; Chi, Xuan; Schwartz, Robert; Zaffran, Stéphane; Niederreither, Karen

    2008-01-01

    Retinoic acid (RA), the active derivative of vitamin A, has been implicated in various steps of cardiovascular development. The retinaldehyde dehydrogenase 2 (RALDH2) enzyme catalyzes the second oxidative step in RA biosynthesis and its loss of function creates a severe embryonic RA deficiency. Raldh2−/− knockout embryos fail to undergo heart looping and have impaired atrial and sinus venosus development. To understand the mechanism(s) producing these changes, we examined the contribution of the second heart field (SHF) to pharyngeal mesoderm, atria, and outflow tract in Raldh2−/− embryos. RA deficiency alters SHF gene expression in two ways. First, Raldh2−/− embryos exhibited a posterior expansion of anterior markers of the SHF, including Tbx1, Fgf8, and the Mlc1v-nlacZ-24/Fgf10 reporter transgene as well as of Islet1. This occurred at early somite stages, when cardiac defects became irreversible in an avian vitamin A-deficiency model, indicating that endogenous RA is required to restrict the SHF posteriorly. Explant studies showed that this expanded progenitor population cannot differentiate properly. Second, RA up-regulated cardiac Bmp expression levels at the looping stage. The contribution of the SHF to both inflow and outflow poles was perturbed under RA deficiency, creating a disorganization of the heart tube. We also investigated genetic cross-talk between Nkx2.5 and RA signaling by generating double mutant mice. Strikingly, Nkx2.5 deficiency was able to rescue molecular defects in the posterior region of the Raldh2−/− mutant heart, in a gene dosage-dependent manner. PMID:18287057

  16. Retinoic acid deficiency alters second heart field formation.

    PubMed

    Ryckebusch, Lucile; Wang, Zengxin; Bertrand, Nicolas; Lin, Song-Chang; Chi, Xuan; Schwartz, Robert; Zaffran, Stéphane; Niederreither, Karen

    2008-02-26

    Retinoic acid (RA), the active derivative of vitamin A, has been implicated in various steps of cardiovascular development. The retinaldehyde dehydrogenase 2 (RALDH2) enzyme catalyzes the second oxidative step in RA biosynthesis and its loss of function creates a severe embryonic RA deficiency. Raldh2(-/-) knockout embryos fail to undergo heart looping and have impaired atrial and sinus venosus development. To understand the mechanism(s) producing these changes, we examined the contribution of the second heart field (SHF) to pharyngeal mesoderm, atria, and outflow tract in Raldh2(-/-) embryos. RA deficiency alters SHF gene expression in two ways. First, Raldh2(-/-) embryos exhibited a posterior expansion of anterior markers of the SHF, including Tbx1, Fgf8, and the Mlc1v-nlacZ-24/Fgf10 reporter transgene as well as of Islet1. This occurred at early somite stages, when cardiac defects became irreversible in an avian vitamin A-deficiency model, indicating that endogenous RA is required to restrict the SHF posteriorly. Explant studies showed that this expanded progenitor population cannot differentiate properly. Second, RA up-regulated cardiac Bmp expression levels at the looping stage. The contribution of the SHF to both inflow and outflow poles was perturbed under RA deficiency, creating a disorganization of the heart tube. We also investigated genetic cross-talk between Nkx2.5 and RA signaling by generating double mutant mice. Strikingly, Nkx2.5 deficiency was able to rescue molecular defects in the posterior region of the Raldh2(-/-) mutant heart, in a gene dosage-dependent manner. PMID:18287057

  17. A theoretical model for the production of Ac-225 for cancer therapy by neutron capture transmutation of Ra-226.

    PubMed

    Melville, G; Melville, P

    2013-02-01

    Radium needles that were once implanted into tumours as a cancer treatment are now obsolete and constitute a radioactive waste problem, as their half-life is 1600 years. We are investigating the reduction of radium by transmutation by bombarding Ra-226 with high-energy neutrons from a neutron source to produce Ra-225 and hence Ac-225, which can be used as a generator to produce Bi-213 for use in 'Targeted Alpha Therapy' for cancer. This paper examines the possibility of producing Ac-225 by neutron capture using a theoretical model in which neutron energy is convoluted with the corresponding neutron cross sections of Ra-226. The total integrated yield can then be obtained. This study shows that an intense beam of high-energy neutrons could initiate neutron capture on Ra-226 to produce Ra-225 and hence practical amounts of Ac-225 and a useful reduction of Ra-226. PMID:23220026

  18. Effect of Retinoic Acid on Gene Expression in Human Conjunctival Epithelium: Secretory phospholipase A2 mediates retinoic acid induction of MUC16.

    PubMed Central

    Hori, Yuichi; Spurr-Michaud, Sandra J.; Russo, Cindy Leigh; Argüeso, Pablo; Gipson, Ilene K.

    2005-01-01

    Purpose. How vitamin A contributes to the maintenance of the wet-surfaced phenotype at the ocular surface is not well understood. We sought to identify vitamin A responsive genes in ocular surface epithelia using gene microarray analysis of cultures of a human conjunctival epithelial cell line (HCjE) grown with all-trans-retinoic acid (RA). The analysis showed that secretory phospholipase A2 Group IIA (sPLA2-IIA) was the gene most upregulated by RA, followed by the membrane-associated mucin MUC16 at a later time point. Since eicosanoids, the product of arachidonic acid generated by the phospholipase A2 family, have been shown to increase mucin production, we sought to determine if sPLA2 mediates the RA induction of MUC16. Methods. HCjE cells were cultured with or without RA for 3, 6, 24 and 48 hours. Complementary RNA prepared from RNA of the HCjE cells was hybridized to human gene chips (HG-U133A; Affymetrix) and analyzed using Rosetta Resolver software. Microarray data on mucin expression were validated by real-time PCR. To investigate whether sPLA2 is associated with RA-induced MUC16 upregulation, HCjE cells were incubated with RA and the broad spectrum PLA2 inhibitor, aristolochic acid (ArA) or the specific sPLA2-IIA inhibitor LY315920, followed by analysis of MUC16 mRNA and protein by real-time PCR and Western blot analysis. Results. After RA addition, 28 transcripts were upregulated and 6 downregulated by over 2.0-fold (p < 0.01) at both 3 and 6 hours (early phase). Eighty gene transcripts were upregulated and 45 downregulated at both 24 and 48 hours (late phase). Group IIA sPLA2, significantly upregulated by 24 hours, and MUC16 were the most upregulated RNAs by RA at 48 hours. sPLA2 upregulation by RA was confirmed by Western blot analysis. When HCjE cells were incubated with RA plus ArA or specific inhibitor of sPLA2-IIA, LY315920, the RA-induced MUC16 mRNA was significantly reduced (p < 0.01). Conclusion. The retinoic acid-associated upregulation of

  19. Geology and Topography of Ra Patera, Io, in the Voyager era: Prelude to Eruption

    NASA Technical Reports Server (NTRS)

    Schenk, Paul M.; McEwen, Alfred; Davies, A. G.; Davenport, Trevor; Jones, Kevin; Fessler, Brian

    1997-01-01

    Voyager era stereo images are used to map the geology and topography of Ra Patera (a major active volcanic center and possible site of sulfur eruptions on Io). The summit of Ra Patera reaches only approx.1 km above the surrounding plains. Pre-Voyager-era lava flows occur on slopes of 0.1-0.3 deg, comparable to the lunar mare. These flows were emplaced at either low viscosities, high eruption rates, or both. A 600- km-long ridged mountain unit (rising to approx. 8 km near Carancho Patera) forms a 60 by 90 km wide plateau approx. 0.5 km high 50 km east of Ra Patera. The new lava flows observed by Galileo flowed around the southern edge of this plateau.

  20. Simulating magnetospheres with numerical relativity: The GiRaFFE code

    NASA Astrophysics Data System (ADS)

    Babiuc-Hamilton, Maria; Etienne, Zach

    2016-01-01

    Numerical Relativity has shown success over the past several years, especially in the simulation of black holes and gravitational waves. In recent years, teams have tackled the problem of the interaction of gravitational and electromagnetic waves. But where there are plasmas, the simulations often have trouble reproducing nature. Neutron stars, black hole accretion disks, astrophysical jets—all of these represent extreme environments both gravitationally and electromagnetically. We are creating the first open-source, dynamical spacetime general relativity force-free electrodynamics code: GiRaFFE.We present here the performance of GiRaFFE in testing. With this code, we will simulate neutron star magnetospheres, collisions between neutron stars and black holes, and particular attention will be paid to the production of jets through the Blandford-Znajek mechanism.GiRaFFE will be made available to the community.

  1. A Study of LoRa: Long Range & Low Power Networks for the Internet of Things.

    PubMed

    Augustin, Aloÿs; Yi, Jiazi; Clausen, Thomas; Townsley, William Mark

    2016-01-01

    LoRa is a long-range, low-power, low-bitrate, wireless telecommunications system, promoted as an infrastructure solution for the Internet of Things: end-devices use LoRa across a single wireless hop to communicate to gateway(s), connected to the Internet and which act as transparent bridges and relay messages between these end-devices and a central network server. This paper provides an overview of LoRa and an in-depth analysis of its functional components. The physical and data link layer performance is evaluated by field tests and simulations. Based on the analysis and evaluations, some possible solutions for performance enhancements are proposed. PMID:27618064

  2. Diffusion of (226)Ra and (40)K radionuclides reproduced in underwater sedimentary columns in laboratory.

    PubMed

    Ligero, R A; Feria, F; Casas-Ruiz, M; Corredor, C

    2006-01-01

    The potential radiological impact of the increase of radioactive substances in the environment makes interesting the study of the migration of the contaminant radionuclides in soils and sediments, which are the last receiver system of these substances. By using a battery of sedimentary columns controlled in the laboratory, the diffusion of the (226)Ra and (40)K radionuclides has been studied, assessing their respective effective diffusion coefficients in a similar sedimentary medium. A decreasing temporal evolution is obtained, associated to the progressive 'fixation' of the radionuclides by the clay minerals of the sediment, followed by a constant tendency. A timescale of the 'fixation' by the sediment is determined, being of the order of days for (226)Ra and of the order of months for (40)K, so the progressive 'fixation' of (40)K by the clay minerals of the sediments is slower than in the case of (226)Ra. PMID:16488520

  3. Ra-226 concentrations in otter, Lutra canadensis, trapped near uranium tailings at Elliot Lake, Ontario

    SciTech Connect

    Wren, C.D.; Cloutier, N.R.; Lim, T.P.; Dave, N.K.

    1987-02-01

    The Elliot Lake area of Ontario, is currently the major uranium producing region of Canada. It is estimated there are 120 million tons of uranium tailings spread over 600 ha in the vicinity of Elliot Lake. The transfer and fate of uranium-series radionuclides from tailing sites remain primary ecological concerns in these areas. It has been demonstrated that the levels of radionuclides, including Ra-226, are elevated in vegetation, small mammals and fish living on or near tailing disposal sites. However, the transfer potential of Ra-226 to predatory species has not been examined in detail. The objective of this study was to measure Ra-226 levels in otters (Lutra canadensis), captured near tailing sites, to provide further information on the fate of radionuclides in the environment.

  4. Type I collagen degradation does not diminish with RA disease duration

    PubMed Central

    Hakala, M; Aho, K; Aman, S; Luukkainen, R; Kauppi, M; Risteli, J

    2001-01-01

    OBJECTIVE—To assess the relation between type I collagen degradation and the duration of rheumatoid arthritis (RA).
METHODS—The serum concentrations of cross linked carboxyterminal telopeptide of type I collagen (ICTP) measured earlier in a community based series (90 patients) and a hospital based series (59 patients) were re-evaluated with reference to the duration of RA.
RESULTS—The serum ICTP showed a positive correlation with the duration of the disease in the hospital based series (rs=0.40, p<0.01) but not in the community based one (rs=0.18, p=0.10).
CONCLUSIONS—Type I collagen degradation predominantly reflecting pathological bone destruction does not seem to diminish in longlasting RA.

 PMID:11247878

  5. Applications of 211At and 223Ra in Targeted Alpha-Particle Radiotherapy

    PubMed Central

    Vaidyanathan, Ganesan; Zalutsky, Michael R.

    2012-01-01

    Targeted radiotherapy using agents tagged with α-emitting radionuclides is gaining traction with several clinical trials already undertaken or ongoing, and others in the advanced planning stage. The most commonly used α-emitting radionuclides are 213Bi, 211At, 223Ra and 225Ac. While each one of these has pros and cons, it can be argued that 211At probably is the most versatile based on its half life, decay scheme and chemistry. On the other hand, for targeting bone metastases, 223Ra is the ideal radionuclide because simple cationic radium can be used for this purpose. In this review, we will discuss the recent developments taken place in the application of 211At-labeled radiopharmaceuticals and give an overview of the current status of 223Ra for targeted α-particle radiotherapy. PMID:22202151

  6. Applications of 211At and 223Ra in targeted alpha-particle radiotherapy.

    PubMed

    Vaidyanathan, Ganesan; Zalutsky, Michael R

    2011-10-01

    Targeted radiotherapy using agents tagged with α-emitting radionuclides is gaining traction with several clinical trials already undertaken or ongoing, and others in the advanced planning stage. The most commonly used α-emitting radionuclides are 213Bi, 211At, 223Ra and 225Ac. While each one of these has pros and cons, it can be argued that 211At probably is the most versatile based on its half life, decay scheme and chemistry. On the other hand, for targeting bone metastases, 223Ra is the ideal radionuclide because simple cationic radium can be used for this purpose. In this review, we will discuss the recent developments taken place in the application of 211At-labeled radiopharmaceuticals and give an overview of the current status of 223Ra for targeted α-particle radiotherapy. PMID:22202151

  7. Production of Ac-225 for cancer therapy by photon-induced transmutation of Ra-226.

    PubMed

    Melville, G; Meriarty, H; Metcalfe, P; Knittel, T; Allen, B J

    2007-09-01

    The increasing application of Ac-225 for cancer therapy indicates the potential need for its increased production and availability. The production of Ac-225 has been achieved using bremsstrahlung photons from an 18 MV medical linear accelerator (linac) to bombard a Ra-226 target. A linac dose of 2800 Gy produced about 64 microCi of Ra-225, which decays to Ac-225. This result, while consistent with the theoretical calculations, is far too low to be of practical use. A more powerful linac is required that runs at a higher current, longer pulse length and higher frequency for practical production. This process could also lead to the reduction of the nuclear waste product Ra-226. PMID:17532223

  8. Recent Augmentations of the Functionality of the Thermonuclear Reaction Rate Calculator (TReRaC)

    NASA Astrophysics Data System (ADS)

    Thomsen, Kyle; Smith, Michael

    2011-10-01

    The chemical variety of our universe can be explained by stellar nucleosynthesis. Many thermonuclear reactions are studied by reproducing them in accelerator experiments and determining their rates. Using the codes available through the Computational Infrastructure for Nuclear Astrophysics (CINA), researchers can process the results of these experiments. One such program is the Thermonuclear Reaction Rate Calculator (TReRaC), which uses various experimental inputs including resonant energies, strengths, channel widths, and information on non-resonant contributions to calculate reaction rates. Presently, TReRaC is capable of quickly generating accurate rates which closely match those given in a number of publications. This adds to CINA capabilities by enabling a wider variety of nuclear information to generate rates. The next step in TReRaC's evolution is integration into the existing CINA complex so that it can be used by researchers worldwide.

  9. Laser spectroscopy of trapped short-lived Ra{sup +} ions

    SciTech Connect

    Versolato, O. O.; Giri, G. S.; Wansbeek, L. W.; Berg, J. E. van den; Hoek, D. J. van der; Jungmann, K.; Kruithof, W. L.; Onderwater, C. J. G.; Sahoo, B. K.; Santra, B.; Shidling, P. D.; Timmermans, R. G. E.; Willmann, L.; Wilschut, H. W.

