Splicing Factor Prp8 Interacts With NES(AR) and Regulates Androgen Receptor in Prostate Cancer Cells.

PubMed

Wang, Dan; Nguyen, Minh M; Masoodi, Khalid Z; Singh, Prabhpreet; Jing, Yifeng; O'Malley, Katherine; Dar, Javid A; Dhir, Rajiv; Wang, Zhou

2015-12-01

Androgen receptor (AR) plays a pivotal role in the development of primary as well as advanced castration-resistant prostate cancer. Previous work in our lab identified a novel nuclear export signal (NES) (NES(AR)) in AR ligand-binding domain essential for AR nucleocytoplasmic trafficking. By characterizing the localization of green fluorescence protein (GFP)-tagged NES(AR), we designed and executed a yeast mutagenesis screen and isolated 7 yeast mutants that failed to display the NES(AR) export function. One of those mutants was identified as the splicing factor pre-mRNA processing factor 8 (Prp8). We further showed that Prp8 could regulate NES(AR) function using short hairpin RNA knockdown of Prp8 coupled with a rapamycin export assay in mammalian cells and knockdown of Prp8 could induce nuclear accumulation of GFP-tagged AR in PC3 cells. Prp8 expression was decreased in castration-resistant LuCaP35 xenograft tumors as compared with androgen-sensitive xenografts. Laser capture microdissection and quantitative PCR showed Prp8 mRNA levels were decreased in human prostate cancer specimens with high Gleason scores. In prostate cancer cells, coimmunoprecipitation and deletion mutagenesis revealed a physical interaction between Prp8 and AR mainly mediated by NES(AR). Luciferase assay with prostate specific antigen promoter-driven reporter demonstrated that Prp8 regulated AR transcription activity in prostate cancer cells. Interestingly, Prp8 knockdown also increased polyubiquitination of endogenous AR. This may be 1 possible mechanism by which it modulates AR activity. These results show that Prp8 is a novel AR cofactor that interacts with NES(AR) and regulates AR function in prostate cancer cells.

An Interdomain Interaction of the Androgen Receptor Is Required for Its Aggregation and Toxicity in Spinal and Bulbar Muscular Atrophy*

PubMed Central

Orr, Christopher R.; Montie, Heather L.; Liu, Yuhong; Bolzoni, Elena; Jenkins, Shannon C.; Wilson, Elizabeth M.; Joseph, James D.; McDonnell, Donald P.; Merry, Diane E.

2010-01-01

Polyglutamine expansion within the androgen receptor (AR) causes spinal and bulbar muscular atrophy (SBMA) and is associated with misfolded and aggregated species of the mutant AR. We showed previously that nuclear localization of the mutant AR was necessary but not sufficient for SBMA. Here we show that an interdomain interaction of the AR that is central to its function within the nucleus is required for AR aggregation and toxicity. Ligands that prevent the interaction between the amino-terminal FXXLF motif and carboxyl-terminal AF-2 domain (N/C interaction) prevented toxicity and AR aggregation in an SBMA cell model and rescued primary SBMA motor neurons from 5α-dihydrotestosterone-induced toxicity. Moreover, genetic mutation of the FXXLF motif prevented AR aggregation and 5α-dihydrotestosterone toxicity. Finally, selective androgen receptor modulators, which prevent the N/C interaction, ameliorated AR aggregation and toxicity while maintaining AR function, highlighting a novel therapeutic strategy to prevent the SBMA phenotype while retaining AR transcriptional function. PMID:20826791

PDE4 and mAKAPβ are nodal organizers of β2-ARs nuclear PKA signaling in cardiac myocytes.

PubMed

Bedioune, Ibrahim; Lefebvre, Florence; Lechêne, Patrick; Varin, Audrey; Domergue, Valérie; Kapiloff, Michael S; Fischmeister, Rodolphe; Vandecasteele, Grégoire

2018-05-03

β1- and β2-adrenergic receptors (β-ARs) produce different acute contractile effects on the heart partly because they impact on different cytosolic pools of cAMP-dependent protein kinase (PKA). They also exert different effects on gene expression but the underlying mechanisms remain unknown. The aim of this study was to understand the mechanisms by which β1- and β2-ARs regulate nuclear PKA activity in cardiomyocytes. We used cytoplasmic and nuclear targeted biosensors to examine cAMP signals and PKA activity in adult rat ventricular myocytes upon selective β1- or β2-ARs stimulation. Both β1- and β2-AR stimulation increased cAMP and activated PKA in the cytoplasm. While the two receptors also increased cAMP in the nucleus, only β1-ARs increased nuclear PKA activity and up-regulated the PKA target gene and pro-apoptotic factor, inducible cAMP element repressor (ICER). Inhibition of PDE4, but not Gi, PDE3, GRK2 nor caveolae disruption disclosed nuclear PKA activation and ICER induction by β2-ARs. Both nuclear and cytoplasmic PKI prevented nuclear PKA activation and ICER induction by β1-ARs, indicating that PKA activation outside the nucleus is required for subsequent nuclear PKA activation and ICER mRNA expression. Cytoplasmic PKI also blocked ICER induction by β2-AR stimulation (with concomitant PDE4 inhibition). However, in this case nuclear PKI decreased ICER up-regulation by only 30%, indicating that other mechanisms are involved. Down-regulation of mAKAPβ partially inhibited nuclear PKA activation upon β1-AR stimulation, and drastically decreased nuclear PKA activation upon β2-AR stimulation in the presence of PDE4 inhibition. β1- and β2-ARs differentially regulate nuclear PKA activity and ICER expression in cardiomyocytes. PDE4 insulates a mAKAPβ-targeted PKA pool at the nuclear envelope that prevents nuclear PKA activation upon β2-AR stimulation.

14-3-3η Amplifies Androgen Receptor Actions in Prostate Cancer

PubMed Central

Titus, Mark A.; Tan, Jiann-an; Gregory, Christopher W.; Ford, O. Harris; Subramanian, Romesh R.; Fu, Haian; Wilson, Elizabeth M.; Mohler, James L.; French, Frank S.

2009-01-01

Purpose Androgen receptor (AR) abundance and AR-regulated gene expression in castration-recurrent prostate cancer (CaP) are indicative of AR activation in the absence of testicular androgen. AR transactivation of target genes in castration-recurrent CaP occurs in part through mitogen signaling that amplifies the actions of AR and its coregulators. Herein we report on the role of 14-3-3η in AR action. Experimental Design and Results AR and 14-3-3η co-localized in COS cell nuclei with and without androgen and 14-3-3η promoted AR nuclear localization in the absence of androgen. 14-3-3η interacted with AR in cell-free binding and coimmunoprecipitation assays. In the recurrent human CaP cell line, CWR-R1, native endogenous AR transcriptional activation was stimulated by 14-3-3η at low DHT concentrations and was increased by EGF. Moreover, the DHT and EGF dependent increase in AR transactivation was inhibited by a dominant negative 14-3-3η. In the CWR22 CaP xenograft model, 14-3-3η expression was increased by androgen, suggesting a feed-forward mechanism that potentiates both 14-3-3η and AR actions. 14-3-3η mRNA and protein decreased following castration of tumor bearing mice and increased in tumors of castrate mice after treatment with testosterone. CWR22 tumors that recurred 5 months after castration contained 14-3-3η levels similar to the androgen-stimulated tumors removed before castration. In a human prostate tissue microarray of clinical specimens, 14-3-3η localized with AR in nuclei and the similar amounts expressed in castration-recurrent CaP, androgen-stimulated CaP and benign prostatic hyperplasia were consistent with AR activation in recurrent CaP. Conclusion 14-3-3η enhances androgen and mitogen induced AR transcriptional activity in castration-recurrent CaP. PMID:19996220

β-Adrenergic Stimulation Induces Histone Deacetylase 5 (HDAC5) Nuclear Accumulation in Cardiomyocytes by B55α-PP2A-Mediated Dephosphorylation.