    2010-07-15

    As an important step toward an atomic parity violation experiment in one single trapped Ra{sup +} ion, laser spectroscopy on short-lived {sup 212,213,214}Ra{sup +} ions was conducted. The isotope shift of the 6 {sup 2}D{sub 3/2}-7 {sup 2}P{sub 1/2} and 6 {sup 2}D{sub 3/2}-7 {sup 2}P{sub 3/2} transitions and the hyperfine structure constants of the 7 {sup 2}P{sub 1/2} and 6 {sup 2}D{sub 3/2} states in {sup 213}Ra{sup +} were measured, which provides a benchmark for the required atomic theory. A lower limit of 232(4) ms for 6 {sup 2}D{sub 5/2} state lifetime was determined.

  10. Biodistribution of 225Ra citrate in mice: retention of daughter radioisotopes in bone.

    PubMed

    Kennel, Stephen J; Lankford, Trish; Garland, Marc; Sundberg, John P; Mirzadeh, Saed

    2005-11-01

    Alpha-particle-emitting radionuclides have potential for therapy of localized disease due to their high linear energy transformation and short pathlengths. Radiometals that home naturally to bone can be exploited for this purpose, and 223Ra (t(1/2)=11.4 days) recently has been studied for therapy of bone tumors in mice and rats. Actinium-225 (t(1/2)=10 days) is also an attractive radioisotope for endoradiotherapy. In a single decay of a 225Ac nucleus and its subsequent decay daughters, over 27 MeV ( approximately 90% of total energy) is released by sequential emission of four alpha particles, ranging in energy from 5.7 to 8.4 MeV. Although Ac3+ does not home naturally to bone, its parent radioisotope 225Ra (beta(-), t(1/2)=15 days) can be used as an in vivo source for 225Ac. Thus, injection of 225Ra takes advantage of the bone-homing properties of radium coupled with the significant amount of energy released from the 225Ac decay chain. Our data confirm that a large fraction of radium citrate injected intravenously into mice localizes rapidly in bone. Injected doses per gram (ID/g) for 225Ra range from 25% in skull to about 10% in sternum. Once deposited, the 225Ra remains in the bone with a biological half life of >40 days. Furthermore, >95% of the daughter radioisotope, 225Ac, is retained in the bone. However, a significant fraction of one of the daughter radioisotopes, 213Bi, is found in kidney. The biodistribution data indicate that 225Ra injection should be a powerful agent for killing cells associated with bone; however, the toxicity of this radioisotope which is similar to that of other alpha emitters limits the dose that can be tolerated. PMID:16253811

  11. RECOVERY OF METALS FROM ACID MINE DRAINAGE: JOURNAL ARTICLE

    EPA Science Inventory

    NRMRL-CIN-1349A Scharp*, R.A., Kawahara*, F.K., Burckle, J.O., Allen J., and Govind, R. "Recovery of Metals from Acid Mine Drainage." In: Bioremediation of Inorganic Compounds, In Situ and On-Site Bioremediation Sixth International Symposium, San Diego, CA, 6/4-7/2001. Andrea Le...

  12. 226Ra as a standard source for efficiency calibration of Ge(Li) detectors

    NASA Astrophysics Data System (ADS)

    Farouk, M. A.; Al-Soraya, A. M.

    1982-09-01

    The relative intensities of gamma-rays resulting from the decay of 226Ra in equilibrium with its short-lived daughters have been measured using two different high resolution Ge(Li) detectors. The accuracy of the measurements does not exceed 2.5%. The most intense components of gamma-rays from thin 226Ra are recommended for use as a calibration standard Ge(Li) detectors in the energy range from 186 keV to 3.050 MeV.

  13. Initial Results from the Radiation Dosimetry Experiment (RaD-X) Balloon Flight Mission

    NASA Technical Reports Server (NTRS)

    Mertens, Christopher J.

    2015-01-01

    The NASA Radiation Dosimetry Experiment (RaD-X) high-altitude balloon mission was successfully launched from Fort Sumner, New Mexico USA on 25 September, 2015. Over 15 hours of science data were obtained from four dosimeters at altitudes above about 25 km. The four dosimeters flown on the RaD-X science payload are a Hawk version 3.0 Tissue Equivalent Proportional Counter (TEPC) manufactured by Far West Technologies, a Liulin dosimeter-spectrometer produced by the Solar Research and Technology Institute, Bulgarian Academy of Sciences, a total ionizing dose detector manufactured by Teledyne Microelectronic Technologies, and the RaySure detector provided by the University of Surrey.

  14. Skeletal 212Pb retention following 224Ra injection: extrapolation of animal data to adult humans.

    PubMed

    Schlenker, R A

    1988-04-01

    Two methods of interspecies extrapolation, one based on a correlation of skeletal 212Pb/224Ra with body weight, the other based on the mechanistic relationship between skeletal 212Pb/224Ra and reciprocal bone surface-to-volume ratio, lead to the conclusion that the retention of 212Pb in the adult human skeleton is approximately complete a few days after injection. The correlation-based method gives most probable values for 212Pb/224Ra of 1.0 and 1.1 at 2 d and 7 d after injection, compared with values of 1.05 and 1.27 expected at these same times if the retention of 212Pb were complete from the time of injection and if no 212Pb were in the injection solution. The range of values corresponding to one geometric standard error on either side of the most probable value is 0.87 to 1.21 at 2 d post-injection. With the method based on the reciprocal bone surface-to-volume ratio, the best estimate of 212Pb/224Ra at 2 d after injection is 0.88, equal to the value observed in young adult beagles. An alternative interpretation of the results of this latter method leads to the conclusion that retention is complete, with 212Pb/224Ra equal to 1.0 for a 212Pb-free injection solution and 1.1 for a solution containing 212Pb in secular equilibrium with 224Ra. This work, which uses 224Ra daughter product retention data from mice, rats and dogs following 224Ra injection, provides a scientific foundation for retention assumptions made in the calculation of mean skeletal dose for adult humans. There now appear to be few uncertainties in these latter dose values, stemming from inaccurate retention assumptions; but substantial uncertainties remain in the mean skeletal dose values for juveniles and in the endosteal tissue doses regardless of age. Risk coefficients such as those in the BEIR III report that give the lifetime probability of bone tumor induction per unit mean skeletal dose may be correct for adult humans but are probably too low for juveniles due to overestimation of juvenile

  15. Hydrogen Peroxide Is Involved in Salicylic Acid-Elicited Rosmarinic Acid Production in Salvia miltiorrhiza Cell Cultures

    PubMed Central

    Hao, Wenfang; Zhang, Jingyi; Hu, Gege; Yao, Yaqin; Dong, Juane

    2014-01-01

    Salicylic acid (SA) is an elicitor to induce the biosynthesis of secondary metabolites in plant cells. Hydrogen peroxide (H2O2) plays an important role as a key signaling molecule in response to various stimuli and is involved in the accumulation of secondary metabolites. However, the relationship between them is unclear and their synergetic functions on accumulation of secondary metabolites are unknown. In this paper, the roles of SA and H2O2 in rosmarinic acid (RA) production in Salvia miltiorrhiza cell cultures were investigated. The results showed that SA significantly enhanced H2O2 production, phenylalanine ammonia-lyase (PAL) activity, and RA accumulation. Exogenous H2O2 could also promote PAL activity and enhance RA production. If H2O2 production was inhibited by NADPH oxidase inhibitor (IMD) or scavenged by quencher (DMTU), RA accumulation would be blocked. These results indicated that H2O2 is secondary messenger for signal transduction, which can be induced by SA, significantly and promotes RA accumulation. PMID:24995364

  16. Three conazoles increase hepatic microsomal retinoic acid metabolism and decrease mouse hepatic retinoic acid levels in vivo

    SciTech Connect

    Chen, P.-J.; Padgett, William T.; Moore, Tanya; Winnik, Witold; Lambert, Guy R.; Thai, Sheau-Fung; Hester, Susan D.; Nesnow, Stephen

    2009-01-15

    Conazoles are fungicides used in agriculture and as pharmaceuticals. In a previous toxicogenomic study of triazole-containing conazoles we found gene expression changes consistent with the alteration of the metabolism of all trans-retinoic acid (atRA), a vitamin A metabolite with cancer-preventative properties (Ward et al., Toxicol. Pathol. 2006; 34:863-78). The goals of this study were to examine effects of propiconazole, triadimefon, and myclobutanil, three triazole-containing conazoles, on the microsomal metabolism of atRA, the associated hepatic cytochrome P450 (P450) enzyme(s) involved in atRA metabolism, and their effects on hepatic atRA levels in vivo. The in vitro metabolism of atRA was quantitatively measured in liver microsomes from male CD-1 mice following four daily intraperitoneal injections of propiconazole (210 mg/kg/d), triadimefon (257 mg/kg/d) or myclobutanil (270 mg/kg/d). The formation of both 4-hydroxy-atRA and 4-oxo-atRA were significantly increased by all three conazoles. Propiconazole-induced microsomes possessed slightly greater metabolizing activities compared to myclobutanil-induced microsomes. Both propiconazole and triadimefon treatment induced greater formation of 4-hydroxy-atRA compared to myclobutanil treatment. Chemical and immuno-inhibition metabolism studies suggested that Cyp26a1, Cyp2b, and Cyp3a, but not Cyp1a1 proteins were involved in atRA metabolism. Cyp2b10/20 and Cyp3a11 genes were significantly over-expressed in the livers of both triadimefon- and propiconazole-treated mice while Cyp26a1, Cyp2c65 and Cyp1a2 genes were over-expressed in the livers of either triadimefon- or propiconazole-treated mice, and Cyp2b10/20 and Cyp3a13 genes were over-expressed in the livers of myclobutanil-treated mice. Western blot analyses indicated conazole induced-increases in Cyp2b and Cyp3a proteins. All three conazoles decreased hepatic atRA tissue levels ranging from 45-67%. The possible implications of these changes in hepatic atRA levels

  17. Three Conazoles Increase Hepatic Microsomal Retinoic Acid Metabolism and Decrease Mouse Hepatic Retinoic Acid Levels In Vivo

    EPA Science Inventory

    Conazoles are fungicides used in agriculture and as pharmaceuticals. In a previous toxicogenomic study of triazole-containing conazoles we found gene expression changes consistent with the alteration of the metabolism of all trans-retinoic acid (atRA), a vitamin A metabolite with...

  18. The effects of retinoic acid on immunoglobulin synthesis by human cord blood mononuclear cells.

    PubMed

    Israel, H; Odziemiec, C; Ballow, M

    1991-06-01

    Derivatives of vitamin A have attracted considerable attention as agents which have immune potentiating properties and possibly tumor-suppressive effects. Recent investigations have shown that retinoic acid (RA) can augment immunoglobulin production of B-cell hybridomas from patients with immune deficiency. In this study we examined the ability of RA to modify the mitogen-induced polyclonal immunoglobulin synthesis of cord blood mononuclear cells (CBMC). RA in concentrations ranging from 10(-5) to 10(-7) M augmented IgM synthesis of CBMC in response to formalinized Cowans I strain Staphylococcus aureus (SAC) up to 45.6-fold which was greater at suboptimal responses to SAC. There were no changes in IgG or IgA synthesis and minimal effects on SAC-induced proliferative responses. RA did not produce similar changes in IgM synthesis of SAC-stimulated adult peripheral blood mononuclear cells (PBMC), and RA had no effect on the immunoglobulin synthesis of Epstein-Barr virus (EBV)-stimulated CBMC or adult PBMC. Time course studies showed that peak enhancement occurred when RA was added between 4 and 24 hr after culture initiation and required prior activation by SAC for augmentation of IgM synthesis. Cell separation experiments showed that prior incubation (18 hr) of an enriched T-cell fraction with RA enhanced the IgM synthesis of a T-cell-depleted B-cell fraction. These experiments and the findings that RA-induced augmentation of IgM production in response to SAC, but not to EBV suggest that the immunoregulatory effects of RA may be mediated by either T cells or T-cell products. Further studies will be necessary to understand the mechanism by which RA augments IgM synthesis of CBMC. PMID:2029794

  19. Retinoic acid receptor subtype-specific transcriptotypes in the early zebrafish embryo.

    PubMed

    Samarut, Eric; Gaudin, Cyril; Hughes, Sandrine; Gillet, Benjamin; de Bernard, Simon; Jouve, Pierre-Emmanuel; Buffat, Laurent; Allot, Alexis; Lecompte, Odile; Berekelya, Liubov; Rochette-Egly, Cécile; Laudet, Vincent

    2014-02-01

    Retinoic acid (RA) controls many aspects of embryonic development by binding to specific receptors (retinoic acid receptors [RARs]) that regulate complex transcriptional networks. Three different RAR subtypes are present in vertebrates and play both common and specific roles in transducing RA signaling. Specific activities of each receptor subtype can be correlated with its exclusive expression pattern, whereas shared activities between different subtypes are generally assimilated to functional redundancy. However, the question remains whether some subtype-specific activity still exists in regions or organs coexpressing multiple RAR subtypes. We tackled this issue at the transcriptional level using early zebrafish embryo as a model. Using morpholino knockdown, we specifically invalidated the zebrafish endogenous RAR subtypes in an in vivo context. After building up a list of RA-responsive genes in the zebrafish gastrula through a whole-transcriptome analysis, we compared this panel of genes with those that still respond to RA in embryos lacking one or another RAR subtype. Our work reveals that RAR subtypes do not have fully redundant functions at the transcriptional level but can transduce RA signal in a subtype-specific fashion. As a result, we define RAR subtype-specific transcriptotypes that correspond to repertoires of genes activated by different RAR subtypes. Finally, we found genes of the RA pathway (cyp26a1, raraa) the regulation of which by RA is highly robust and can even resist the knockdown of all RARs. This suggests that RA-responsive genes are differentially sensitive to alterations in the RA pathway and, in particular, cyp26a1 and raraa are under a high pressure to maintain signaling integrity. PMID:24422634

  20. The SCFA butyrate stimulates the epithelial production of retinoic acid via inhibition of epithelial HDAC.

    PubMed

    Schilderink, Ronald; Verseijden, Caroline; Seppen, Jurgen; Muncan, Vanesa; van den Brink, Gijs R; Lambers, Tim T; van Tol, Eric A; de Jonge, Wouter J

    2016-06-01

    In the intestinal mucosa, retinoic acid (RA) is a critical signaling molecule. RA is derived from dietary vitamin A (retinol) through conversion by aldehyde dehydrogenases (aldh). Reduced levels of short-chain fatty acids (SCFAs) are associated with pathological microbial dysbiosis, inflammatory disease, and allergy. We hypothesized that SCFAs contribute to mucosal homeostasis by enhancing RA production in intestinal epithelia. With the use of human and mouse epithelial cell lines and primary enteroids, we studied the effect of SCFAs on the production of RA. Functional RA conversion was analyzed by Adlefluor activity assays. Butyrate (0-20 mM), in contrast to other SCFAs, dose dependently induced aldh1a1 or aldh1a3 transcript expression and increased RA conversion in human and mouse epithelial cells. Epithelial cell line data were replicated in intestinal organoids. In these organoids, butyrate (2-5 mM) upregulated aldh1a3 expression (36-fold over control), whereas aldh1a1 was not significantly affected. Butyrate enhanced maturation markers (Mucin-2 and villin) but did not consistently affect stemness markers or other Wnt target genes (lgr5, olfm4, ascl2, cdkn1). In enteroids, the stimulation of RA production by SCFA was mimicked by inhibitors of histone deacetylase 3 (HDAC3) but not by HDAC1/2 inhibitors nor by agonists of butyrate receptors G-protein-coupled receptor (GPR)43 or GPR109A, indicating that butyrate stimulates RA production via HDAC3 inhibition. We conclude that the SCFA butyrate inhibits HDAC3 and thereby supports epithelial RA production. PMID:27151945

  1. Rosmarinic acid content in antidiabetic aqueous extract of Ocimum canum Sims grown in Ghana

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Rosmarinic acid (RA) is an important polyphenol that is found in a variety of herbs including Ocimum canum sims (locally called eme or akokobesa in Ghana). Aqueous extracts from the leaves of O.canum are used as an antidiabetic herbal medicine in Ghana. Interestingly, rosmarinic acid content and p...