PubMed

Weeks, Kate L; Ranieri, Antonella; Karaś, Agnieszka; Bernardo, Bianca C; Ashcroft, Alexandra S; Molenaar, Chris; McMullen, Julie R; Avkiran, Metin

2017-03-25

Class IIa histone deacetylase (HDAC) isoforms such as HDAC5 are critical signal-responsive repressors of maladaptive cardiomyocyte hypertrophy, through nuclear interactions with transcription factors including myocyte enhancer factor-2. β-Adrenoceptor (β-AR) stimulation, a signal of fundamental importance in regulating cardiac function, has been proposed to induce both phosphorylation-independent nuclear export and phosphorylation-dependent nuclear accumulation of cardiomyocyte HDAC5. The relative importance of phosphorylation at Ser259/Ser498 versus Ser279 in HDAC5 regulation is also controversial. We aimed to determine the impact of β-AR stimulation on the phosphorylation, localization, and function of cardiomyocyte HDAC5 and delineate underlying molecular mechanisms. A novel 3-dimensional confocal microscopy method that objectively quantifies the whole-cell nuclear/cytoplasmic distribution of green fluorescent protein tagged HDAC5 revealed the β-AR agonist isoproterenol to induce β 1 -AR-mediated and protein kinase A-dependent HDAC5 nuclear accumulation in adult rat cardiomyocytes, which was accompanied by dephosphorylation at Ser259/279/498. Mutation of Ser259/Ser498 to Ala promoted HDAC5 nuclear accumulation and myocyte enhancer factor-2 inhibition, whereas Ser279 ablation had no such effect and did not block isoproterenol-induced nuclear accumulation. Inhibition of the Ser/Thr phosphatase PP2A blocked isoproterenol-induced HDAC5 dephosphorylation. Co-immunoprecipitation revealed a specific interaction of HDAC5 with the PP2A targeting subunit B55α, as well as catalytic and scaffolding subunits, which increased >3-fold with isoproterenol. Knockdown of B55α in neonatal cardiomyocytes attenuated isoproterenol-induced HDAC5 dephosphorylation. β-AR stimulation induces HDAC5 nuclear accumulation in cardiomyocytes by a mechanism that is protein kinase A-dependent but requires B55α-PP2A-mediated dephosphorylation of Ser259/Ser498 rather than protein kinase A-mediated phosphorylation of Ser279. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Male hormones activate EphA2 to facilitate Kaposi’s sarcoma-associated herpesvirus infection: Implications for gender disparity in Kaposi’s sarcoma

PubMed Central

Deng, Zhaohui; Liang, Deguang; Zhou, Xin; Sun, Rui

2017-01-01

There is increasing consensus that males are more vulnerable than females to infection by several pathogens. However, the underlying mechanism needs further investigation. Here, it was showed that knockdown of androgen receptor (AR) expression or pre-treatment with 5α-dihydrotestosterone, the AR agonist, led to a considerably dysregulated Kaposi’s sarcoma-associated herpesvirus (KSHV) infection. In endothelial cells, membrane-localized AR promoted the endocytosis and nuclear trafficking of KSHV. The AR interacted with ephrin receptor A2 (EphA2) and increased its phosphorylation at residue Ser897, which was specifically upregulated upon KSHV infection. This phosphorylation resulted from the AR-mediated recruitment of Src, which resulted in the activation of p90 ribosomal S6 kinase 1 (RSK1), which directly phosphorylates EphA2 at Ser897. Finally, the EphA2-mediated entry of KSHV was abolished in a Ser897Asn EphA2 mutant. Taken together, membrane-localized AR was identified as a KSHV entry factor that cooperatively activates Src/RSK1/EphA2 signaling, which subsequently promotes KSHV infection of both endothelial and epithelial cells. PMID:28957431

Androgen Receptor Gene Polymorphisms and Alterations in Prostate Cancer: Of Humanized Mice and Men

PubMed Central

Robins, Diane M.

2011-01-01

Germline polymorphisms and somatic mutations of the androgen receptor (AR) have been intensely investigated in prostate cancer but even with genomic approaches their impact remains controversial. To assess the functional significance of AR genetic variation, we converted the mouse gene to the human sequence by germline recombination and engineered alleles to query the role of a polymorphic glutamine (Q) tract implicated in cancer risk. In a prostate cancer model, AR Q tract length influences progression and castration response. Mutation profiling in mice provides direct evidence that somatic AR variants are selected by therapy, a finding validated in human metastases from distinct treatment groups. Mutant ARs exploit multiple mechanisms to resist hormone ablation, including alterations in ligand specificity, target gene selectivity, chaperone interaction and nuclear localization. Regardless of their frequency, these variants permute normal function to reveal novel means to target wild type AR and its key interacting partners. PMID:21689727

Identification and Characterization of ART-27, a Novel Coactivator for the Androgen Receptor N Terminus

PubMed Central

Markus, Steven M.; Taneja, Samir S.; Logan, Susan K.; Li, Wenhui; Ha, Susan; Hittelman, Adam B.; Rogatsky, Inez; Garabedian, Michael J.

2002-01-01

The androgen receptor (AR) is a ligand-regulated transcription factor that stimulates cell growth and differentiation in androgen-responsive tissues. The AR N terminus contains two activation functions (AF-1a and AF-1b) that are necessary for maximal transcriptional enhancement by the receptor; however, the mechanisms and components regulating AR transcriptional activation are not fully understood. We sought to identify novel factors that interact with the AR N terminus from an androgen-stimulated human prostate cancer cell library using a yeast two-hybrid approach designed to identify proteins that interact with transcriptional activation domains. A 157-amino acid protein termed ART-27 was cloned and shown to interact predominantly with the AR153–336, containing AF-1a and a part of AF-1b, localize to the nucleus and increase the transcriptional activity of AR when overexpressed in cultured mammalian cells. ART-27 also enhanced the transcriptional activation by AR153–336 fused to the LexA DNA-binding domain but not other AR N-terminal subdomains, suggesting that ART-27 exerts its effect via an interaction with a defined region of the AR N terminus. ART-27 interacts with AR in nuclear extracts from LNCaP cells in a ligand-independent manner. Interestingly, velocity gradient sedimentation of HeLa nuclear extracts suggests that native ART-27 is part of a multiprotein complex. ART-27 is expressed in a variety of human tissues, including sites of androgen action such as prostate and skeletal muscle, and is conserved throughout evolution. Thus, ART-27 is a novel cofactor that interacts with the AR N terminus and plays a role in facilitating receptor-induced transcriptional activation. PMID:11854421

Identification and characterization of ART-27, a novel coactivator for the androgen receptor N terminus.

PubMed

Markus, Steven M; Taneja, Samir S; Logan, Susan K; Li, Wenhui; Ha, Susan; Hittelman, Adam B; Rogatsky, Inez; Garabedian, Michael J

2002-02-01

The androgen receptor (AR) is a ligand-regulated transcription factor that stimulates cell growth and differentiation in androgen-responsive tissues. The AR N terminus contains two activation functions (AF-1a and AF-1b) that are necessary for maximal transcriptional enhancement by the receptor; however, the mechanisms and components regulating AR transcriptional activation are not fully understood. We sought to identify novel factors that interact with the AR N terminus from an androgen-stimulated human prostate cancer cell library using a yeast two-hybrid approach designed to identify proteins that interact with transcriptional activation domains. A 157-amino acid protein termed ART-27 was cloned and shown to interact predominantly with the AR(153-336), containing AF-1a and a part of AF-1b, localize to the nucleus and increase the transcriptional activity of AR when overexpressed in cultured mammalian cells. ART-27 also enhanced the transcriptional activation by AR(153-336) fused to the LexA DNA-binding domain but not other AR N-terminal subdomains, suggesting that ART-27 exerts its effect via an interaction with a defined region of the AR N terminus. ART-27 interacts with AR in nuclear extracts from LNCaP cells in a ligand-independent manner. Interestingly, velocity gradient sedimentation of HeLa nuclear extracts suggests that native ART-27 is part of a multiprotein complex. ART-27 is expressed in a variety of human tissues, including sites of androgen action such as prostate and skeletal muscle, and is conserved throughout evolution. Thus, ART-27 is a novel cofactor that interacts with the AR N terminus and plays a role in facilitating receptor-induced transcriptional activation.

Inhibition of androgen receptor by decoy molecules delays progression to castration-recurrent prostate cancer.

PubMed

Myung, Jae-Kyung; Wang, Gang; Chiu, Helen H L; Wang, Jun; Mawji, Nasrin R; Sadar, Marianne D

2017-01-01

Androgen receptor (AR) is a member of the steroid receptor family and a therapeutic target for all stages of prostate cancer. AR is activated by ligand binding within its C-terminus ligand-binding domain (LBD). Here we show that overexpression of the AR NTD to generate decoy molecules inhibited both the growth and progression of prostate cancer in castrated hosts. Specifically, it was shown that lentivirus delivery of decoys delayed hormonal progression in castrated hosts as indicated by increased doubling time of tumor volume, prolonged time to achieve pre-castrate levels of serum prostate-specific antigen (PSA) and PSA nadir. These clinical parameters are indicative of delayed hormonal progression and improved therapeutic response and prognosis. Decoys reduced the expression of androgen-regulated genes that correlated with reduced in situ interaction of the AR with androgen response elements. Decoys did not reduce levels of AR protein or prevent nuclear localization of the AR. Nor did decoys interact directly with the AR. Thus decoys did not inhibit AR transactivation by a dominant negative mechanism. This work provides evidence that the AR NTD plays an important role in the hormonal progression of prostate cancer and supports the development of AR antagonists that target the AR NTD.

Inhibition of androgen receptor by decoy molecules delays progression to castration-recurrent prostate cancer

PubMed Central

Myung, Jae-Kyung; Wang, Gang; Chiu, Helen H. L.; Wang, Jun; Mawji, Nasrin R.; Sadar, Marianne D.

2017-01-01

Androgen receptor (AR) is a member of the steroid receptor family and a therapeutic target for all stages of prostate cancer. AR is activated by ligand binding within its C-terminus ligand-binding domain (LBD). Here we show that overexpression of the AR NTD to generate decoy molecules inhibited both the growth and progression of prostate cancer in castrated hosts. Specifically, it was shown that lentivirus delivery of decoys delayed hormonal progression in castrated hosts as indicated by increased doubling time of tumor volume, prolonged time to achieve pre-castrate levels of serum prostate-specific antigen (PSA) and PSA nadir. These clinical parameters are indicative of delayed hormonal progression and improved therapeutic response and prognosis. Decoys reduced the expression of androgen-regulated genes that correlated with reduced in situ interaction of the AR with androgen response elements. Decoys did not reduce levels of AR protein or prevent nuclear localization of the AR. Nor did decoys interact directly with the AR. Thus decoys did not inhibit AR transactivation by a dominant negative mechanism. This work provides evidence that the AR NTD plays an important role in the hormonal progression of prostate cancer and supports the development of AR antagonists that target the AR NTD. PMID:28306720

Prediction of sub-surface 37 Ar concentrations at locations in the Northwestern United States

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fritz, Bradley G.; Aalseth, Craig E.; Back, Henning O.

The Comprehensive Nuclear Test-Ban Treaty, which is intended to prevent nuclear weapon testing, includes a verification regime, which provides monitoring to identify potential nuclear testing. The presence of elevated 37Ar is one way to identify subsurface nuclear testing. However, the naturally occurring formation of 37Ar in the subsurface adds a complicating factor. Prediction of the naturally occurring concentration of 37Ar can help to determine if a measured 37Ar concentration is elevated. The naturally occurring 37Ar background concentration has been shown to vary between less than 1 mBq/m3 to greater than 100 mBq/m3 (Riedmann and Purtschert 2011). Here, we evaluate amore » model for predicting the average concentration of 37Ar at any depth under transient barometric pressures, and compare it with measurements. This model is shown to compare favorably with concentrations of 37Ar measured at multiple locations in the Northwestern United States.« less

Intracellular colocalization of HAP1/STBs with steroid hormone receptors and its enhancement by a proteasome inhibitor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fujinaga, Ryutaro; Takeshita, Yukio; Yoshioka, Kazuhiro

2011-07-15

The stigmoid body (STB) is a cytoplasmic inclusion containing huntingtin-associated protein 1 (HAP1), and HAP1/STB formation is induced by transfection of the HAP1 gene into cultured cells. In the present study, we examined the intracellular colocalization of HAP1/STBs with steroid hormone receptors (SHRs), including the androgen receptor (AR), estrogen receptor, glucocorticoid receptor (GR), and mineralocorticoid receptor, in COS-7 cells cotransfected with HAP1 and each receptor. We found that C-terminal ligand-binding domains of all SHRs had potential for colocalization with HAP1/STBs, whereas only AR and GR were clearly colocalized with HAP1/STBs when each full-length SHR was coexpressed with HAP1. In addition,more » it appeared that HAP1/STBs did not disrupt GR and AR functions because the receptors on HAP1/STBs maintained nuclear translocation activity in response to their specific ligands. When the cells were treated with a proteasome inhibitor, GR and AR localized outside HAP1/STBs translocated into the nucleus, whereas the receptors colocalized with HAP1/STBs persisted in their colocalization even after treatment with their ligands. Therefore, HAP1/STBs may be involved in cytoplasmic modifications of the nuclear translocation of GR and AR in a ubiquitin-proteasome system.« less

Prediction of sub-surface 37Ar concentrations at locations in the Northwestern United States.