  2. Retinoic acid inhibits angiogenesis and tumor growth of thyroid cancer cells.

    PubMed

    Hoffmann, Sebastian; Rockenstein, Andreas; Ramaswamy, Anette; Celik, Ilhan; Wunderlich, Anette; Lingelbach, Susanne; Hofbauer, Lorenz C; Zielke, Andreas

    2007-01-29

    The anti-proliferative effect of retinoic acid (RA) has been documented for various tumors. Some 40% of patients with advanced and poorly differentiated thyroid cancer have been shown to respond to RA with increased uptake of radioiodine. It has been suggested that these effects may be caused by redifferentiation. Presently, little is known about the effects of RA on tumor angiogenesis, a prerequisite for growth and metastatic spread. The aim of the current study was to determine, whether tumor-induced angiogenesis of thyroid cancer is affected by RA. In vitro, the effect of 0.1/10 microM 13-cis RA on tumor cell number (MTT assay) and secretion of VEGF (ELISA) was analyzed in three thyroid cancer cell lines (FTC 236, C634 and XTC), as well as in endothelial cells (HUVEC) over several passages. In vivo, tumor growth, VEGF-expression and microvessel density (VSD) of RA treated thyroid cancer cells after xenotransplantation to nude mice was evaluated by morphometric analysis. In vitro, thyroid cancer cell lines responded to RA with reduced proliferation, ranging from 26 to 34% after 2 weeks of treatment and with up to 80% reduced secretion of VEGF. In vivo, tumor volumes of animals receiving RA were reduced by 33% (FTC 236), 27% (C643) and 6% (XTC), respectively. VSD of experimental tumors was diminished in the FTC 236 (25%) and the C643 cell line (15%), and almost unchanged in XTC tumors (7%). In vivo, VEGF-expression and apoptosis were not significantly affected by RA. In vitro, proliferation of HUVEC was inhibited by conditioned medium of C643 cells pretreated with RA (0.1/10 microM), as well as by administration of RA (0.1/10 microM). This study confirms thyroid tumor cell growth to be inhibited by RA. It demonstrates a decrease of in vitro VEGF accumulation and reduction of VSD in experimental undifferentiated thyroid carcinoma, suggesting that reduced angiogenesis may be an important mechanism responsible for the therapeutic effect of RA in thyroid cancer

  3. The modulatory effect of ellagic acid and rosmarinic acid on ultraviolet-B-induced cytokine/chemokine gene expression in skin keratinocyte (HaCaT) cells.

    PubMed

    Lembo, Serena; Balato, Anna; Di Caprio, Roberta; Cirillo, Teresa; Giannini, Valentina; Gasparri, Franco; Monfrecola, Giuseppe

    2014-01-01

    Ultraviolet radiation (UV) induces an increase in multiple cutaneous inflammatory mediators. Ellagic acid (EA) and rosmarinic acid (RA) are natural anti-inflammatory and immunomodulatory compounds found in many plants, fruits, and nuts. We assessed the ability of EA and RA to modulate IL-1β, IL-6, IL-8, IL-10, MCP-1, and TNF-α gene expression in HaCaT cells after UVB irradiation. Cells were treated with UVB (100 mJ/cm(2)) and simultaneously with EA (5 μM in 0.1% DMSO) or RA (2.7 μM in 0.5% DMSO). Moreover, these substances were added to the UVB-irradiated cells 1 h or 6 h before harvesting, depending on the established UVB-induced cytokine expression peak. Cytokine gene expression was examined using quantitative real time polymerase chain reaction. RA produced a significant reduction in UVB-induced expression of IL-6, IL-8, MCP-1, and TNF-α when applied at the same time as irradiation. EA showed milder effects compared with RA, except for TNF-α. Both substances decreased IL-6 expression, also when applied 5 h after irradiation, and always produced a significant increase in UVB-induced IL-10 expression. Our findings suggest that EA and RA are able to prevent and/or limit the UVB-induced inflammatory cascade, through a reduction in proinflammatory mediators and the enhancement of IL-10, with its protective function. PMID:25162011

  4. Functional Analysis of the Phycomyces carRA Gene Encoding the Enzymes Phytoene Synthase and Lycopene Cyclase

    PubMed Central

    Sanz, Catalina; Velayos, Antonio; Álvarez, María Isabel; Benito, Ernesto P.; Eslava, Arturo P.

    2011-01-01

    Phycomyces carRA gene encodes a protein with two domains. Domain R is characterized by red carR mutants that accumulate lycopene. Domain A is characterized by white carA mutants that do not accumulate significant amounts of carotenoids. The carRA-encoded protein was identified as the lycopene cyclase and phytoene synthase enzyme by sequence homology with other proteins. However, no direct data showing the function of this protein have been reported so far. Different Mucor circinelloides mutants altered at the phytoene synthase, the lycopene cyclase or both activities were transformed with the Phycomyces carRA gene. Fully transcribed carRA mRNA molecules were detected by Northern assays in the transformants and the correct processing of the carRA messenger was verified by RT-PCR. These results showed that Phycomyces carRA gene was correctly expressed in Mucor. Carotenoids analysis in these transformants showed the presence of ß-carotene, absent in the untransformed strains, providing functional evidence that the Phycomyces carRA gene complements the M. circinelloides mutations. Co-transformation of the carRA cDNA in E. coli with different combinations of the carotenoid structural genes from Erwinia uredovora was also performed. Newly formed carotenoids were accumulated showing that the Phycomyces CarRA protein does contain lycopene cyclase and phytoene synthase activities. The heterologous expression of the carRA gene and the functional complementation of the mentioned activities are not very efficient in E. coli. However, the simultaneous presence of both carRA and carB gene products from Phycomyces increases the efficiency of these enzymes, presumably due to an interaction mechanism. PMID:21858003

  5. Amino acids

    MedlinePlus

    Amino acids are organic compounds that combine to form proteins . Amino acids and proteins are the building blocks of life. When proteins are digested or broken down, amino acids are left. The human body uses amino acids ...

  6. Retinoic Acid Signaling Regulates Differential Expression of the Tandemly-Duplicated Long Wavelength-Sensitive Cone Opsin Genes in Zebrafish

    PubMed Central

    Frey, Ruth A.; Hunter, Samuel S.; Ashino, Ryuichi; Kawamura, Shoji; Stenkamp, Deborah L.

    2015-01-01

    The signaling molecule retinoic acid (RA) regulates rod and cone photoreceptor fate, differentiation, and survival. Here we elucidate the role of RA in differential regulation of the tandemly-duplicated long wavelength-sensitive (LWS) cone opsin genes. Zebrafish embryos were treated with RA from 48 hours post-fertilization (hpf) to 75 hpf, and RNA was isolated from eyes for microarray analysis. ~170 genes showed significantly altered expression, including several transcription factors and components of cellular signaling pathways. Of interest, the LWS1 opsin gene was strongly upregulated by RA. LWS1 is the upstream member of the tandemly duplicated LWS opsin array and is normally not expressed embryonically. Embryos treated with RA 48 hpf to 100 hpf or beyond showed significant reductions in LWS2-expressing cones in favor of LWS1-expressing cones. The LWS reporter line, LWS-PAC(H) provided evidence that individual LWS cones switched from LWS2 to LWS1 expression in response to RA. The RA signaling reporter line, RARE:YFP indicated that increased RA signaling in cones was associated with this opsin switch, and experimental reduction of RA signaling in larvae at the normal time of onset of LWS1 expression significantly inhibited LWS1 expression. A role for endogenous RA signaling in regulating differential expression of the LWS genes in postmitotic cones was further supported by the presence of an RA signaling domain in ventral retina of juvenile zebrafish that coincided with a ventral zone of LWS1 expression. This is the first evidence that an extracellular signal may regulate differential expression of opsin genes in a tandemly duplicated array. PMID:26296154

  7. Retinoic acid promotes primary fetal alveolar epithelial type II cell proliferation and differentiation to alveolar epithelial type I cells.

    PubMed

    Gao, Rui-wei; Kong, Xiang-yong; Zhu, Xiao-xi; Zhu, Guo-qing; Ma, Jin-shuai; Liu, Xiu-xiang

    2015-05-01

    Retinoic acid (RA) plays an important role in lung development and maturation. Many stimuli can induce alveolar epithelial cell damage which will result in the injury of lung parenchyma. The aim of this study was to observe the effect of RA on the proliferation and differentiation of primary fetal alveolar epithelial type II cells (fAECIIs). Primary fAECIIs were isolated from fetal rats at 19 d of gestation and purified by a differential centrifugation and adhesion method. The cells were randomly divided into control (dimethyl sulfoxide, DMSO) and RA groups. Cell proliferation, viability, apoptosis, cycle, and expression of target protein were examined at 24, 48, and 72 h. We found that the proliferation and viability of cells in the RA-exposed group significantly increased compared with the DMSO control group. The proportion (%) of cells in the G2 and S phases in the RA group was significantly higher than that in control group cells. The proportion (%) of both early apoptotic cells and late apoptotic cells decreased significantly in cells exposed to RA compared with cells exposed to DMSO. RA significantly enhanced the expression of aquaporin 5 (AQP5). The expression level of pulmonary surfactant C (SPC) was elevated after cells were exposed to RA for 24 and 72 h but was inhibited when cells were exposed to RA for 48 h. These results suggest that RA promotes fAECII proliferation by improving cell viability, promoting S phase entry and inhibiting apoptosis and RA promotes fAECIIs differentiation to alveolar epithelial type I cells (AECIs). PMID:25515249

  8. PI3K/Akt pathway regulates retinoic acid-induced Hox gene expression in F9 cells.

    PubMed

    Lee, Youra; Lee, Ji-Yeon; Kim, Myoung Hee

    2014-09-01

    Retinoic acid (RA), the most potent natural form of vitamin A, is a key morphogen in vertebrate development and a potent regulator of both adult and embryonic cell differentiation. Specifically, RA regulates clustered Hox gene expression during embryogenesis and is required to establish the anteroposterior body plan. The PI3K/Akt pathway was also reported to play an essential role in the process of RA-induced cell differentiation. Therefore, we tested whether the PI3K/Akt pathway is involved in RA-induced Hox gene expression in a F9 murine embryonic teratocarcinoma cells. To examine the effect of PI3K/Akt signaling on RA-induced initiation of collinear expression of Hox genes, F9 cells were treated with RA in the presence or absence of PI3K inhibitor LY294002, and time-course gene expression profiles for all 39 Hox genes located in four different clusters-Hoxa, Hoxb, Hoxc, and Hoxd-were analyzed. Collinear expression of Hoxa and -b cluster genes was initiated earlier than that of the -c and -d clusters upon RA treatment. When LY294002 was applied along with RA, collinear expression induced by RA was delayed, suggesting that the PI3K/Akt signaling pathway somehow regulates RA-induced collinear expression of Hox genes in F9 cells. The initiation of Hox collinear expression by RA and the delayed expression following LY294002 in F9 cells would provide a good model system to decipher the yet to be answered de novo collinear expression of Hox genes during gastrulation, which make the gastrulating cells to remember their positional address along the AP body axis in the developing embryo. PMID:25212816

  9. [Long-term plasticity of HVC-RA synapses in adult male zebra finches].

    PubMed

    Li, Feng-Ling; Li, Dong-Feng

    2013-12-25

    Long-term synaptic plasticity is considered as a key part of the neural mechanism of learning and memory. The production of learned vocalization of male zebra finches is closely related to high vocal center (HVC)-robust nucleus of the arcopallium (RA) pathway. However, the long-term plasticity of HVC-RA synapses is unclear. This study investigated the long-term plasticity of HVC-RA synapses in adult male zebra finches through in vivo field potential recording. The results showed that physiologic stimulation, i.e., δ rhythmic stimulation and low frequency stimulation could not effectively induce long-term synaptic plasticity. The former leaded to no change of the amplitudes of evoked population spikes, and the latter induced short-term depression (STD) of the amplitudes of the second evoked population spikes caused by paired pulses. But high frequency stimulation induced long-term depression (LTD) of the amplitudes of evoked population spikes to show out long-term synaptic plasticity. These results suggest that LTD represents the long-term plasticity of HVC-RA synapses in adult male zebra finches, which may be a key part of the neural mechanism of vocal learning and memory and can explain the plasticity of adult song to some degree. PMID:24343715

  10. ALTERED RA SIGNALING IN THE GENESIS OF ETHANOL-INDUCED LIMB DEFECTS

    EPA Science Inventory

    Altered RA Signaling in the Genesis of Ethanol-Induced Limb Defects

    Johnson CS(1), Sulik KK(1,2) Hunter, ES III(3)
    (1) Dept of Cell and Developmental Biology, UNC-Chapel Hill (2) Bowles Center for Alcohol Studies, UNC-CH (3) NHEERL, ORD, US EPA, RTP, NC

    Administr...

  11. Imaging of Ra-223 with a small-pixel CdTe detector

    NASA Astrophysics Data System (ADS)

    Scuffham, J. W.; Pani, S.; Seller, P.; Sellin, P. J.; Veale, M. C.; Wilson, M. D.; Cernik, R. J.

    2015-01-01

    Ra-223 Dichloride (Xofigo™) is a promising new radiopharmaceutical offering survival benefit and palliation of painful bone metastases in patients with hormone-refractory prostate cancer [1]. The response to radionuclide therapy and toxicity are directly linked to the absorbed radiation doses to the tumour and organs at risk respectively. Accurate dosimetry necessitates quantitative imaging of the biodistribution and kinetics of the radiopharmaceutical. Although primarily an alpha-emitter, Ra-223 also has some low-abundance X-ray and gamma emissions, which enable imaging of the biodistribution in the patient. However, the low spectral resolution of conventional gamma camera detectors makes in-vivo imaging of Ra-223 challenging. In this work, we present spectra and image data of anthropomorphic phantoms containing Ra-223 acquired with a small-pixel CdTe detector (HEXITEC) [2] with a pinhole collimator. Comparison is made with similar data acquired using a clinical gamma camera. The results demonstrate the advantages of the solid state detector in terms of scatter rejection and quantitative accuracy of the images. However, optimised collimation is needed in order for the sensitivity to rival current clinical systems. As different dosage levels and administration regimens for this drug are explored in current clinical trials, there is a clear need to develop improved imaging technologies that will enable personalised treatments to be designed for patients.

  12. 68. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    68. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 SPLICE in REAR PLATE of LEAN-TO, EAST BAY REAR, INTERMEDIATE POST LOOKING NORTH & DOWN - Colonel Paul Wentworth House, Dover Street (moved to MA, Dover), Dover, Strafford County, NH

  13. 86. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    86. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ELEVATION of NORTH EAST CORNER POST, MAIN HOUSE Notice that End Girt Extends beyond Wall Line - Colonel Paul Wentworth House, Dover Street (moved to MA, Dover), Dover, Strafford County, NH

  14. 82. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    82. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 LAPPING of PURLINS over INTERMEDIATE RAFTER LOOKING EAST, WEST BAY 2nd RAFTER from WEST END, MAIN HOUSE - Colonel Paul Wentworth House, Dover Street (moved to MA, Dover), Dover, Strafford County, NH

  15. 67. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    67. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 SPLICE in REAR PLATE of LEAN-TO, EAST BAY REAR, INTERMEDIATE POST LOOKING NORTH & UP - Colonel Paul Wentworth House, Dover Street (moved to MA, Dover), Dover, Strafford County, NH

  16. 61. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    61. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 WEST INTERMEDIATE POST on FRONT of MAIN HOUSE SHOWING TENON SLOT for CHIMNEY GIRT LOOKING SOUTH WEST - Colonel Paul Wentworth House, Dover Street (moved to MA, Dover), Dover, Strafford County, NH

  17. Ra-Th disequilibria systematics: Timescale of carbonatite magma formation at Oldoinyo Lengai volcano, Tanzania

    NASA Astrophysics Data System (ADS)

    Williams, Ross W.; Gill, James B.; Bruland, Kenneth W.