PubMed

Fritz, Bradley G; Aalseth, Craig E; Back, Henning O; Hayes, James C; Humble, Paul H; Ivanusa, Pavlo; Mace, Emily K

2018-01-01

The Comprehensive Nuclear-Test-Ban Treaty, which is intended to prevent nuclear weapon test explosions and any other nuclear explosions, includes a verification regime, which provides monitoring to identify potential nuclear explosions. The presence of elevated 37 Ar is one way to identify subsurface nuclear explosive testing. However, the naturally occurring formation of 37 Ar in the subsurface adds a complicating factor. Prediction of the naturally occurring concentration of 37 Ar can help to determine if a measured 37 Ar concentration is elevated relative to background. The naturally occurring 37 Ar background concentration has been shown to vary between less than 1 mBq/m 3 to greater than 100 mBq/m 3 (Riedmann and Purtschert, 2011). The purpose of this work was to enhance the understanding of the naturally occurring background concentrations of 37 Ar, allowing for better interpretation of results. To that end, we present and evaluate a computationally efficient model for predicting the average concentration of 37 Ar at any depth under transient barometric pressures. Further, measurements of 37 Ar concentrations in samples collected at multiple locations are provided as validation of the concentration prediction model. The model is shown to compare favorably with concentrations of 37 Ar measured at multiple locations in the Northwestern United States. Copyright © 2017 Elsevier Ltd. All rights reserved.

Experimental investigation of differential confinement effects in a rotating helicon plasma

NASA Astrophysics Data System (ADS)

Gueroult, Renaud; Evans, Eugene; Zweben, Stewart J.; Fisch, Nathaniel J.; Levinton, Fred

2014-10-01

Although plasmas have long been considered for isotope separation, challenges presented by nuclear waste remediation and nuclear spent fuel reprocessing have recently sparked a renewed interest for high-throughput plasma based mass separation techniques. Different filter concepts relying on rotating plasmas have been proposed to address these needs. However, one of the challenges common to these concepts is the need to control the plasma rotation profile, which is generally assumed to be provided by means of dedicated electrodes. An experimental effort aiming to evaluate the practicality of these plasma filter concepts has recently been started at PPPL. For this purpose, a linear helicon plasma source is used in combination with concentric ring electrodes. Preliminary biasing experiments results indicate floating potential profiles locally suitable for mass discrimination for different gas mixtures (Ar/Ne, Ar/N2, Ar/Kr). Radially resolved spectroscopic measurements and neutral gas composition analysis at two different axial positions are being planned to assess the mass separation effect. Work supported by US DOE under Contract No. DE-AC02-09CH11466.

Analytic Validation of RNA In Situ Hybridization (RISH) for AR and AR-V7 Expression in Human Prostate Cancer

PubMed Central

Guedes, Liana B.; Morais, Carlos L.; Almutairi, Fawaz; Haffner, Michael C.; Zheng, Qizhi; Isaacs, John T.; Antonarakis, Emmanuel S.; Lu, Changxue; Tsai, Harrison; Luo, Jun; De Marzo, Angelo M.; Lotan, Tamara L.

2016-01-01

Purpose RNA expression of androgen receptor splice variants may be a biomarker of resistance to novel androgen deprivation therapies in castrate resistant prostate cancer (CRPC). We analytically validated an RNA in situ hybridization (RISH) assay for total AR and AR-V7 for use in formalin fixed paraffin embedded (FFPE) prostate tumors. Experimental Design We used prostate cell lines and xenografts to validate chromogenic RISH to detect RNA containing AR exon 1 (AR-E1, surrogate for total AR RNA species) and cryptic exon 3 (AR-CE3, surrogate for AR-V7 expression). RISH signals were quantified in FFPE primary tumors and CRPC specimens, comparing to known AR and AR-V7 status by immunohistochemistry and RT-PCR. Results The quantified RISH results correlated significantly with total AR and AR-V7 levels by RT-PCR in cell lines, xenografts and autopsy metastases. Both AR-E1 and AR-CE3 RISH signals were localized in nuclear punctae in addition to the expected cytoplasmic speckles. Compared to admixed benign glands, AR-E1 expression was significantly higher in primary tumor cells with a median fold increase of 3.0 and 1.4 in two independent cohorts (p<0.0001 and p=0.04, respectively). While AR-CE3 expression was detectable in primary prostatic tumors, levels were substantially higher in a subset of CRPC metastases and cell lines, and were correlated with AR-E1 expression. Conclusions RISH for AR-E1 and AR-CE3 is an analytically valid method to examine total AR and AR-V7 RNA levels in FFPE tissues. Future clinical validation studies are required to determine whether AR RISH is a prognostic or predictive biomarker in specific clinical contexts. PMID:27166397

Measurements of Argon-39 at the U20az underground nuclear explosion site.

PubMed

McIntyre, J I; Aalseth, C E; Alexander, T R; Back, H O; Bellgraph, B J; Bowyer, T W; Chipman, V; Cooper, M W; Day, A R; Drellack, S; Foxe, M P; Fritz, B G; Hayes, J C; Humble, P; Keillor, M E; Kirkham, R R; Krogstad, E J; Lowrey, J D; Mace, E K; Mayer, M F; Milbrath, B D; Misner, A; Morley, S M; Panisko, M E; Olsen, K B; Ripplinger, M D; Seifert, A; Suarez, R

2017-11-01

Pacific Northwest National Laboratory reports on the detection of 39 Ar at the location of an underground nuclear explosion on the Nevada Nuclear Security Site. The presence of 39 Ar was not anticipated at the outset of the experimental campaign but results from this work demonstrated that it is present, along with 37 Ar and 85 Kr in the subsurface at the site of an underground nuclear explosion. Our analysis showed that by using state-of-the-art technology optimized for radioargon measurements, it was difficult to distinguish 39 Ar from the fission product 85 Kr. Proportional counters are currently used for high-sensitivity measurement of 37 Ar and 39 Ar. Physical and chemical separation processes are used to separate argon from air or soil gas, yielding pure argon with contaminant gases reduced to the parts-per-million level or below. However, even with purification at these levels, the beta decay signature of 85 Kr can be mistaken for that of 39 Ar, and the presence of either isotope increases the measurement background level for the measurement of 37 Ar. Measured values for the 39 Ar measured at the site ranged from 36,000 milli- Becquerel/standard-cubic-meter-of-air (mBq/SCM) for shallow bore holes to 997,000 mBq/SCM from the rubble chimney from the underground nuclear explosion. Published by Elsevier Ltd.

Cross Sections of the 36Ar(d,α)34mCl, 40Ar(d,α)38Cl and 40Ar(d,p)41Ar Nuclear Reactions below 8.4 MeV

PubMed Central

Engle, J W; Severin, G W; Barnhart, T E; Knutson, L D; Nickles, R J

2011-01-01

We have measured the cross section for production of the medically interesting isotope 34mCl, along with 38Cl and 41Ar, using deuteron bombardments of 36Ar and 40Ar below 8.4 MeV. ALICE/ASH analytical codes were employed to determine the shape of nuclear excitation functions, and experiments were performed using the University of Wisconsin tandem electrostatic accelerator to irradiate thin targets of argon gas. PMID:22041299

Cross sections of the 36Ar(d,α)34mCl, 40Ar(d,α)38Cl, and 40Ar(d,p)41Ar nuclear reactions below 8.4 MeV.

PubMed

Engle, J W; Severin, G W; Barnhart, T E; Knutson, L D; Nickles, R J

2012-02-01

We have measured the cross section for production of the medically interesting isotope (34m)Cl, along with (38)Cl and (41)Ar, using deuteron bombardments of (36)Ar and (40)Ar below 8.4 MeV. ALICE/ASH analytical codes were employed to determine the shape of nuclear excitation functions, and experiments were performed using the University of Wisconsin tandem electrostatic accelerator to irradiate thin targets of argon gas. Copyright © 2011 Elsevier Ltd. All rights reserved.

Analytical Validation and Clinical Qualification of a New Immunohistochemical Assay for Androgen Receptor Splice Variant-7 Protein Expression in Metastatic Castration-resistant Prostate Cancer.

PubMed

Welti, Jonathan; Rodrigues, Daniel Nava; Sharp, Adam; Sun, Shihua; Lorente, David; Riisnaes, Ruth; Figueiredo, Ines; Zafeiriou, Zafeiris; Rescigno, Pasquale; de Bono, Johann S; Plymate, Stephen R

2016-10-01

The androgen receptor splice variant-7 (AR-V7) has been implicated in the development of castration-resistant prostate cancer (CRPC) and resistance to abiraterone and enzalutamide. To develop a validated assay for detection of AR-V7 protein in tumour tissue and determine its expression and clinical significance as patients progress from hormone-sensitive prostate cancer (HSPC) to CRPC. Following monoclonal antibody generation and validation, we retrospectively identified patients who had HSPC and CRPC tissue available for AR-V7 immunohistochemical (IHC) analysis. Nuclear AR-V7 expression was determined using IHC H score (HS) data. The change in nuclear AR-V7 expression from HSPC to CRPC and the association between nuclear AR-V7 expression and overall survival (OS) was determined. Nuclear AR-V7 expression was significantly lower in HSPC (median HS 50, interquartile range [IQR] 17.5-90) compared to CRPC (HS 135, IQR 80-157.5; p<0.0001), and in biopsy tissue taken before (HS 80, IQR 30-136.3) compared to after (HS 140, IQR 105-167.5; p=0.007) abiraterone or enzalutamide treatment. Lower nuclear AR-V7 expression at CRPC biopsy was associated with longer OS (hazard ratio 1.012, 95% confidence interval 1.004-1.020; p=0.003). While this monoclonal antibody primarily binds to AR-V7 in PC biopsy tissue, it may also bind to other proteins. We provide the first evidence that nuclear AR-V7 expression increases with emerging CRPC and is prognostic for OS, unlike antibody staining for the AR N-terminal domain. These data indicate that AR-V7 is important in CRPC disease biology; agents targeting AR splice variants are needed to test this hypothesis and further improve patient outcome from CRPC. In this study we found that levels of the protein AR-V7 were higher in patients with advanced prostate cancer. A higher level of AR-V7 identifies a group of patients who respond less well to certain prostate cancer treatments and live for a shorter period of time. Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Overexpression of nuclear AR-V7 protein in primary prostate cancer is an independent negative prognostic marker in men with high-risk disease receiving adjuvant therapy.

PubMed

Chen, Xin; Bernemann, Christof; Tolkach, Yuri; Heller, Martina; Nientiedt, Cathleen; Falkenstein, Michael; Herpel, Esther; Jenzer, Maximilian; Grüllich, Carsten; Jäger, Dirk; Sültmann, Holger; Duensing, Anette; Perner, Sven; Cronauer, Marcus V; Stephan, Carsten; Debus, Jürgen; Schrader, Andres Jan; Kristiansen, Glen; Hohenfellner, Markus; Duensing, Stefan

2018-04-01

Overexpression of the androgen receptor (AR) splice variant 7 (AR-V7) has recently been reported to be associated with resistance to antihormonal therapy. Herein, we address the question whether tumor cells with AR-V7 expression can be detected at the time of radical prostatectomy, that is, before long-term hormonal manipulation and castration resistance, and what the potential prognostic impact on the biochemical recurrence (BCR)-free survival may be. An anti-AR-V7 antibody was first validated in a training set of prostate cancer specimens by a comparison of AR-V7 protein to AR-V7 mRNA expression. We then analyzed nuclear AR-V7 protein expression in the primary tumors and lymph node metastases from 163 predominantly high-risk patients (cohort I) as well as the primary tumors from patients of a second, consecutive patient cohort (n = 238, cohort II) not selected for any clinicopathological features. Staining results were correlated to patient characteristics and BCR-free patient survival. High nuclear AR-V7 protein expression was detected in approximately 30%-40% of patients in cohort I and II at the time of radical prostatectomy. High baseline expression of nuclear AR-V7 protein was associated with an unfavorable BCR-free survival in the high-risk patient cohort I but not in the unselected consecutive cohort II. Remarkably, AR-V7 was an independent negative prognostic factor in high-risk prostate cancer patients of cohort I who were selected to receive adjuvant treatment. Prostate cancer cells with high nuclear AR-V7 protein expression can be detected in a substantial proportion of tumors at the time of radical prostatectomy. The presence of AR-V7-positive tumor cells is associated with an unfavorable prognosis for BCR-free survival in a high-risk patient cohort including a subgroup of patients selected to receive adjuvant therapy, in which AR-V7 was an independent negative prognosticator. Overexpression of nuclear AR-V7 protein hence identifies a subset of tumors with remarkably aggressive growth characteristics among clinically and histologically high-risk patients at the time of radical prostatectomy. Copyright © 2017 Elsevier Inc. All rights reserved.

Nuclear scaffold attachment stimulates, but is not essential for ARS activity in Saccharomyces cerevisiae: analysis of the Drosophila ftz SAR.

PubMed Central

Amati, B; Pick, L; Laroche, T; Gasser, S M

1990-01-01

Nuclei isolated from eukaryotic cells can be depleted of histones and most soluble nuclear proteins to isolate a structural framework called the nuclear scaffold. This structure maintains specific interactions with genomic DNA at sites known as scaffold attached regions (SARs), which are thought to be the bases of DNA loops. In both Saccharomyces cerevisiae and Schizosaccharomyces pombe, genomic ARS elements are recovered as SARs. In addition, SARs from Drosophila melanogaster bind to yeast nuclear scaffolds in vitro and a subclass of these promotes autonomous replication of plasmids in yeast. In the present report, we present fine mapping studies of the Drosophila ftz SAR, which has both SAR and ARS activities in yeast. The data establish a close relationship between the sequences involved in ARS activity and scaffold binding: ARS elements that can bind the nuclear scaffold in vitro promote more efficient plasmid replication in vivo, but scaffold association is not a strict prerequisite for ARS function. Efficient interaction with nuclear scaffolds from both yeast and Drosophila requires a minimal length of SAR DNA that contains reiteration of a narrow minor groove structure of the double helix. Images Fig. 1. Fig. 2. Fig. 3. Fig. 4. PMID:2123454

Androgen receptor antagonism drives cytochrome P450 17A1 inhibitor efficacy in prostate cancer

PubMed Central

Norris, John D.; Ellison, Stephanie J.; Baker, Jennifer G.; Stagg, David B.; Wardell, Suzanne E.; Park, Sunghee; Alley, Holly M.; Baldi, Robert M.; Yllanes, Alexander; Andreano, Kaitlyn J.; Stice, James P.; Lawrence, Scott A.; Eisner, Joel R.; Price, Douglas K.; Moore, William R.; Figg, William D.; McDonnell, Donald P.