    1986-06-01

    Carbonatite magma can form and erupt within 7 to 18 years, and the event seems associated with prior volcanic eruptions. This determination of magma age is possible because the carbonatite lava and ash which were erupted in 1960-1966 from Oldoinyo Lengai volcano, Tanzania, have the most extreme disequilibria between U and Th series nuclides yet measured in volcanic rocks. At the time of eruption: ( 228Ra) /( 232Th) ≈ 27 and ( 226Ra) /( 230Th) > 60 ; ( 238U) /( 232Th) > 10 , while ( 232Th) /( 232Th) = 1.0 ; and ( 210Pb) /( 226Ra) ≈ 0.3 . Three end-member models are presented which enable interpretation of these disequilibria. If the disequilibrium formed instantaneously, the event occurred about 7 years before initial eruption, and just before the last preceding but small eruption of Oldoinyo Lengai. If, instead, the disequilibrium formed continuously, the process must have begun 15 to 18 years before initial eruption, just after the last preceding major eruption. The disequilibria data confirm that the carbonatites are not fused trona, but do not distinguish between other genetic options (mantle fusion, selective assimilation, liquid immiscibility). However, the shortness of magma-formation time together with mass-balance considerations suggest formation due to the continuous exsolution of 2 to 20% of carbonatite from nephelinite which was itself Ra-enriched.

  18. 111. HISTORIC AMERICAN BUILDINGS SURVEY R.A. Waugh, Photographer October 1936 ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    111. HISTORIC AMERICAN BUILDINGS SURVEY R.A. Waugh, Photographer October 1936 OLD WINDOW FRAME in PLACE. NORTH WALL of ORIGINAL KITCHEN LOOKING SOUTH from LEAN-TO - Colonel Paul Wentworth House, Dover Street (moved to MA, Dover), Dover, Strafford County, NH

  19. ETV Report: Siemens Model V-40R-A150 Open Channel UV System

    EPA Science Inventory

    Verification testing of the Siemens Barrier Sunlight V-40R-A150 UV System was completed at the UV Validation and Research Center of New York (UV Center), located in Johnstown, NY. The V-40R System supplied by Siemens utilizes 40 high-output, low-pressure amalgam lamps, oriented ...

  20. Evolution of the Role of RA and FGF Signals in the Control of Somitogenesis in Chordates.

    PubMed

    Bertrand, Stéphanie; Aldea, Daniel; Oulion, Silvan; Subirana, Lucie; de Lera, Angel R; Somorjai, Ildiko; Escriva, Hector

    2015-01-01

    During vertebrate development, the paraxial mesoderm becomes segmented, forming somites that will give rise to dermis, axial skeleton and skeletal muscles. Although recently challenged, the "clock and wavefront" model for somitogenesis explains how interactions between several cell-cell communication pathways, including the FGF, RA, Wnt and Notch signals, control the formation of these bilateral symmetric blocks. In the cephalochordate amphioxus, which belongs to the chordate phylum together with tunicates and vertebrates, the dorsal paraxial mesendoderm also periodically forms somites, although this process is asymmetric and extends along the whole body. It has been previously shown that the formation of the most anterior somites in amphioxus is dependent upon FGF signalling. However, the signals controlling somitogenesis during posterior elongation in amphioxus are still unknown. Here we show that, contrary to vertebrates, RA and FGF signals act independently during posterior elongation and that they are not mandatory for posterior somites to form. Moreover, we show that RA is not able to buffer the left/right asymmetry machinery that is controlled through the asymmetric expression of Nodal pathway actors. Our results give new insights into the evolution of the somitogenesis process in chordates. They suggest that RA and FGF pathways have acquired specific functions in the control of somitogenesis in vertebrates. We propose that the "clock and wavefront" system was selected specifically in vertebrates in parallel to the development of more complex somite-derived structures but that it was not required for somitogenesis in the ancestor of chordates. PMID:26371756

  1. 108. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    108. Historic American Buildings Survey R.A. Waugh, Photographer October 1936 DIAGONAL LATHING AROUND OLD WINDOW OPENING WEST ROOM, 1st. FLOOR, MAIN HOUSE on NORTH WALL - Colonel Paul Wentworth House, Dover Street (moved to MA, Dover), Dover, Strafford County, NH

  2. Evolution of the Role of RA and FGF Signals in the Control of Somitogenesis in Chordates

    PubMed Central

    Bertrand, Stéphanie; Aldea, Daniel; Oulion, Silvan; Subirana, Lucie; de Lera, Angel R.; Somorjai, Ildiko; Escriva, Hector

    2015-01-01

    During vertebrate development, the paraxial mesoderm becomes segmented, forming somites that will give rise to dermis, axial skeleton and skeletal muscles. Although recently challenged, the "clock and wavefront" model for somitogenesis explains how interactions between several cell-cell communication pathways, including the FGF, RA, Wnt and Notch signals, control the formation of these bilateral symmetric blocks. In the cephalochordate amphioxus, which belongs to the chordate phylum together with tunicates and vertebrates, the dorsal paraxial mesendoderm also periodically forms somites, although this process is asymmetric and extends along the whole body. It has been previously shown that the formation of the most anterior somites in amphioxus is dependent upon FGF signalling. However, the signals controlling somitogenesis during posterior elongation in amphioxus are still unknown. Here we show that, contrary to vertebrates, RA and FGF signals act independently during posterior elongation and that they are not mandatory for posterior somites to form. Moreover, we show that RA is not able to buffer the left/right asymmetry machinery that is controlled through the asymmetric expression of Nodal pathway actors. Our results give new insights into the evolution of the somitogenesis process in chordates. They suggest that RA and FGF pathways have acquired specific functions in the control of somitogenesis in vertebrates. We propose that the "clock and wavefront" system was selected specifically in vertebrates in parallel to the development of more complex somite-derived structures but that it was not required for somitogenesis in the ancestor of chordates. PMID:26371756

  3. Challenges and opportunities in the search for electric dipole moment (EDM) in 225Ra atom

    NASA Astrophysics Data System (ADS)

    Kalita, Mukut; Bailey, Kevin; Dietrich, Matthew; Greene, John; Holt, Roy; Korsch, Wolfgang; Lu, Zheng-Tian; Mueller, Peter; O'Connor, Thomas; Parker, Richard; Sulai, Ibrahim; Singh, Jaideep

    2011-10-01

    The observation of a permanent electric dipole moment (EDM) in a non-degenerate system would indicate violation of time reversal symmetry. 225Ra atom is a particularly attractive candidate for this search since it has a nuclear spin I = 1/2 and has a significant nuclear octupole deformation. This property increases the Schiff moment of the nucleus and therefore enhances the atomic EDM. The half life (t1/2 = 14.9 days) of 225Ra is sufficiently long to perform EDM searches. Our group has already demonstrated the trapping of laser cooled Ra atoms in a magneto-optical trap (MOT) and transferring them to a far off resonant optical dipole trap (ODT). We will discuss our recent progress on manipulation of ultra cold Ra atoms in the ODT, efforts in improving our laser systems and generation of electric and magnetic fields required for the measurement. This work is supported by DOE, Office of Nuclear Physics, under contract No. DE-AC02-06CH11357 and contract No. DE-FG02-99ER41101.

  4. Self-cleaning in an estuarine area formerly affected by 226Ra anthropogenic enhancements.

    PubMed

    Absi, A; Villa, M; Moreno, H P; Manjón, G; Periañez, R

    2004-08-15

    The estuary of the Odiel River has been affected by both direct discharges of phosphogypsum (radium enriched industrial waste) and dissolution and weathering of the exposed piles where this radium enriched waste was stored. In 1998 the waste management policy for industries changed. The direct discharges stopped and the new phosphogypsum piles were well protected against dissolution processes, avoiding any transference of radium into the environment. This work presents a study of the evolution with time (1999-2002) of the levels of 226Ra in river water and sediment samples with the new waste management policy. A liquid scintillation technique was used to measure the 226Ra activity concentration in sediment samples. A gas-proportional counter was also used to measure the 226Ra activity concentration in river water samples. The main conclusion is that a systematic and continuous decrease of the activity concentration of 226Ra with time in the Odiel River estuary is occurring. Thus, a possible self-cleaning in the estuary, once the direct waste discharges were avoided, can be inferred. PMID:15262166

  5. AQUIFER TRANSPORT OF TH, U, RA, AND RN IN SOLUTION AND ON COLLOIDS

    EPA Science Inventory

    The purpose of this study is to investigate the behavior of naturally occurring U, Th, Ra, and Rn isotopes in groundwater and to utilize these elements as natural analogues for waste radionuclides in predicting migration behavior in potentially impacted aquifers. The study will o...

  6. Daughter growth in freshly separated Ra-226, Ac-227 and U-232

    NASA Technical Reports Server (NTRS)

    Basile, L. J.; Macias, E. S.; Milstead, J.; Stewart, D. C.

    1969-01-01

    Report provides computer-calculated curves and tables for the daughter buildup of Ra-226, Ac-227 and U-232 chains. Data are presented as a function of time beginning with pure samples of each parent. The information may be of interest to those using decay chains as isotopic alpha sources or neutron sources.

  7. Supply of purified Th228 for Ra224 generators. Final CRADA Report .

    SciTech Connect

    Ehst, D. A.; Nuclear Engineering Division

    2009-10-02

    CRADA was terminated when it was determined that the Russians could not perform the terms of the subcontract. It became apparent that the Russians would not be a reliable source of Th228, as a precursor in the decay chain which leads to Ra224. Their government policies will prohibit the export of Th228 in quantities needed for commercial cancer therapy.

  8. RaPAL Bulletin, Numbers 5-13, 1988-1990.

    ERIC Educational Resources Information Center

    RaPAL Bulletin, 1988

    1988-01-01

    This document consists of a 3-year compilation (9 issues) of the RaPAL (Research and Practice in Adult Literacy) Bulletin. Typical articles are: "Student Involvement in Research" (a report of a workshop by Alex Golightly, Nick Nicola, and Marilyn Stone); part of a dialogue between Paolo Freire and Ira Shor, writer/educators of Brazil and the…

  9. 36. Photocopy of photograph, R.A. Hoffman, Bridge Engineer, Arizona Highway ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    36. Photocopy of photograph, R.A. Hoffman, Bridge Engineer, Arizona Highway Department, photographer, June 1928 (original print located at Arizona Department of Transportation, Phoenix AZ) COMPLETION OF SOUTH ARM. - Navajo Bridge, Spanning Colorado River at U.S. Highway 89 Alternate, Page, Coconino County, AZ

  10. 35. Photocopy of photograph, R.A. Hoffman, Bridge Engineer, Arizona Highway ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    35. Photocopy of photograph, R.A. Hoffman, Bridge Engineer, Arizona Highway Department, photographer, June 1928 (original print located at Arizona Department of Transportation, Phoenix AZ). ELEVENTH (LAST) PANEL OF SOUTH ARM UNDER CONSTRUCTION, SHOWING ERECTION TRAVELER. - Navajo Bridge, Spanning Colorado River at U.S. Highway 89 Alternate, Page, Coconino County, AZ

  11. 37. Photocopy of photograph, R.A. Hoffman, Bridge Engineer, Arizona Highway ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    37. Photocopy of photograph, R.A. Hoffman, Bridge Engineer, Arizona Highway Department, photographer, ca. July 1928 (original print located at Arizona Department of Transportation, Phoenix AZ). CONSTRUCTION ON THIRD PANEL OF NORTH ARM. - Navajo Bridge, Spanning Colorado River at U.S. Highway 89 Alternate, Page, Coconino County, AZ

  12. 39. Photocopy of photograph, R.A. Hoffman, Bridge Engineer, Arizona Highway ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    39. Photocopy of photograph, R.A. Hoffman, Bridge Engineer, Arizona Highway Department, photographer, ca. July 1928 (original print located at Arizona Department of Transportation, Phoenix AZ). ASSEMBLY OF TRAVELER ON NORTH ARM, SHOWING TEMPORARY TIEBACKS AND ANCHORAGE ARMS. - Navajo Bridge, Spanning Colorado River at U.S. Highway 89 Alternate, Page, Coconino County, AZ

  13. 38. Photocopy of photograph, R.A. Hoffman, Bridge Engineer, Arizona Highway ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    38. Photocopy of photograph, R.A. Hoffman, Bridge Engineer, Arizona Highway Department, photographer, ca. July 1928 (original print located at Arizona Department of Transportation, Phoenix AZ). VIEW FROM CANYON OF THIRD PANEL OF NORTH ARM UNDER CONSTRUCTION. - Navajo Bridge, Spanning Colorado River at U.S. Highway 89 Alternate, Page, Coconino County, AZ

  14. 33. Photocopy of photograph, R.A. Hoffman, Bridge Engineer, Arizona Highway ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    33. Photocopy of photograph, R.A. Hoffman, Bridge Engineer, Arizona Highway Department, photographer, ca. May 1928 (original print located at Arizona Department of Transportation, Phoenix AZ). CONSTRUCTION OF SOUTH ARM, SHOWING ERECTION TRAVELER. - Navajo Bridge, Spanning Colorado River at U.S. Highway 89 Alternate, Page, Coconino County, AZ

  15. 32. Photocopy of photograph, R.A. Hoffman, Bridge Engineer, Arizona Highway ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    32. Photocopy of photograph, R.A. Hoffman, Bridge Engineer, Arizona Highway Department, photographer, April 1928 (original print located at Arizona Department of Transportation, Phoenix AZ). CONSTRUCTION OF SOUTH ARM. - Navajo Bridge, Spanning Colorado River at U.S. Highway 89 Alternate, Page, Coconino County, AZ

  16. 34. Photocopy of photograph, R.A. Hoffman, Bridge Engineer, Arizona Highway ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    34. Photocopy of photograph, R.A. Hoffman, Bridge Engineer, Arizona Highway Department, photographer, ca. May 1928 (original print located at Arizona Department of Transportation, Phoenix AZ). CONSTRUCTION ON EIGHT PANEL OF SOUTH ARM. - Navajo Bridge, Spanning Colorado River at U.S. Highway 89 Alternate, Page, Coconino County, AZ

  17. 31. Photocopy of photograph, R.A. Hoffman, Bridge Engineer, Arizona Highway ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    31. Photocopy of photograph, R.A. Hoffman, Bridge Engineer, Arizona Highway Department, photographer, April 1928 (original print located at Arizona Department of Transportation, Phoenix AZ). INITIAL CONSTRUCTION ON SOUTH ARM. - Navajo Bridge, Spanning Colorado River at U.S. Highway 89 Alternate, Page, Coconino County, AZ

  18. 41. Photocopy of photograph, R.A. Hoffman, Bridge Engineer, Arizona Highway ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    41. Photocopy of photograph, R.A. Hoffman, Bridge Engineer, Arizona Highway Department, photographer, 12 September 1928 (original print located at Arizona Department of Transportation, Phoenix AZ). INSERTION OF CENTER PIN. - Navajo Bridge, Spanning Colorado River at U.S. Highway 89 Alternate, Page, Coconino County, AZ

  19. 40. Photocopy of photograph, R.A. Hoffman, Bridge Engineer, Arizona Highway ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    40. Photocopy of photograph, R.A. Hoffman, Bridge Engineer, Arizona Highway Department, photographer, ca. July 1928 (original print located at Arizona Department of Transportation, Phoenix AZ). CONSTRUCTION OF NORTH ARM, FROM SOUTH ARM. - Navajo Bridge, Spanning Colorado River at U.S. Highway 89 Alternate, Page, Coconino County, AZ

  20. Association between cytoplasmic CRABP2, altered retinoic acid signaling, and poor prognosis in glioblastoma.

    PubMed

    Liu, Rong-Zong; Li, Shuai; Garcia, Elizabeth; Glubrecht, Darryl D; Yin Poon, Ho; Easaw, Jacob C; Godbout, Roseline