2017-01-01

The clinical utility of inhibiting cytochrome P450 17A1 (CYP17), a cytochrome p450 enzyme that is required for the production of androgens, has been exemplified by the approval of abiraterone for the treatment of castration-resistant prostate cancer (CRPC). Recently, however, it has been reported that CYP17 inhibitors can interact directly with the androgen receptor (AR). A phase I study recently reported that seviteronel, a CYP17 lyase–selective inhibitor, ædemonstrated a sustained reduction in prostate-specific antigen in a patient with CRPC, and another study showed seviteronel’s direct effects on AR function. This suggested that seviteronel may have therapeutically relevant activities in addition to its ability to inhibit androgen production. Here, we have demonstrated that CYP17 inhibitors, with the exception of orteronel, can function as competitive AR antagonists. Conformational profiling revealed that the CYP17 inhibitor–bound AR adopted a conformation that resembled the unliganded AR (apo-AR), precluding nuclear localization and DNA binding. Further, we observed that seviteronel and abiraterone inhibited the growth of tumor xenografts expressing the clinically relevant mutation AR-F876L and that this activity could be attributed entirely to competitive AR antagonism. The results of this study suggest that the ability of CYP17 inhibitors to directly antagonize the AR may contribute to their clinical efficacy in CRPC. PMID:28463227

Discovery Proteomics Identifies a Molecular Link between the Coatomer Protein Complex I and Androgen Receptor-dependent Transcription*

PubMed Central

Hsiao, Jordy J.; Smits, Melinda M.; Ng, Brandon H.; Lee, Jinhee; Wright, Michael E.

2016-01-01

Aberrant androgen receptor (AR)-dependent transcription is a hallmark of human prostate cancers. At the molecular level, ligand-mediated AR activation is coordinated through spatial and temporal protein-protein interactions involving AR-interacting proteins, which we designate the “AR-interactome.” Despite many years of research, the ligand-sensitive protein complexes involved in ligand-mediated AR activation in prostate tumor cells have not been clearly defined. Here, we describe the development, characterization, and utilization of a novel human LNCaP prostate tumor cell line, N-AR, which stably expresses wild-type AR tagged at its N terminus with the streptavidin-binding peptide epitope (streptavidin-binding peptide-tagged wild-type androgen receptor; SBP-AR). A bioanalytical workflow involving streptavidin chromatography and label-free quantitative mass spectrometry was used to identify SBP-AR and associated ligand-sensitive cytosolic proteins/protein complexes linked to AR activation in prostate tumor cells. Functional studies verified that ligand-sensitive proteins identified in the proteomic screen encoded modulators of AR-mediated transcription, suggesting that these novel proteins were putative SBP-AR-interacting proteins in N-AR cells. This was supported by biochemical associations between recombinant SBP-AR and the ligand-sensitive coatomer protein complex I (COPI) retrograde trafficking complex in vitro. Extensive biochemical and molecular experiments showed that the COPI retrograde complex regulates ligand-mediated AR transcriptional activation, which correlated with the mobilization of the Golgi-localized ARA160 coactivator to the nuclear compartment of prostate tumor cells. Collectively, this study provides a bioanalytical strategy to validate the AR-interactome and define novel AR-interacting proteins involved in ligand-mediated AR activation in prostate tumor cells. Moreover, we describe a cellular system to study how compartment-specific AR-interacting proteins influence AR activation and contribute to aberrant AR-dependent transcription that underlies the majority of human prostate cancers. PMID:27365400

Novel Nine-Exon AR Transcripts (Exon 1/Exon 1b/Exons 2-8) in Normal and Cancerous Breast and Prostate Cells.

PubMed

Hu, Dong Gui; McKinnon, Ross A; Hulin, Julie-Ann; Mackenzie, Peter I; Meech, Robyn

2016-12-27

Nearly 20 different transcripts of the human androgen receptor (AR) are reported with two currently listed as Refseq isoforms in the NCBI database. Isoform 1 encodes wild-type AR (type 1 AR) and isoform 2 encodes the variant AR45 (type 2 AR). Both variants contain eight exons: they share common exons 2-8 but differ in exon 1 with the canonical exon 1 in isoform 1 and the variant exon 1b in isoform 2. Splicing of exon 1 or exon 1b is reported to be mutually exclusive. In this study, we identified a novel exon 1b (1b/TAG) that contains an additional TAG trinucleotide upstream of exon 1b. Moreover, we identified AR transcripts in both normal and cancerous breast and prostate cells that contained either exon 1b or 1b/TAG spliced between the canonical exon 1 and exon 2, generating nine-exon AR transcripts that we have named isoforms 3a and 3b. The proteins encoded by these new AR variants could regulate androgen-responsive reporters in breast and prostate cancer cells under androgen-depleted conditions. Analysis of type 3 AR-GFP fusion proteins showed partial nuclear localization in PC3 cells under androgen-depleted conditions, supporting androgen-independent activation of the AR. Type 3 AR proteins inhibited androgen-induced growth of LNCaP cells. Microarray analysis identified a small set of type 3a AR target genes in LNCaP cells, including genes known to modulate growth and proliferation of prostate cancer ( PCGEM1 , PEG3 , EPHA3 , and EFNB2 ) or other types of human cancers ( TOX3 , ST8SIA4 , and SLITRK3 ), and genes that are diagnostic/prognostic biomarkers of prostate cancer ( GRINA3 , and BCHE ).

Development of Selective Androgen Receptor Modulators (SARMs)

PubMed Central

Narayanan, Ramesh; Coss, Christopher C.; Dalton, James T.

2018-01-01

The Androgen Receptor (AR), a member of the steroid hormone receptor family, plays important roles in the physiology and pathology of diverse tissues. AR ligands, which include circulating testosterone and locally synthesized dihydrotestosterone, bind to and activate the AR to elicit their effects. Ubiquitous expression of the AR, metabolism and cross reactivity with other receptors limit broad therapeutic utilization of steroidal androgens. However, the discovery of selective androgen receptor modulators (SARMs) and other tissue-selective nuclear hormone receptor modulators that activate their cognate receptors in a tissue-selective manner provides an opportunity to promote the beneficial effects of androgens and other hormones in target tissues with greatly reduced unwanted side-effects. In the last two decades, significant resources have been dedicated to the discovery and biological characterization of SARMs in an effort to harness the untapped potential of the AR. SARMs have been proposed as treatments of choice for various diseases, including muscle-wasting, breast cancer, and osteoporosis. This review provides insight into the evolution of SARMs from proof-of-concept agents to the cusp of therapeutic use in less than two decades, while covering contemporary views of their mechanisms of action and therapeutic benefits. PMID:28624515

Nuclear pumped laser II

NASA Technical Reports Server (NTRS)

Deyoung, R. J.; Lee, J. H.; Pinkston, W. T.

1977-01-01

The first direct nuclear pumped laser using the He-2-(n,p) H-3 reaction is reported. Lasing took place on the 1.79 microns Ar I transition in a mixture of He-3-Ar at approximately 600 Torr total pressure. It was found that the electrically pulsed afterglow He-Ar laser had the same concentration profile as the nuclear pumped laser. As a result, nuclear lasing was also achieved in He-3-Xe (2.027 micron) and He-3-Kr (2.52 micron). Scaling of laser output with both thermal flux and total pressure as well as minority concentration has been completed. A peak output (He-3-Ar) of 3.7 watts has been achieved at a total pressure of 4 atm. Direct nuclear pumping of He-3-Ne has also been achieved. Nuclear pumping of a He-3-NF3 mixture was attempted, lasing in FI at approximately 7000 A, without success, although the potential lasing transitions appeared in spontaneous emission. Both NF3 and 238UF6 appear to quench spontaneous emission when they constitute more than 1% of the gas mixture.