    2016-06-01

    Retinoic acid (RA), a metabolite of vitamin A, is required for the regulation of growth and development. Aberrant expression of molecules involved in RA signaling has been reported in various cancer types including glioblastoma multiforme (GBM). Cellular retinoic acid-binding protein 2 (CRABP2) has previously been shown to play a key role in the transport of RA to retinoic acid receptors (RARs) to activate their transcription regulatory activity. Here, we demonstrate that CRABP2 is predominantly located in the cytoplasm of GBM tumors. Cytoplasmic, but not nuclear, CRABP2 levels in GBM tumors are associated with poor patient survival. Treatment of malignant glioma cell lines with RA results in a dose-dependent increase in accumulation of CRABP2 in the cytoplasm. CRABP2 knockdown reduces proliferation rates of malignant glioma cells, and enhances RA-induced RAR activation. Levels of CRYAB, a small heat shock protein with anti-apoptotic activity, and GFAP, an astrocyte-specific intermediate filament protein, are greatly reduced in CRABP2-depleted cells. Restoration of CRYAB expression partially but significantly reversed the effect of CRABP2 depletion on RAR activation. Our combined in vivo and in vitro data indicate that: (i) CRABP2 is an important determinant of clinical outcome in GBM patients, and (ii) the mechanism of action of CRABP2 in GBM involves sequestration of RA in the cytoplasm and activation of an anti-apoptotic pathway, thereby enhancing proliferation and preventing RA-mediated cell death and differentiation. We propose that reducing CRABP2 levels may enhance the therapeutic index of RA in GBM patients. GLIA 2016;64:963-976. PMID:26893190

  1. Protective effects of rosmarinic acid against radiation-induced damage to the hematopoietic system in mice

    PubMed Central

    Xu, Wenqing; Yang, Fujun; Zhang, Yujie; Shen, Xiu

    2016-01-01

    Rosmarinic acid (RA) is an ester of caffeic acid and 3, 4-dihydroxyphenyl lactic acid. It is a potent antioxidant that functions by scavenging free radicals. Here, we used a 30-day survival assay to investigate the radioprotective effects of RA. Mice were treated with RA once per day for 10 consecutive days starting at 3 days before gamma irradiation at 7.5 Gy until 7 days post irradiation. Mice treated with 100 and 200 mg/kg body weight (bw) of RA had 30-day survival rates of 89% and 72%, respectively, compared with 32% in the control group, and the differences were statistically significant (P = 0.0008 and 0.0421, respectively). Spleen colony–forming units (CFU-S), the number of nucleated cells in the bone marrow (BMNC), bone marrow DNA content, and hematological parameters of the peripheral blood were measured to investigate the radioprotective effect of RA on the hematopoietic system. The treatment groups that received RA at 50, 100 and 150 mg/kg bw and whole-body exposure to 5.5 Gy of 137Cs γ- radiation had significantly higher CFU-S, BMNC and DNA content than the irradiation-only group. Assessment of hematological parameters in the peripheral blood showed that the treatment groups receiving RA at doses of 50, 100 and 150 mg/kg bw had higher white blood cell counts, hemoglobin and platelets than the radiation-only group. These results suggested that the administration of RA promoted the recovery of peripheral blood cells in irradiated mice. PMID:27006381

  2. Protective effects of rosmarinic acid against radiation-induced damage to the hematopoietic system in mice.

    PubMed

    Xu, Wenqing; Yang, Fujun; Zhang, Yujie; Shen, Xiu

    2016-07-01

    Rosmarinic acid (RA) is an ester of caffeic acid and 3, 4-dihydroxyphenyl lactic acid. It is a potent antioxidant that functions by scavenging free radicals. Here, we used a 30-day survival assay to investigate the radioprotective effects of RA. Mice were treated with RA once per day for 10 consecutive days starting at 3 days before gamma irradiation at 7.5 Gy until 7 days post irradiation. Mice treated with 100 and 200 mg/kg body weight (bw) of RA had 30-day survival rates of 89% and 72%, respectively, compared with 32% in the control group, and the differences were statistically significant (P = 0.0008 and 0.0421, respectively). Spleen colony-forming units (CFU-S), the number of nucleated cells in the bone marrow (BMNC), bone marrow DNA content, and hematological parameters of the peripheral blood were measured to investigate the radioprotective effect of RA on the hematopoietic system. The treatment groups that received RA at 50, 100 and 150 mg/kg bw and whole-body exposure to 5.5 Gy of (137)Cs γ- radiation had significantly higher CFU-S, BMNC and DNA content than the irradiation-only group. Assessment of hematological parameters in the peripheral blood showed that the treatment groups receiving RA at doses of 50, 100 and 150 mg/kg bw had higher white blood cell counts, hemoglobin and platelets than the radiation-only group. These results suggested that the administration of RA promoted the recovery of peripheral blood cells in irradiated mice. PMID:27006381

  3. Ψ-RA: a parallel sparse index for genomic read alignment

    PubMed Central

    2011-01-01

    Background Genomic read alignment involves mapping (exactly or approximately) short reads from a particular individual onto a pre-sequenced reference genome of the same species. Because all individuals of the same species share the majority of their genomes, short reads alignment provides an alternative and much more efficient way to sequence the genome of a particular individual than does direct sequencing. Among many strategies proposed for this alignment process, indexing the reference genome and short read searching over the index is a dominant technique. Our goal is to design a space-efficient indexing structure with fast searching capability to catch the massive short reads produced by the next generation high-throughput DNA sequencing technology. Results We concentrate on indexing DNA sequences via sparse suffix arrays (SSAs) and propose a new short read aligner named Ψ-RA (PSI-RA: parallel sparse index read aligner). The motivation in using SSAs is the ability to trade memory against time. It is possible to fine tune the space consumption of the index based on the available memory of the machine and the minimum length of the arriving pattern queries. Although SSAs have been studied before for exact matching of short reads, an elegant way of approximate matching capability was missing. We provide this by defining the rightmost mismatch criteria that prioritize the errors towards the end of the reads, where errors are more probable. Ψ-RA supports any number of mismatches in aligning reads. We give comparisons with some of the well-known short read aligners, and show that indexing a genome with SSA is a good alternative to the Burrows-Wheeler transform or seed-based solutions. Conclusions Ψ-RA is expected to serve as a valuable tool in the alignment of short reads generated by the next generation high-throughput sequencing technology. Ψ-RA is very fast in exact matching and also supports rightmost approximate matching. The SSA structure that Ψ-RA is built

  4. Critical function of RA-GEF-2/Rapgef6, a guanine nucleotide exchange factor for Rap1, in mouse spermatogenesis.

    PubMed

    Okada, Keisuke; Miyake, Hideaki; Yamaguchi, Kohei; Chiba, Koji; Maeta, Kazuhiro; Bilasy, Shymaa E; Edamatsu, Hironori; Kataoka, Tohru; Fujisawa, Masato

    2014-02-28

    Small GTPase Rap1 has been implicated in the proper differentiation of testicular germ cells. In the present study, we investigated the functional significance of RA-GEF-2/Rapgef6, a guanine nucleotide exchange factor for Rap1, in testicular differentiation using mice lacking RA-GEF-2. RA-GEF-2 was expressed predominantly on the luminal side of the seminiferous tubules in wild-type mice. No significant differences were observed in the body weights or hormonal parameters of RA-GEF-2(-)(/)(-) and wild-type mice. However, the testes of RA-GEF-2(-)(/)(-) male mice were significantly smaller than those of wild-type mice and were markedly atrophied as well as hypospermatogenic. The concentration and motility of epididymal sperm were also markedly reduced and frequently had an abnormal shape. The pregnancy rate and number of fetuses were markedly lower in wild-type females after they mated with RA-GEF-2(-)(/)(-) males than with wild-type males, which demonstrated the male infertility phenotype of RA-GEF-2(-)(/)(-) mice. Furthermore, a significant reduction and alteration were observed in the expression level and cell junctional localization of N-cadherin, respectively, in RA-GEF-2(-)(/)(-) testes, which may, at least in part, account for the defects in testicular differentiation and spermatogenesis in these mice. PMID:24491570

  5. [sup 226]Ra-[sup 230]Th disequilibrium in axial and off-axis mid-ocean ridge basalts

    SciTech Connect

    Volpe, A.M.; Goldstein, S.J. Los Alamos National Lab., NM )

    1993-03-01

    The authors describe [sup 226]Ra-[sup 230]Th disequilibrium in mid-ocean ridge basalt (MORB) glasses from the Juan de Fuca, Gorda, and East Pacific ridges. These first mass spectrometric measurements of [sup 226]Ra in MORB glasses at sub-picogram abundance levels confirm the large excesses over [sup 230]Th determined by radon-emanation techniques and alpha spectrometry. All off-axis MORB glasses have [sup 226]Ra-[sup 230]Th and [sup 234]U-[sup 238]U in secular equilibrium. This suggests that magmatic processes, not secondary post-eruption alteration, generate [sup 238]U-series disequilibrium in these MORB. Least evolved, N-MORB from axial valleys have ([sup 226]Ra/[sup 230]Th) between 2.2-2.3. Differentiated and enriched E-type MORB have consistently low ([sup 226]Ra/[sup 230]Th) ratios compared with N-MORB from the same ridge sections. Ra-Th fractionation may be less pronounced, or magma residence-transit periods may be long for differentiated MORB. Also, E-MORB may be generated by different melt extraction volumes and rates. Estimated [sup 226]Ra-[sup 230]Th ages for N-MORB agree with location on and off ridge segments, and with Th-U model ages. These preliminary results show that [sup 226]Ra-[sup 230]Th disequilibrium could be used to quantify volcanic episodicity at ocean ridges. 39 refs., 6 figs., 4 tabs.

  6. Disequilibrium between [sup 226]Ra and supported [sup 210]Pb in a sediment core from a shallow Florida lake

    SciTech Connect

    Brenner, M.; Peplov, A.J.; Schelske, C.L. )

    1994-07-01

    [sup 210]Pb dating can be used to assign ages in lake sediment cores, calculate rates of sediment accumulation, and determine the timing of recent changes in lake-watershed ecosystems. We used low-background gamma counting to measure [sup 226]Ra and total [sup 210]Pb activity in a core from Lake Rowell, Florida. [sup 226]Ra activity was high and strongly variable throughout the core, even exceeding total [sup 210]Pb activity in recently deposited sediments. We traced one source of Ra-rich sediments to the only inflow, Alligator Creek, where stream-bottom deposits display disequilibrium between [sup 226]Ra and supported [sup 210]Pb. High and variable [sup 226]Ra activity in the Lake Rowell profile argues for direct estimates of in situ Ra in lake sediment cores from disturbed watersheds that have Ra-bearing bedrock. Isotopic disequilibrium between [sup 226]Ra and supported [sup 210]Pb makes it difficult to distinguish between supported and unsupported [sup 210]Pb activity throughout the Lake Rowell core and would require special assumptions and nonconventional dating models to establish age-depth relationships. 78 refs., 3 figs., 1 tab.

  7. Targeted disruption of retinoic acid receptor alpha (RAR alpha) and RAR gamma results in receptor-specific alterations in retinoic acid-mediated differentiation and retinoic acid metabolism.

    PubMed Central

    Boylan, J F; Lufkin, T; Achkar, C C; Taneja, R; Chambon, P; Gudas, L J

    1995-01-01

    F9 embryonic teratocarcinoma stem cells differentiate into an epithelial cell type called extraembryonic endoderm when treated with retinoic acid (RA), a derivative of retinol (vitamin A). This differentiation is presumably mediated through the actions of retinoid receptors, the RARs and RXRs. To delineate the functions of each of the different retinoid receptors in this model system, we have generated F9 cell lines in which both copies of either the RAR alpha gene or the RAR gamma gene are disrupted by homologous recombination. The absence of RAR alpha is associated with a reduction in the RA-induced expression of both the CRABP-II and Hoxb-1 (formerly 2.9) genes. The absence of RAR gamma is associated with a loss of the RA-inducible expression of the Hoxa-1 (formerly Hox-1.6), Hoxa-3 (formerly Hox-1.5), laminin B1, collagen IV (alpha 1), GATA-4, and BMP-2 genes. Furthermore, the loss of RAR gamma is associated with a reduction in the metabolism of all-trans-RA to more polar derivatives, while the loss of RAR alpha is associated with an increase in metabolism of RA relative to wild-type F9 cells. Thus, each of these RARs exhibits some specificity with respect to the regulation of differentiation-specific gene expression. These results provide an explanation for the expression of multiple RAR types within one cell type and suggest that each RAR has specific functions. PMID:7823950

  8. Routine use of Zenit RA, a novel chemiluminescent immunoanalyzer in autoimmune disease diagnosis.

    PubMed

    Ghillani, P; Dufat, L; Himeur, S; Miyara, M; Amoura, Z; Musset, L

    2012-04-01

    The detection of antibodies is useful to diagnose and/or to classify autoimmune diseases as connective tissue diseases and vasculitis. Zenit RA is a fully automated immunoanalyzer. The aim of this study was to compare the predictive and discriminative performance of the Zenit RA anti-cyclic citrullinated peptide (CCP), anti-cardiolipin (aCL) and anti-β 2 glycoprotein 1 (aB2GP1) tests to conventional ELISAs on clinically well-defined groups of patients and to daily evaluate the determination of anti-extractable nuclear antigen (ENA), anti-double stranded DNA (dsDNA), anti-myeloperoxidase (MPO) and anti-proteinase 3 (PR3) antibodies in a hospital laboratory. Reagents available on Zenit RA analyzer exhibit good diagnostic performances, regarding sensitivity, specificity, positive and negative predictive values. Global agreements between Zenit RA and conventional tests were from 90 to 98 % (Kappa-values ranging 0.56-0.94): 96 % for anti-CCP, 90-94 % for aCL and aB2GP1, 94 % for anti-dsDNA, 97 % for anti-ENA, 98 % for anti-MPO and 95 % for anti-PR3 antibodies. Zenit RA analyzer is easy to rapidly detect the most common autoantibodies in autoimmune diseases. This system has a potential to provide clinically useful data within a short time. Because of the flexibility of its work modalities, it is well adapted to determine antigenic specificities in daily practice. PMID:26000125

  9. Human Alveolar Macrophage Gene Responses to Mycobacterium tuberculosis Strains H37Ra and H37Rv

    PubMed Central

    Silver, Richard F.; Walrath, Jessica; Lee, Hung; Jacobson, Bruce A.; Horton, Heidi; Bowman, Michael R.; Nocka, Karl; Sypek, Joseph P.

    2009-01-01

    H37Rv and H37Ra have been widely used as models of virulent and avirulent strains, respectively, of Mycobacterium tuberculosis. Since the sequencing of H37Rv, microarrays have been used to investigate gene expression of M. tuberculosis strains under various conditions, and to compare gene expression of specific isolates of the organism. Because differences in the virulence of these organisms could also be manifest via their differential induction of host genes, we used Affymetrix Human Genome Arrays U133A and U133B to evaluate human alveolar macrophage (AM) responses to infection with H37Rv and H37Ra. H37Rv altered expression of far more genes than did H37Ra. Moreover, the genes induced by H37Rv to a greater extent than by H37Ra were predominantly associated with the development of effective immunity. H37Rv markedly increased expression of IL-23 p19, whereas neither organism significantly induced IL-12 p35 expression. Quantitative PCR confirmed that H37Rv induced significantly more AM p19 expression than did H37Ra. After low-level infection of both AM and peripheral blood monocytes (MN) with H37Rv, neither cell type produced IL-12 (by ELISA). In contrast, AM displayed significant IL-23 production in response to H37Rv, whereas MN did not. Our findings thus suggest an important role for IL-23 in human host responses to pulmonary infection with M. tuberculosis, and are consistent with epidemiologic and genetic studies that imply that H37Rv may not have unusual capacity to cause human disease. PMID:18787177

  10. IL-1RA +2018 polymorphism and the susceptivity to pneumoconiosis: a Meta-analysis

    PubMed Central

    Zhou, Yan; Kang, Yan; Zhang, Zhongwei; Liu, Jin

    2014-01-01

    Background and objectives: It has been reported that host genetic factors may play a crucial role in pneumoconiosis susceptibility. The present study aimed to study the association between IL-1RA +2018 polymorphism and pneumoconiosis by Meta-analysis. Materials and methods: Literatures addressing the association between IL-1RA gene polymorphisms and pneumoconiosis were selected from the PubMed, Cochrane Library, EMBASE, CNKI and Wanfang databases. Statistical analyses were performed by Review Manager Software 5.0.24 and STATA 11.0 software. Results: 5 case-control studies with a total of 609 pneumoconiosis patients and 579 controls were retrieved. Meta-analysis results showed significant association between IL-1RA +2018 polymorphism and pneumoconiosis risk. The C allele carriers have increased risk compared with the T allele carriers (OR=1.68, 95% CI: 1.25-2.27, P=0.0007). Individuals who carry TC or CC genotype have higher risk than those with TT homozygote (OR=1.79, 95% CI: 1.18, 2.71, P=0.006). In subgroup analysis by pneumoconiosis type, a significant association between IL-1RA +2018 polymorphism and pneumoconiosis risk were found in silicosis (C vs T: OR=2.12, 95% CI: 1.63-2.76, P=0.000; TC+CC vs TT: OR=1.79, 95% CI: 1.18-2.71, P=0.006) but not in coal workers’ pneumoconiosis. Conclusion: This Meta-analysis suggests that IL-1RA +2018 polymorphism might be risk factors for pneumoconiosis, especially in silicosis. PMID:25232408

  11. Gender, body mass index and rheumatoid arthritis disease activity: results from the QUEST-RA study

    PubMed Central

    Jawaheer, Damini; Olsen, Jørn; Lahiff, Maureen; Forsberg, Sinikka; Lähteenmäki, Jukka; Silveira, Ines Guimaraes da; Rocha, Francisco Airton; Laurindo, Ieda Maria Magalhães; Mota, Licia Maria Henrique da; Drosos, Alexandros A.; Murphy, Eithne; Sheehy, Claire; Quirke, Edel; Cutolo, Maurizio; Rexhepi, Sylejman; Dadoniene, Jolanta; Verstappen, Suzan M.M.; Sokka, Tuulikki

    2010-01-01

    Objective To investigate whether body mass index (BMI), as a proxy for body fat, influences rheumatoid arthritis (RA) disease activity in a gender-specific manner. Methods Consecutive patients with RA were enrolled from 25 countries into the QUEST-RA program between 2005 and 2008. Clinical and demographic data were collected by treating rheumatologists and by patient self-report. Distributions of Disease Activity Scores (DAS28), BMI, age, and disease duration were assessed for each country and for the entire dataset; mean values between genders were compared using Student’s t-tests. An association between BMI and DAS28 was investigated using linear regression, adjusting for age, disease duration and country. Results A total of 5,161 RA patients (4,082 women and 1,079 men) were included in the analyses. Overall, women were younger, had longer disease duration, and higher DAS28 scores than men, but BMI was similar between genders. The mean DAS28 scores increased with increasing BMI from normal to overweight and obese, among women, whereas the opposite trend was observed among men. Regression results showed BMI (continuous or categorical) to be associated with DAS28. Compared to the normal BMI range, being obese was associated with a larger difference in mean DAS28 (0.23, 95% CI: 0.11, 0.34) than being overweight (0.12, 95% CI: 0.03, 0.21); being underweight was not associated with disease activity. These associations were more pronounced among women, and were not explained by any single component of the DAS28. Conclusion BMI appears to be associated with RA disease activity in women, but not in men. PMID:20810033

  12. Retinoic acid facilitates inactivated transmissible gastroenteritis virus induction of CD8+ T-cell migration to the porcine gut

    PubMed Central

    Chen, Xiaojuan; Tu, Chongzhi; Qin, Tao; Zhu, Liqi; Yin, Yinyan; Yang, Qian

    2016-01-01

    The digestive tract is the entry site for transmissible gastroenteritis virus (TGEV). TGEV transmission can be prevented if local immunity is established with increased lymphocytes. The current parenteral mode of vaccination stimulates systemic immunity well, but it does not induce sufficient mucosal immunity. Retinoic acid (RA) plays an important role in the induction of cells that imprint gut-homing molecules. We examined whether RA assist parenteral vaccination of pigs could improve mucosal immunity. We demonstrated that elevated numbers of gut-homing CD8+ T cells (which express α4β7 and CCR9 molecules) were presented in porcine inguinal lymph nodes and were recruited to the small intestine by RA. Intestinal mucosal immunity (IgA titre) and systemic immunity (serum IgG titre) were enhanced by RA. Therefore, we hypothesized that RA could induce DCs to form an immature mucosal phenotype and could recruit them to the small intestinal submucosa. Porcine T-cells expressed β7 integrin and CCR9 receptors and migrated to CCL25 by a mechanism that was dependent of activation by RA-pretreated DCs, rather than direct activation by RA. Together, our results provide powerful evidence that RA can assist whole inactivated TGEV (WI-TGEV) via subcutaneous (s.c.) immunization to generate intestinal immunity, and offer new vaccination strategies against TGEV. PMID:27080036

  13. Retinoic acid facilitates inactivated transmissible gastroenteritis virus induction of CD8(+) T-cell migration to the porcine gut.

    PubMed

    Chen, Xiaojuan; Tu, Chongzhi; Qin, Tao; Zhu, Liqi; Yin, Yinyan; Yang, Qian

    2016-01-01

    The digestive tract is the entry site for transmissible gastroenteritis virus (TGEV). TGEV transmission can be prevented if local immunity is established with increased lymphocytes. The current parenteral mode of vaccination stimulates systemic immunity well, but it does not induce sufficient mucosal immunity. Retinoic acid (RA) plays an important role in the induction of cells that imprint gut-homing molecules. We examined whether RA assist parenteral vaccination of pigs could improve mucosal immunity. We demonstrated that elevated numbers of gut-homing CD8(+) T cells (which express α4β7 and CCR9 molecules) were presented in porcine inguinal lymph nodes and were recruited to the small intestine by RA. Intestinal mucosal immunity (IgA titre) and systemic immunity (serum IgG titre) were enhanced by RA. Therefore, we hypothesized that RA could induce DCs to form an immature mucosal phenotype and could recruit them to the small intestinal submucosa. Porcine T-cells expressed β7 integrin and CCR9 receptors and migrated to CCL25 by a mechanism that was dependent of activation by RA-pretreated DCs, rather than direct activation by RA. Together, our results provide powerful evidence that RA can assist whole inactivated TGEV (WI-TGEV) via subcutaneous (s.c.) immunization to generate intestinal immunity, and offer new vaccination strategies against TGEV. PMID:27080036

  14. Rdh10a Provides a Conserved Critical Step in the Synthesis of Retinoic Acid during Zebrafish Embryogenesis

    PubMed Central

    D’Aniello, Enrico; Ravisankar, Padmapriyadarshini; Waxman, Joshua S.

    2015-01-01

    The first step in the conversion of vitamin A into retinoic acid (RA) in embryos requires retinol dehydrogenases (RDHs). Recent studies have demonstrated that RDH10 is a critical core component of the machinery that produces RA in mouse and Xenopus embryos. If the conservation of Rdh10 function in the production of RA extends to teleost embryos has not been investigated. Here, we report that zebrafish Rdh10a deficient embryos have defects consistent with loss of RA signaling, including anteriorization of the nervous system and enlarged hearts with increased cardiomyocyte number. While knockdown of Rdh10a alone produces relatively mild RA deficient phenotypes, Rdh10a can sensitize embryos to RA deficiency and enhance phenotypes observed when Aldh1a2 function is perturbed. Moreover, excess Rdh10a enhances embryonic sensitivity to retinol, which has relatively mild teratogenic effects compared to retinal and RA treatment. Performing Rdh10a regulatory expression analysis, we also demonstrate that a conserved teleost rdh10a enhancer requires Pax2 sites to drive expression in the eyes of transgenic embryos. Altogether, our results demonstrate that Rdh10a has a conserved requirement in the first step of RA production within vertebrate embryos. PMID:26394147

  15. Involvement of apoptotic cell death and cell cycle perturbation in retinoic acid-induced cleft palate in mice

    SciTech Connect

    Okano, Junko . E-mail: okajun@anat1.med.kyoto-u.ac.jp; Suzuki, Shigehiko; Shiota, Kohei

    2007-05-15

    Retinoic acid (RA), a metabolite of vitamin A, plays a key role in a variety of biological processes and is essential for normal embryonic development. On the other hand, exogenous RA could cause cleft palate in offspring when it is given to pregnant animals at either the early or late phases of palatogenesis, but the pathogenetic mechanism of cleft palate caused by excess RA remains not fully elucidated. The aim of the present study was to investigate the effects of excess of RA on early palatogenesis in mouse fetuses and analyze the teratogenic mechanism, especially at the stage prior to palatal shelf elevation. We gave all-trans RA (100 mg/kg) orally to E11.5 ICR pregnant mice and observed the changes occurring in the palatal shelves of their fetuses. It was found that apoptotic cell death increased not only in the epithelium of the palatal shelves but also in the tongue primordium, which might affect tongue withdrawal movement during palatogenesis and impair the horizontal elevation of palatal shelves. In addition, RA was found to prevent the G{sub 1}/S progression of palatal mesenchymal cells through upregulation of p21 {sup Cip1}, leading to Rb hypophospholylation. Thus, RA appears to cause G{sub 1} arrest in palatal mesenchymal cells in a similar manner as in various cancer and embryonic cells. It is likely that apoptotic cell death and cell cycle disruption are involved in cleft palate formation induced by RA.

  16. Retinoic acid induces homing of protective T and B cells to the gut after subcutaneous immunization in mice.

    PubMed

    Hammerschmidt, Swantje I; Friedrichsen, Michaela; Boelter, Jasmin; Lyszkiewicz, Marcin; Kremmer, Elisabeth; Pabst, Oliver; Förster, Reinhold

    2011-08-01

    Diarrheal diseases represent a major health burden in developing countries. Parenteral immunization typically does not induce efficient protection against enteropathogens because it does not stimulate migration of immune cells to the gut. Retinoic acid (RA) is critical for gut immunity, inducing upregulation of gut-homing receptors on activated T cells. In this study, we have demonstrated that RA can redirect immune responses elicited by s.c. vaccination of mice from skin-draining inguinal LNs (ingLNs) to the gut. When present during priming, RA induced robust upregulation of gut-homing receptors in ingLNs, imprinting gut-homing capacity on T cells. Concurrently, RA triggered the generation of gut-tropic IgA+ plasma cells in ingLNs and raised the levels of antigen-specific IgA in the intestinal lumen and blood. RA applied s.c. in vivo induced autonomous RA production in ingLN DCs, further driving efficient induction of gut-homing molecules on effector cells. Importantly, RA-supplemented s.c. immunization elicited a potent immune response in the small intestine that protected mice from cholera toxin–induced diarrhea and diminished bacterial loads in Peyer patches after oral infection with Salmonella. Thus, the use of RA as a gut-homing navigator represents a powerful tool to induce protective immunity in the intestine after s.c. immunization, offering what we believe to be a novel approach for vaccination against enteropathogens. PMID:21737878

  17. Insights into the protective role of solid lipid nanoparticles on rosmarinic acid bioactivity during exposure to simulated gastrointestinal conditions.

    PubMed

    Madureira, Ana Raquel; Campos, Débora A; Oliveira, Ana; Sarmento, Bruno; Pintado, Maria Manuela; Gomes, Ana Maria

    2016-03-01

    The evaluation of the digestion effects on bioactive solid lipid nanoparticles (SLN) was performed. For this purpose, witepsol and carnauba SLN loaded with rosmarinic acid (RA) were exposed to the simulated gastrointestinal tract (GIT) conditions prevailing in stomach and small intestine. The simulation of intestinal epithelium was made with a dialysis bag and intestinal cell culture lines. Changes on SLN physical properties, RA release and absorption profiles were followed at each step. Combination of digestion pH and enzymes showed a significant effect upon SLN physical properties. Zeta potential values increased at stomach conditions and decreased at small intestine simulation. Also, at intestine, SLN increased their sizes and released 40-60% of RA, maintaining its initial antioxidant activity values. Sustained release of 40% of RA from SLN was also observed in dialysis tube. At CaCo-2 cell line, both types of SLN showed similar absorbed RA % (ca. 30%). Nevertheless, in CaCo-2/HT29x mix cell lines, for carnauba SLN a lower adsorption RA % was observed than for witepsol SLN. Solid lipid nanoparticles protected RA bioactivity (in terms of antioxidant activity) until reaching the intestine. A controlled release of RA from SLN was achieved and a significant absorption was observed at intestinal cells. Overall, SLN produced with witepsol showed a higher stability than carnauba SLN. PMID:26766625

  18. A comparison of the natural survival of beagle dogs injected intravenously with low levels of 239Pu, 226Ra, 228Ra, 228Th, or 90Sr.

    PubMed

    Bruenger, F W; Miller, S C; Lloyd, R D

    1991-06-01

    The natural survival, relative to properly chosen controls, of 26 beagle dogs injected once intravenously with an average of 0.58 +/- 0.04 kBq 239Pu/kg, 23 dogs injected with 2.31 +/- 0.43 kBq 226Ra/kg, 13 dogs injected with 1.84 +/- 0.26 kBq 228Ra/kg, 12 dogs injected with 0.56 +/- 0.030 kBq 228Th/kg, and 12 dogs injected with 21.13 +/- 1.74 kBq 90Sr/kg was evaluated statistically. The amounts of these radionuclides are related directly to the estimated maximum permissible body burdens for humans suggested in ICRP II (1959). They constitute a level of exposure that initially was assumed to cause no deleterious effects in dogs. This study had two objectives: (1) identification of homogeneous control groups against which to evaluate the survival of the irradiated groups and (2) comparison of the survival characteristics and estimation of mortality or hazard rate ratios for control dogs vs dogs injected with the baseline dosages given above. It was shown, by goodness-of-fit plots, that the Cox proportional hazards model was an appropriate method of analysis. Therefore, covariates that possibly could influence survival were tested for significance. Only the effects of grand mal seizure, which is caused in epileptic dogs by an external stimulus and can be fatal if untreated, were significant (P less than 0.0001). Consequently, in the final model, death from grand mal seizure was considered as accidental. After censoring the dogs dying from grand mal seizure, it was established that the data for the control groups from previous and contemporary experiments could be pooled. The change in hazard rates relative to controls resulting from exposure to the baseline radionuclide level was modest, 1.6 times for 239Pu (P = 0.033), 1.0(4) for 226Ra (P = 0.86), 1.9 for 228Ra (P = 0.035), 2.5 for 228Th (P less than 0.001), and 0.52 for 90Sr (P = 0.041). Bone tumor induction was clearly elevated in dogs injected with 239Pu and 228Th. When the effect of these bone tumors on survival

  19. Signalling Through Retinoic Acid Receptors is Required for Reprogramming of Both Mouse Embryonic Fibroblast Cells and Epiblast Stem Cells to Induced Pluripotent Stem Cells

    PubMed Central

    Yang, Jian; Wang, Wei; Ooi, Jolene; Campos, Lia S.