Regulation of Androgen Receptor Expression Alters AMPK Phosphorylation in the Endometrium: In Vivo and In Vitro Studies in Women with Polycystic Ovary Syndrome

PubMed Central

Li, Xin; Pishdari, Bano; Cui, Peng; Hu, Min; Yang, Hong-Ping; Guo, Yan-Rong; Jiang, Hong-Yuan; Feng, Yi; Billig, Håkan; Shao, Ruijin

2015-01-01

The failure of reproductive success in polycystic ovary syndrome (PCOS) patients could be in part due to endometrial dysfunction. However, no studies have investigated any causality between androgen, androgen receptor (AR) expression, and adenosine monophosphate activated protein kinase (AMPK) activation in the endometrium under physiological and pathological conditions. In the present study, we show that 1) endometrial AR expression levels fluctuate in non-PCOS and PCOS patients during the menstrual cycle; 2) the menstrual phase-dependent alteration of p-AMPKα expression occurs in non-PCOS patients but not in PCOS patients; 3) AR expression is higher in PCOS patients than non-PCOS patients during hyperplasia while AMPKα activation (indicated by the ratio of p-AMPKα to AMPKα); and 4) co-localization of AR and Ki-67 in epithelial cell nuclei is observed in endometrial hyperplasia. Importantly, using in vitro human tissue culture and an in vivo 5α-dihydrotestosterone-treated rat model, we show that the action of androgen on AMPKα activation is likely mediated through nuclear AR, especially in epithelial cells. Collectively, we present evidence that AR expression and AMPKα activation depend on menstrual cycle phase and the presence of PCOS, and the data suggest that AR-mediated regulation of AMPKα activation might play a role in the development of endometrial hyperplasia. PMID:26681917

Preliminary study on the inhibition of nuclear internalization of Tat peptides by conjugation with a receptor-specific peptide and fluorescent dyes

NASA Astrophysics Data System (ADS)

Shen, Duanwen; Liang, Kexiang; Ye, Yunpeng; Tetteh, Elizabeth; Achilefu, Samuel

2006-02-01

Numerous studies have shown that basic Tat peptide (48-57) internalized non-specifically in cells and localized in the nucleus. However, localization of imaging agents in cellular nucleus is not desirable because of the potential mutagenesis. When conjugated to the peptides that undergo receptor-mediated endocytosis, Tat peptide could target specific cells or pathologic tissue. We tested this hypothesis by incorporating a somatostatin receptor-avid peptide (octreotate, Oct) and two different fluorescent dyes, Cypate 2 (Cy2) and fluorescein 5'-carboxlic acid (5-FAM), into the Tat-peptide sequence. In addition to the Cy2 or 5-FAM-labeled Oct conjugated to Tat peptide (Tat) to produce Tat-Oct-Cypate2 or Tat-Oct-5-FAM, we also labeled the Tat the Tat peptide with these dyes (Tat-Cy2 and Tat-5-FAM) to serve as positive control. A somatostatin receptor-positive pancreatic tumor cell line, AR42J, was used to assess cell internalization. The results show that Tat-5-FAM and Tat-Cypate2 localized in both nucleus and cytoplasm of the cells. In contrast to Tat-Oct-Cypate2, which localized in both the cytoplasm and nucleus, Tat-Oct-5-FAM internalized in the cytoplasm but not in the nucleus of AR42J cells. The internalizations were inhibited by adding non-labeled corresponding peptides, suggesting that the endocytoses of each group of labeled and the corresponding unlabeled compounds occurred through a common pathway. Thus, fluorescent probes and endocytosis complex between octreotate and somatostatin receptors in cytoplasm could control nuclear internalization of Tat peptides.

In situ dating on Mars: A new approach to the K-Ar method utilizing cosmogenic argon

NASA Astrophysics Data System (ADS)

Cassata, William S.

2014-01-01

Cosmogenic argon isotopes are produced in feldspars via nuclear reactions between cosmic rays and Ca and K atoms within the lattice. These cosmogenic isotopes can be used as proxies for K and Ca, much like nuclear reactor-derived 39Ar and 37Ar are used as proxies for K and Ca, respectively, in 40Ar/39Ar geochronology. If Ca and K are uniformly distributed, then the ratio of radiogenic 40Ar (40Ar*) to cosmogenic 38Ar or 36Ar (38Arcos or 36Arcos) is proportional to the difference between the radioisotopic and exposure ages, as well as the K/Ca ratio of the degassing phase. Thus cosmogenic, radiogenic, and trapped Ar isotopes, all of which can be measured remotely and are stable over geologic time, are sufficient to generate an isochron-like diagram from which the isotopic composition of the trapped component may be inferred. Such data also provide a means to assess the extent to which the system has remained closed with respect to 40Ar*, thereby mitigating otherwise unquantifiable uncertainties that complicate the conventional K-Ar dating method.

Casualty Estimation for Nuclear and Radiological Weapons

DTIC Science & Technology

2016-06-01

usually defined as energy deposited (joule) per unit of mass (kilogram). See gray and rad. Acute Radiation Syndrome (ARS): ARS is a serious illness...I-2 ARS Acute Radiation Syndrome BSA body surface area CBRN chemical, biological, radiological, and nuclear CONV convalescent CUT cutaneous DOW...include acute effects, which may result from internal or external radiation exposure. The severity of these effects is directly related to the dosage

Measurement of 37Ar to support technology for On-site Inspection under the Comprehensive Nuclear-Test-Ban Treaty

DOE Office of Scientific and Technical Information (OSTI.GOV)

Aalseth, Craig E.; Day, Anthony R.; Haas, Derek A.

On-Site Inspection (OSI) is a key component of the verification regime for the Comprehensive Nuclear-Test-Ban Treaty (CTBT). Measurements of radionuclide isotopes created by an underground nuclear explosion are a valuable signature of a Treaty violation. Argon-37 is produced from neutron interaction with calcium in soil, 40Ca(n,α)37Ar. For OSI, the 35-day half-life of 37Ar provides both high specific activity and sufficient time for completion of an inspection before decay limits sensitivity. This paper presents a low-background internal-source gas proportional counter with an 37Ar measurement sensitivity level equivalent to 45.1 mBq/SCM in whole air.

High levels of the AR-V7 Splice Variant and Co-Amplification of the Golgi Protein Coding YIPF6 in AR Amplified Prostate Cancer Bone Metastases.