    2015-01-01

    Abstract We previously demonstrated that coexpressing retinoic acid (RA) receptor gamma and liver receptor homolog‐1 (LRH1 or NR5A2) with OCT4, MYC, KLF4, and SOX2 (4F) rapidly reprograms mouse embryonic fibroblast cells (MEFs) into induced pluripotent stem cells (iPSCs). Here, we further explore the role of RA in reprogramming and report that the six factors (6F) efficiently and directly reprogram MEFs into integration‐free iPSCs in defined medium (N2B27) in the absence of feeder cells. Through genetic and chemical approaches, we find that RA signalling is essential, in a highly dose‐sensitive manner, for MEF reprogramming. The removal of exogenous RA from N2B27, the inhibition of endogenous RA synthesis or the expression of a dominant‐negative form of RARA severely impedes reprogramming. By contrast, supplementing N2B27 with various retinoids substantially boosts reprogramming. In addition, when coexpressed with LRH1, RA receptors (RARs) can promote reprogramming in the absence of both exogenous and endogenously synthesized RA. Remarkably, the reprogramming of epiblast stem cells into embryonic stem cell‐like cells also requires low levels of RA, which can modulate Wnt signalling through physical interactions of RARs with β‐catenin. These results highlight the important functions of RA signalling in reprogramming somatic cells and primed stem cells to naïve pluripotency. Stem Cells 2015;33:1390–1404 PMID:25546009

  20. Activation of Notch1 inhibits medial edge epithelium apoptosis in all-trans retinoic acid-induced cleft palate in mice.

    PubMed

    Zhang, Yadong; Dong, Shiyi; Wang, Weicai; Wang, Jianning; Wang, Miao; Chen, Mu; Hou, Jinsong; Huang, Hongzhang

    2016-08-26

    Administration of all-trans retinoic acid (atRA) on E12.0 (embryonic day 12.0) leads to failure of medial edge epithelium (MEE) disappearance and cleft palate. However, the molecular mechanism underlying the relationship between atRA and MEE remains to be identified. In this study, atRA (200 mg/kg) administered by gavage induced a 75% incidence of cleft palate in C57BL/6 mice. Notch1 was up-regulated in MEE cells in the atRA-treated group compared with the controls at E15.0, together with reduced apoptosis and elevated proliferation. Next, we investigated the mechanisms underlying atRA, Notch1 and MEE degradation in palate organ culture. Our results revealed that down-regulation of Notch1 partially rescued the inhibition of atRA-induced palate fusion. Molecular analysis indicated that atRA increased the expression of Notch1 and Rbpj and decreased the expression of P21. In addition, depletion of Notch1 expression decreased the expression of Rbpj and increased the expression of P21. Moreover, inhibition of Rbpj expression partially reversed atRA-induced MEE persistence and increased P21 expression. These findings demonstrate that atRA inhibits MEE degradation, which in turn induces a cleft palate, possibly through the Notch1/RBPjk/P21 signaling pathway. PMID:27343556

  1. Lysyl oxidase-like 4 involvement in retinoic acid epithelial wound healing.

    PubMed

    Comptour, Aurélie; Rouzaire, Marion; Belville, Corinne; Bonnin, Nicolas; Daniel, Estelle; Chiambaretta, Frédéric; Blanchon, Loïc; Sapin, Vincent

    2016-01-01

    Vitamin A and its active forms (retinoic acids/RAs) are known to have pro-healing properties, but their mechanisms of action are still poorly understood. This work aimed to identify the cellular and molecular processes by which atRA (all-trans RA) improves wound healing, using an in vivo model of mouse corneal alkali burns and an in vitro cellular human corneal epithelial injury model. Regulation by atRA has been studied on most of the cellular events that occur in wound healing. We investigated the direct influence of atRA on a specific target gene known to be involved in the extracellular matrix (ECM) dynamics, one of the pathways contributing to epithelial repair. Our results demonstrate that atRA promotes corneal epithelial wound healing by acting preferentially on migration. The induction of lysyl oxidase-like 4 (LOXL4) expression by atRA in the corneal epithelium environment was established as essential in the mechanism of atRA-dependent wound healing. Our study describes for the first time a direct link between a retinoic-induced gene and protein, LOXL4, and its general clinical pro-healing properties in ECM dynamics. PMID:27597564

  2. Hydroxycinnamate conjugates as potential monolignol replacements: in vitro lignification and cell wall studies with rosmarinic acid.

    PubMed

    Tobimatsu, Yuki; Elumalai, Sasikumar; Grabber, John H; Davidson, Christy L; Pan, Xuejun; Ralph, John

    2012-04-01

    The plasticity of lignin biosynthesis should permit the inclusion of new compatible phenolic monomers, such as rosmarinic acid (RA) and analogous catechol derivatives, into cell-wall lignins that are consequently less recalcitrant to biomass processing. In vitro lignin polymerization experiments revealed that RA readily underwent peroxidase-catalyzed copolymerization with monolignols and lignin oligomers to form polymers with new benzodioxane inter-unit linkages. Incorporation of RA permitted extensive depolymerization of synthetic lignins by mild alkaline hydrolysis, presumably by cleavage of ester intra-unit linkages within RA. Copolymerization of RA with monolignols into maize cell walls by in situ peroxidases significantly enhanced alkaline lignin extractability and promoted subsequent cell wall saccharification by fungal enzymes. Incorporating RA also improved cell wall saccharification by fungal enzymes and by rumen microflora even without alkaline pretreatments, possibly by modulating lignin hydrophobicity and/or limiting cell wall cross-linking. Consequently, we anticipate that bioengineering approaches for partial monolignol substitution with RA and analogous plant hydroxycinnamates would permit more efficient utilization of plant fiber for biofuels or livestock production. PMID:22359379

  3. Nuclear CD38 in retinoic acid-induced HL-60 cells

    SciTech Connect

    Yalcintepe, Leman . E-mail: lemany@istanbul.edu.tr; Albeniz, Isil; Adin-Cinar, Suzan; Tiryaki, Demir; Bermek, Engin; Graeff, Richard M.; Lee, Hon Cheung

    2005-02-01

    The cell surface antigen, CD38, is a 45-kDa transmembrane protein which is predominantly expressed on hematopoietic cells during differentiation. As a bifunctional ectoenzyme, it catalyzes the synthesis of cyclic ADP-ribose (cADPR) from NAD{sup +} and hydrolysis of either NAD{sup +} or cADPR to ADP-ribose. All-trans-retinoic acid (RA) is a potent and specific inducer of CD38 in myeloid cells. In this report, we demonstrate that the nuclei of RA-treated human HL-60 myeloblastic cells reveal enzymatic activities inherent to CD38. Thus, GDP-ribosyl cyclase and NAD{sup +} glycohydrolase activities in the nuclear fraction increased very significantly in response to incubation with RA. With Western blotting, we detected in the nuclear protein fraction from RA-treated cells a {approx}43-kDa protein band which was reactive with the CD38-specific monoclonal antibody OKT10. The expression of CD38 in HL-60 nuclei was also shown with FACScan analysis. RA treatment gave rise to an increase in in vitro ADP ribosylation of the {approx}43-kDa nuclear protein. Moreover, nuclei isolated from RA-treated HL-60 cells revealed calcium release in response to cADPR, whereas a similar response was not observed in control nuclei. These results suggest that CD38 is expressed in HL-60 cell nuclei during RA-induced differentiation.

  4. Differential Regulation of Bcl-xL Gene Expression by Corticosterone, Progesterone, and Retinoic Acid.

    PubMed

    Morrissy, Steve J; Sun, Haipeng; Zhang, Jack; Strom, Joshua; Chen, Qin M

    2016-06-01

    Corticosterone (CT), progesterone (PG), and retinoic acid (RA) are capable of inhibiting Doxorubicin (Dox) from inducing apoptosis in rat cardiomyocytes. Mechanistically, CT, PG, and RA induce increases of Bcl-xL protein and mRNA, and activate a 3.2 kb bcl-x gene promoter. CT and RA, but not PG, induced the activity of a 0.9 kb bcl-x promoter, containing sequences for AP-1 and NF-kB binding. RA, but not CT or PG, induced NF-kB activation. CT, but not PG or RA, induced AP-1 activation, and induction of the 0.9 kb bcl-x reporter by CT was inhibited by dominant negative c-Jun TAM-67 or removal of AP-1 binding site. Therefore, although CT, PG, and RA all induce Bcl-xL mRNA and protein, three independent mechanisms are in operation: while CT induces Bcl-xL via AP-1 transcription factor, and RA induces NF-kB activation and bcl-x promoter activity, PG induces Bcl-xL via a mechanism independent of NF-kB or AP-1. PMID:26915917

  5. Synergistic effects of retinoic acid and tamoxifen on human breast cancer cells: Proteomic characterization

    SciTech Connect

    Wang Ying; He Qingyu; Chen Hongming; Chiu Jenfu . E-mail: jfchiu@hkucc.hku.hk

    2007-01-15

    The anti-estrogen tamoxifen and vitamin A-related compound, all-trans retinoic acid (RA), in combination act synergistically to inhibit the growth of MCF-7 human breast cancer cells. In the present study, we applied two-dimensional gel electrophoresis based proteomic approach to globally analyze this synergistic effect of RA and tamoxifen. Proteomic study revealed that multiple clusters of proteins were involved in RA and tamoxifen-induced apoptosis in MCF-7 breast cancer cells, including post-transcriptional and splicing factors, proteins related to cellular proliferation or differentiation, and proteins related to energy production and internal degradation systems. The negative growth factor-transforming growth factor {beta} (TGF{beta}) was secreted by RA and/or tamoxifen treatment and was studies as a potential mediator of the synergistic effects of RA and tamoxifen in apoptosis. By comparing protein alterations in treatments of RA and tamoxifen alone or in combination to those of TGF{beta} treatment, or co-treatment with TGF{beta} inhibitor SB 431542, proteomic results showed that a number of proteins were involved in TGF{beta} signaling pathway. These results provide valuable insights into the mechanisms of RA and tamoxifen-induced TGF{beta} signaling pathway in breast cancer cells.

  6. Stability studies on trans-rosmarinic acid and GC-MS analysis of its degradation product.

    PubMed

    Razboršek, Maša Islamčević

    2011-07-15

    The stability of trans-rosmarinic acid (trans-RA, an important phenolic compound with anti-oxidant, anti-inflammatory, anti-bacterial, and anti-viral properties) exposed to different stress conditions (daylight, higher temperatures, different solvents, and humidity) was investigated. Gas chromatography-mass spectrometry (GC-MS) was used to analyse the degraded samples, and structural identification of degradation products was assigned based upon MS fragmentation pattern. The GC-MS method was validated in terms of linearity, precision as repeatability, accuracy, limit of detection (LOD), limit of quantitation (LOQ) and recovery. The stability experiments were performed on pure trans-RA and on trans-RA present in commercially available rosemary extract. The cis-isomer of RA was the only degradation product. The results showed that trans-RA was readily isomerized into its cis-form within a few hours when dissolved in ethanol, methanol or tetrahydrofuran, and exposed to darkness or daylight at different temperatures. Isomerization took place to a greater extent in protic than in aprotic solvents. Trans-RA in the solid state was found to be stable for up to three months under all tested conditions. The described GC-MS method was also applied to the determination of trans-RA in eight different species of Lamiaceae family. PMID:21515014

  7. Apoptotic and anti-proliferative effects of all-trans retinoic acid

    SciTech Connect

    Zamora, Monica; Ortega, Juan Alberto; Alana, Lide; Vinas, Octavi; Mampel, Teresa . E-mail: tmampel@ub.edu

    2006-06-10

    We examined the apoptotic and anti-proliferative effects of all-trans retinoic acid (atRA) in HeLa cells. Our results demonstrated that HeLa cells were more sensitive to the anti-proliferative effects of atRA than to its apoptotic effects. Furthermore, we demonstrated that caspase inhibition attenuates cell death but does not alter the atRA-dependent reduction in cell proliferation, which suggests that atRA-induced apoptosis is independent of the arrest in cell proliferation. To check whether ANT proteins mediated these atRA effects, we transiently transfected cells with expression vectors encoding for individual ANT (adenine nucleotide translocase 1-3). Our results revealed that ANT1 and ANT3 over-expressing HeLa cells increased their atRA sensitivity. Thus, our results not only demonstrate the different functional activities of ANT isoforms, but also contribute to a better understanding of the properties of atRA as an anti-tumoral agent used in cancer therapy.

  8. Once and again: retinoic acid signaling in the developing and regenerating olfactory pathway.

    PubMed

    Rawson, N E; LaMantia, A-S

    2006-06-01

    Retinoic acid (RA), a member of the steroid/thyroid superfamily of signaling molecules, is an essential regulator of morphogenesis, differentiation, and regeneration in the mammalian olfactory pathway. RA-mediated teratogenesis dramatically alters olfactory pathway development, presumably by disrupting retinoid-mediated inductive signaling that influences initial olfactory epithelium (OE) and bulb (OB) morphogenesis. Subsequently, RA modulates the genesis, growth, or stability of subsets of OE cells and OB interneurons. RA receptors, cofactors, and synthetic enzymes are expressed in the OE, OB, and anterior subventricular zone (SVZ), the site of neural precursors that generate new OB interneurons throughout adulthood. Their expression apparently accommodates RA signaling in OE cells, OB interneurons, and slowly dividing SVZ neural precursors. Deficiency of vitamin A, the dietary metabolic RA precursor, leads to cytological changes in the OE, as well as olfactory sensory deficits. Vitamin A therapy in animals with olfactory system damage can accelerate functional recovery. RA-related pathology as well as its potential therapeutic activity may reflect endogenous retinoid regulation of neuronal differentiation, stability, or regeneration in the olfactory pathway from embryogenesis through adulthood. These influences may be in register with retinoid effects on immune responses, metabolism, and modulation of food intake. PMID:16688760

  9. Lysyl oxidase-like 4 involvement in retinoic acid epithelial wound healing

    PubMed Central

    Comptour, Aurélie; Rouzaire, Marion; Belville, Corinne; Bonnin, Nicolas; Daniel, Estelle; Chiambaretta, Frédéric; Blanchon, Loïc; Sapin, Vincent

    2016-01-01

    Vitamin A and its active forms (retinoic acids/RAs) are known to have pro-healing properties, but their mechanisms of action are still poorly understood. This work aimed to identify the cellular and molecular processes by which atRA (all-trans RA) improves wound healing, using an in vivo model of mouse corneal alkali burns and an in vitro cellular human corneal epithelial injury model. Regulation by atRA has been studied on most of the cellular events that occur in wound healing. We investigated the direct influence of atRA on a specific target gene known to be involved in the extracellular matrix (ECM) dynamics, one of the pathways contributing to epithelial repair. Our results demonstrate that atRA promotes corneal epithelial wound healing by acting preferentially on migration. The induction of lysyl oxidase-like 4 (LOXL4) expression by atRA in the corneal epithelium environment was established as essential in the mechanism of atRA-dependent wound healing. Our study describes for the first time a direct link between a retinoic-induced gene and protein, LOXL4, and its general clinical pro-healing properties in ECM dynamics. PMID:27597564

  10. Retinoic acid, local cell-cell interactions, and pattern formation in vertebrate limbs.

    PubMed

    Bryant, S V; Gardiner, D M

    1992-07-01

    Retinoic acid (RA), a derivative of vitamin A, has remarkable effects on developing and regenerating limbs. These effects include teratogenesis, arising from RA's ability to inhibit growth and pattern formation. They also include pattern duplication, arising as a result of the stimulation of additional growth and pattern formation. In this review we present evidence that the diverse effects of RA are consistent with a singular, underlying explanation. We propose that in all cases exogenously applied RA causes the positional information of pattern formation-competent cells to be reset to a value that is posterior-ventral-proximal with respect to the limb. The diversity of outcomes can be seen as a product of the mode of application of exogenous RA (global versus local) coupled with the unifying concept that growth and pattern formation in both limb development and limb regeneration are controlled by local cell-cell interactions, as formulated in the polar coordinate model. We explore the possibility that the major role of endogenous RA in limb development is in the establishment of the limb field rather than as a diffusible morphogen that specifies graded positional information across the limb as previously proposed. Finally, we interpret the results of the recent finding that RA can turn tail regenerates into limbs, as evidence that intercalary interactions may also be involved in the formation of the primary body axis. PMID:1628749

  11. CDX4 and retinoic acid interact to position the hindbrain-spinal cord transition.

    PubMed

    Chang, Jessie; Skromne, Isaac; Ho, Robert K

    2016-02-15

    The sub-division of the posterior-most territory of the neural plate results in the formation of two distinct neural structures, the hindbrain and the spinal cord. Although many of the molecular signals regulating the development of these individual structures have been elucidated, the mechanisms involved in delineating the boundary between the hindbrain and spinal cord remain elusive. Two molecules, retinoic acid (RA) and the Cdx4 transcription factor have been previously implicated as important regulators of hindbrain and spinal cord development, respectively. Here, we provide evidence that suggests multiple regulatory interactions occur between RA signaling and the Cdx4 transcription factor to establish the anterior-posterior (AP) position of the transition between the hindbrain and spinal cord. Using chemical inhibitors to alter RA concentrations and morpholinos to knock-down Cdx4 function in zebrafish, we show that Cdx4 acts to prevent RA degradation in the presumptive spinal cord domain by suppressing expression of the RA degradation enzyme, Cyp26a1. In the hindbrain, RA signaling modulates its own concentration by activating the expression of cyp26a1 and inhibiting the expansion of cdx4. Therefore, interactions between Cyp26a1 and Cdx4 modulate RA levels along the AP axis to segregate the posterior neural plate into the hindbrain and spinal cord territories. PMID:26773000

  12. Epigenomic reorganization of the clustered Hox genes in embryonic stem cells induced by retinoic acid.

    PubMed

    Kashyap, Vasundhra; Gudas, Lorraine J; Brenet, Fabienne; Funk, Patricia; Viale, Agnes; Scandura, Joseph M

    2011-02-01

    Retinoic acid (RA) regulates clustered Hox gene expression during embryogenesis and is required to establish the anterior-posterior body plan. Using mutant embryonic stem cell lines deficient in the RA receptor γ (RARγ) or Hoxa1 3'-RA-responsive element, we studied the kinetics of transcriptional and epigenomic patterning responses to RA. RARγ is essential for RA-induced Hox transcriptional activation, and deletion of its binding site in the Hoxa1 enhancer attenuates transcriptional and epigenomic activation of both Hoxa and Hoxb gene clusters. The kinetics of epigenomic reorganization demonstrate that complete erasure of the polycomb repressive mark H3K27me3 is not necessary to initiate Hox transcription. RARγ is not required to establish the bivalent character of Hox clusters, but RA/RARγ signaling is necessary to erase H3K27me3 from activated Hox genes during embryonic stem cell differentiation. Highly coordinated, long range epigenetic Hox cluster reorganization is closely linked to transcriptional activation and is triggered by RARγ located at the Hoxa1 3'-RA-responsive element. PMID:21087926

  13. Hydroxycinnamate Conjugates as Potential Monolignol Replacements: In vitro Lignification and Cell Wall Studies with Rosmarinic Acid

    SciTech Connect

    Yuki, Tobimatsu; Sasikumar, Elumalai; Grabber, John H.; Davidson, Christy L.; Xuejun, Pan; John, Ralph

    2012-04-01

    The plasticity of lignin biosynthesis should permit the inclusion of new compatible phenolic monomers, such as rosmarinic acid (RA) and analogous catechol derivatives, into cell-wall lignins that are consequently less recalcitrant to biomass processing. In vitro lignin polymerization experiments revealed that RA readily underwent peroxidase-catalyzed copolymerization with monolignols and lignin oligomers to form polymers with new benzodioxane inter-unit linkages. Incorporation of RA permitted extensive depolymerization of synthetic lignins by mild alkaline hydrolysis, presumably by cleavage of ester intra-unit linkages within RA. Copolymerization of RA with monolignols into maize cell walls by in situ peroxidases significantly enhanced alkaline lignin extractability and promoted subsequent cell wall saccharification by fungal enzymes. Incorporating RA also improved cell wall saccharification by fungal enzymes and by rumen microflora even without alkaline pretreatments, possibly by modulating lignin hydrophobicity and/or limiting cell wall cross-linking. Consequently, we anticipate that bioengineering approaches for partial monolignol substitution with RA and analogous plant hydroxycinnamates would permit more efficient utilization of plant fiber for biofuels or livestock production.

  14. ERF and ETV3L are retinoic acid-inducible repressors required for primary neurogenesis.

    PubMed

    Janesick, Amanda; Abbey, Rachelle; Chung, Connie; Liu, Sophia; Taketani, Mao; Blumberg, Bruce

    2013-08-01

    Cells in the developing neural tissue demonstrate an exquisite balance between proliferation and differentiation. Retinoic acid (RA) is required for neuronal differentiation by promoting expression of proneural and neurogenic genes. We show that RA acts early in the neurogenic pathway by inhibiting expression of neural progenitor markers Geminin and Foxd4l1, thereby promoting differentiation. Our screen for RA target genes in early Xenopus development identified Ets2 Repressor Factor (Erf) and the closely related ETS repressors Etv3 and Etv3-like (Etv3l). Erf and Etv3l are RA responsive and inhibit the action of ETS genes downstream of FGF signaling, placing them at the intersection of RA and growth factor signaling. We hypothesized that RA regulates primary neurogenesis by inducing Erf and Etv3l to antagonize proliferative signals. Loss-of-function analysis showed that Erf and Etv3l are required to inhibit proliferation of neural progenitors to allow differentiation, whereas overexpression of Erf led to an increase in the number of primary neurons. Therefore, these RA-induced ETS repressors are key components of the proliferation-differentiation switch during primary neurogenesis in vivo. PMID:23824578

  15. Studies of transport pathways of Th, U, rare earths, Ra-228, and Ra-226 from soil to plants and farm animals: Final progress report, 1983-1988

    SciTech Connect

    Linsalata, P

    1988-07-01

    This report consists of three parts. Part 1 discusses a field study conducted in an area of enhanced, natural radioactivity to assess the soil to edible vegetable concentration ratios (CR = concentration in dry vegetable/concentration in dry soil) of Th-232, Th-230, Ra-226, Ra-228, and the light rare earth elements (REE's), La, Ce, and Nd. Twenty-eight soil, and approximately 42 vegetable samples consisting of relatively equal numbers of seven varieties, were obtained from 11 farms on the Pocos de Caldas Plateau in the state of Minas Gerais, Brazil. This region is the site of a major natural analogue study to assess the mobilization and retardation processes affecting thorium and the REE's at the Morro do Ferro ore body, and uranium series radionuclides at the Osamu Utsumi open pit uranium mine. Thorium (IV) serves as a chemical analogue for quadrivalent plutonium, the light REE's (III) as chemical analogues for trivalent americium and curium, and uranium (VI) as an analogue for transuranics with stable oxidation states above IV, e.g., Pu(VI). Part 2 includes our final measurement results for naturally occurring light rare earth elements (REE's include La, Ce, Nd, and SM), U-series and Th-series radionuclides in adult farm animal tissues, feeds and soils. Our findings on soil-to-tissue concentration ratios (CR's) and the comparative behavior of these elements in farm animals raised under natural conditions by local farmers are presented. Part 3 summarizes our findings to date on the distribution and mobilization of Th-232, light rare earth elements (LREE), U-238 and Ra-228 in the MF basin. Estimates of first order, present day, mobilization rate constants resulting from ground water solubilization and seepage/stream transport are calculated using revised inventory estimates for the occurrence of these elements in the ore body and annual flux estimates for the transport of these elements away from the ore body. 151 refs., 20 figs., 40 tabs.

  16. Soil to rice transfer factors for (226)Ra, (228)Ra, (210)Pb, (40)K and (137)Cs: a study on rice grown in India.

    PubMed

    Karunakara, N; Rao, Chetan; Ujwal, P; Yashodhara, I; Kumara, Sudeep; Ravi, P M

    2013-04-01

    India is the second largest producer of rice (Oryza sativa L.) in the world and rice is an essential component of the diet for a majority of the population in India. However, detailed studies aimed at the evaluation of radionuclide transfer factors (F(v)) for the rice grown in India are almost non-existent. This paper presents the soil to rice transfer factors for natural ((226)Ra, (228)Ra, (40)K, and (210)Pb) and artificial ((137)Cs) radionuclides for rice grown in natural field conditions on the West Coast of India. A rice field was developed very close to the Kaiga nuclear power plant and the water required for this field was drawn from the cooling water discharge canal of the power plant. For a comparative study of the radionuclide transfer factors, rice samples were also collected from the rice fields of nearby villages. The study showed that the (226)Ra and (228)Ra activity concentrations were below detection levels in different organs of the rice plant. The soil to un-hulled rice grain (40)K transfer factor varied in the range of 6.5 × 10(-1) to 2.9 with a mean of 0.15 × 10(1), and of (210)Pb varied in the range of <1.2 × 10(-2) to 8.1 × 10(-1) with a mean of 1.4 × 10(-1), and of (137)Cs varied in the range of 6.6 × 10(-2) to 3.4 × 10(-1) with a mean of 2.1 × 10(-1). The mean values of un-hulled grain to white rice processing retention factors (F(r)) were 0.12 for (40)K, 0.03 for (210)Pb, and 0.14 for (137)Cs. Using these processing retention factors, the soil to white rice transfer factors were estimated and these were found to have mean values of 1.8 × 10(-1), 4.2 × 10(-3), and 3.0 × 10(-2) for (40)K, (210)Pb, and (137)Cs, respectively. The study has shown that the transfer of (40)K was higher for above the ground organs than for the root, but (210)Pb and (137)Cs were retained in the root and their transfer to above the ground organs of the rice plant is significantly lower. PMID:23266913

  17. A third human retinoic acid receptor, hRAR-. gamma

    SciTech Connect

    Krust, A.; Kastner, Ph.; Petkovich, M.; Zelent, A.; Chambon, P. )

    1989-07-01

    Retinoic acid receptors (RARs) are retinoic acid (RA)-inducible enhancer factors belonging to the superfamily of steroid/thyroid nuclear receptors. The authors have previously characterized two human RAR (hRAR-{alpha} and hRAR-{beta}) cDNAs and have recently cloned their murine cognates (mRAR-{alpha} and mRAR-{beta}) together with a third RAR (mRAR-{gamma}) whose RNA was detected predominantly in skin, a well-known target for RA. mRAR-{gamma} cDNA was used here to clone its human counterpart (hRAR-{gamma}) from a T47D breast cancer cell cDNA library. Using a transient transfection assay in HeLa cells and a reporter gene harboring a synthetic RA responsive element, they demonstrate that hRAR-{gamma} cDNA indeed encodes a RA-inducible transcriptional trans-activator. Interestingly, comparisons of the amino acid sequences of all six human and mouse RARs indicate that the interspecies conservation of a given member of the RAR subfamily (either {alpha}, {beta}, or {gamma}) is much higher than the conservation of all three receptors within a given species. These observations indicate that RAR-{alpha}, -{beta}, and -{gamma} may perform specific functions. They show also that hRAR-{gamma} RNA is the predominant RAR RNA species in human skin, which suggests that hRAR-{gamma} mediates some of the retinoid effects in this tissue.

  18. SIRT1-mediated deacetylation of CRABPII regulates cellular retinoic acid signaling and modulates embryonic stem cell differentiation

    PubMed Central

    Tang, Shuang; Huang, Gang; Fan, Wei; Chen, Yue; Ward, James M.; Xu, Xiaojiang; Xu, Qing; Kang, Ashley; McBurney, Michael W.; Fargo, David C.; Hu, Guang; Baumgart-Vogt, Eveline; Zhao, Yingming; Li, Xiaoling

    2014-01-01

    Summary Retinoid homeostasis is critical for normal embryonic development. Both the deficiency and excess of these compounds are associated with congenital malformations. Here we demonstrate that SIRT1, the most conserved mammalian NAD+-dependent protein deacetylase, contributes to homeostatic retinoic acid (RA) signaling and modulates mouse embryonic stem cell (mESC) differentiation in part through deacetylation of cellular retinoic acid binding protein II (CRABPII). We show that RA-mediated acetylation of CRABPII at K102 is essential for its nuclear accumulation and subsequent activation of RA signaling. SIRT1 interacts with and deacetylates CRABPII, regulating its subcellular localization. Consequently, SIRT1 deficiency induces hyper-acetylation and nuclear accumulation of CRABPII, enhancing RA signaling and accelerating mESC differentiation in response to RA. Consistently, SIRT1 deficiency is associated with elevated RA signaling and development defects in mice. Our findings reveal a novel molecular mechanism that regulates RA signaling, and highlight the importance of SIRT1 in regulation of ESC pluripotency and embryogenesis. PMID:25155613

  19. RALDH2, the enzyme for retinoic acid synthesis, mediates meiosis initiation in germ cells of the female embryonic chickens.

    PubMed

    Yu, Minli; Yu, Ping; Leghari, Imdad H; Ge, Chutian; Mi, Yuling; Zhang, Caiqiao

    2013-02-01

    Meiosis is a process unique to the differentiation of germ cells and exhibits sex-specific in timing. Previous studies showed that retinoic acid (RA) as the vitamin A metabolite is crucial for controlling Stra8 (Stimulated by retinoic acid gene 8) expression in the gonad and to initiate meiosis; however, the mechanism by which retinoid-signaling acts has remained unclear. In the present study, we investigated the role of the enzyme retinaldehyde dehydrogenase 2 (RALDH2) which catalyzes RA synthesizes by initiating meiosis in chicken ovarian germ cells. Meiotic germ cells were first detected at day 15.5 in chicken embryo ovary when the expression of synaptonemal complex protein 3 (Scp3) and disrupted meiotic cDNA 1 homologue (Dmc1) became elevated, while Stra8 expression was specifically up-regulated at day 12.5 before meiosis onset. It was observed from the increase in Raldh2 mRNA expression levels and decreases in Cyp26b1 (the enzyme for RA catabolism) expression levels during meiosis that requirement for RA accumulation is essential to sustain meiosis. This was also revealed by RA stimulation of the cultured ovaries with the initiation of meiosis response, and the knocking down of the Raldh2 expression during meiosis, leading to abolishment of RA-dependent action. Altogether, these studies indicate that RA synthesis by the enzyme RALDH2 and signaling through its receptor is crucial for meiosis initiation in chicken embryonic ovary. PMID:22733143

  20. Rosmarinic Acid Attenuates Sodium Taurocholate-Induced Acute Pancreatitis in Rats by Inhibiting Nuclear Factor-κB Activation.

    PubMed

    Fan, Yu-Ting; Yin, Guo-Jian; Xiao, Wen-Qin; Qiu, Lei; Yu, Ge; Hu, Yan-Ling; Xing, Miao; Wu, De-Qing; Cang, Xiao-Feng; Wan, Rong; Wang, Xing-Peng; Hu, Guo-Yong

    2015-01-01

    Rosmarinic Acid (RA), a caffeic acid ester, has been shown to exert anti-inflammation, anti-oxidant and antiallergic effects. Our study aimed to investigate the effect of RA in sodium taurocholate ( NaTC )-induced acute pancreatitis, both in vivo and in vitro. In vivo, RA (50 mg/kg) was administered intraperitoneally 2 h before sodium taurocholate injection. Rats were sacrificed 12 h, 24 h or 48 h after sodium taurocholate injection. Pretreatment with RA significantly ameliorated pancreas histopathological changes, decreased amylase and lipase activities in serum, lowered myeloperoxidase activity in the pancreas, reduced systematic and pancreatic interleukin-1 β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α) levels, and inhibited NF-κB translocation in pancreas. In vitro, pretreating the fresh rat pancreatic acinar cells with 80 μ mol/L RA 2 h before 3750 nmol/L sodium taurocholate or 10 ng/L TNF-α administration significantly attenuated the reduction of isolated pancreatic acinar cell viability and inhibited the nuclear activation and translocation of NF-κB. Based on our findings, RA appears to attenuate damage in sodium taurocholate-induced acute pancreatitis and reduce the release of inflammatory cytokines by inhibiting the activation of NF-κB. These findings might provide a basis for investigating the therapeutic role of RA in managing acute pancreatits. PMID:26364660