PubMed

Djusberg, Erik; Jernberg, Emma; Thysell, Elin; Golovleva, Irina; Lundberg, Pia; Crnalic, Sead; Widmark, Anders; Bergh, Anders; Brattsand, Maria; Wikström, Pernilla

2017-05-01

The relation between androgen receptor (AR) gene amplification and other mechanisms behind castration-resistant prostate cancer (CRPC), such as expression of constitutively active AR variants and steroid-converting enzymes has been poorly examined. Specific aim was to examine AR amplification in PC bone metastases and to explore molecular and functional consequences of this, with the long-term goal of identifying novel molecular targets for treatment. Gene amplification was assessed by fluorescence in situ hybridization in cryo-sections of clinical PC bone metastases (n = 40) and by PCR-based copy number variation analysis. Whole genome mRNA expression was analyzed using H12 Illumina Beadchip arrays and specific transcript levels were quantified by qRT-PCR. Protein localization was analyzed using immunohistochemistry and confocal microscopy. The YIPF6 mRNA expression was transiently knocked down and stably overexpressed in the 22Rv1 cell line as representative for CRPC, and effects on cell proliferation, colony formation, migration, and invasion were determined in vitro. Extracellular vesicles (EVs) were isolated from cell cultures using size-exclusion chromatography and enumerated by nanoparticle tracking analysis. Protein content was identified by LC-MS/MS analysis. Blood coagulation was measured as activated partial thromboplastin time (APTT). Functional enrichment analysis was performed using the MetaCore software. AR amplification was detected in 16 (53%) of the bone metastases examined from CRPC patients (n = 30), and in none from the untreated patients (n = 10). Metastases with AR amplification showed high AR and AR-V7 mRNA levels, increased nuclear AR immunostaining, and co-amplification of genes such as YIPF6 in the AR proximity at Xq12. The YIPF6 protein was localized to the Golgi apparatus. YIPF6 overexpression in 22Rv1 cells resulted in reduced cell proliferation and colony formation, and in enhanced EV secretion. EVs from YIPF6 overproducing 22Rv1 cells were enriched for proteins involved in blood coagulation and, accordingly, decreased the APTT in a dose-dependent fashion. AR amplified CRPC bone metastases show high AR-V7 expression that probably gives resistance to AR-targeting drugs. Co-amplification of the Golgi protein coding YIPF6 gene with the AR may enhance the secretion of pro-coagulative EVs from cancer cells and thereby stimulate tumor progression and increase the coagulopathy risk in CRPC patients. Prostate 77: 625-638, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

In situ dating on Mars: A new approach to the K–Ar method utilizing cosmogenic argon

DOE PAGES

Cassata, William S.

2013-08-22

In this paper, cosmogenic argon isotopes are produced in feldspars via nuclear reactions between cosmic rays and Ca and K atoms within the lattice. These cosmogenic isotopes can be used as proxies for K and Ca, much like nuclear reactor-derived 39Ar and 37Ar are used as proxies for K and Ca, respectively, in 40Ar/ 39Ar geochronology. If Ca and K are uniformly distributed, then the ratio of radiogenic 40Ar ( 40Ar*) to cosmogenic 38Ar or 36Ar ( 38Ar cos or 36Ar cos) is proportional to the difference between the radioisotopic and exposure ages, as well as the K/Ca ratio ofmore » the degassing phase. Thus cosmogenic, radiogenic, and trapped Ar isotopes, all of which can be measured remotely and are stable over geologic time, are sufficient to generate an isochron-like diagram from which the isotopic composition of the trapped component may be inferred. Finally, such data also provide a means to assess the extent to which the system has remained closed with respect to 40Ar*, thereby mitigating otherwise unquantifiable uncertainties that complicate the conventional K–Ar dating method.« less

Genome-Wide Analysis of Androgen Receptor Targets Reveals COUP-TF1 as a Novel Player in Human Prostate Cancer

PubMed Central

Perets, Ruth; Kaplan, Tommy; Stein, Ilan; Hidas, Guy; Tayeb, Shay; Avraham, Eti; Ben-Neriah, Yinon; Simon, Itamar; Pikarsky, Eli

2012-01-01

Androgen activity plays a key role in prostate cancer progression. Androgen receptor (AR) is the main mediator of androgen activity in the prostate, through its ability to act as a transcription mediator. Here we performed a genome-wide analysis of human AR binding to promoters in the presence of an agonist or antagonist in an androgen dependent prostate cancer cell line. Many of the AR bound promoters are bound in all examined conditions while others are bound only in the presence of an agonist or antagonist. Several motifs are enriched in AR bound promoters, including the AR Response Element (ARE) half-site and recognition elements for the transcription factors OCT1 and SOX9. This suggests that these 3 factors could define a module of co-operating transcription factors in the prostate. Interestingly, AR bound promoters are preferentially located in AT rich genomic regions. Analysis of mRNA expression identified chicken ovalbumin upstream promoter-transcription factor 1 (COUP-TF1) as a direct AR target gene that is downregulated upon binding by the agonist liganded AR. COUP-TF1 immunostaining revealed nucleolar localization of COUP-TF1 in epithelium of human androgen dependent prostate cancer, but not in adjacent benign prostate epithelium. Stromal cells both in human and mouse prostate show nuclear COUP-TF1 staining. We further show that there is an inverse correlation between COUP-TF1 expression in prostate stromal cells and the rising levels of androgen with advancing puberty. This study extends the pool of recognized putative AR targets and identifies a negatively regulated target of AR – COUP-TF1 – which could possibly play a role in human prostate cancer. PMID:23056316

Genome-wide analysis of androgen receptor targets reveals COUP-TF1 as a novel player in human prostate cancer.

PubMed

Perets, Ruth; Kaplan, Tommy; Stein, Ilan; Hidas, Guy; Tayeb, Shay; Avraham, Eti; Ben-Neriah, Yinon; Simon, Itamar; Pikarsky, Eli

2012-01-01

Androgen activity plays a key role in prostate cancer progression. Androgen receptor (AR) is the main mediator of androgen activity in the prostate, through its ability to act as a transcription mediator. Here we performed a genome-wide analysis of human AR binding to promoters in the presence of an agonist or antagonist in an androgen dependent prostate cancer cell line. Many of the AR bound promoters are bound in all examined conditions while others are bound only in the presence of an agonist or antagonist. Several motifs are enriched in AR bound promoters, including the AR Response Element (ARE) half-site and recognition elements for the transcription factors OCT1 and SOX9. This suggests that these 3 factors could define a module of co-operating transcription factors in the prostate. Interestingly, AR bound promoters are preferentially located in AT rich genomic regions. Analysis of mRNA expression identified chicken ovalbumin upstream promoter-transcription factor 1 (COUP-TF1) as a direct AR target gene that is downregulated upon binding by the agonist liganded AR. COUP-TF1 immunostaining revealed nucleolar localization of COUP-TF1 in epithelium of human androgen dependent prostate cancer, but not in adjacent benign prostate epithelium. Stromal cells both in human and mouse prostate show nuclear COUP-TF1 staining. We further show that there is an inverse correlation between COUP-TF1 expression in prostate stromal cells and the rising levels of androgen with advancing puberty. This study extends the pool of recognized putative AR targets and identifies a negatively regulated target of AR - COUP-TF1 - which could possibly play a role in human prostate cancer.

Estimations of electron densities and temperatures in He-3 dominated plasmas. [in nuclear pumped lasers

NASA Technical Reports Server (NTRS)

Depaola, B. D.; Marcum, S. D.; Wrench, H. K.; Whitten, B. L.; Wells, W. E.

1979-01-01

It is very useful to have a method of estimation for electron temperature and electron densities in nuclear pumped plasmas because measurements of such quantities are very difficult. This paper describes a method, based on rate equation analysis of the ionized species in the plasma and the electron energy balance. In addition to the ionized species, certain neutral species must also be calculated. Examples are given for pure helium and a mixture of helium and argon. In the HeAr case, He(+), He2(+), He/2 3S/, Ar(+), Ar2(+), and excited Ar are evaluated.

Novel Nine-Exon AR Transcripts (Exon 1/Exon 1b/Exons 2–8) in Normal and Cancerous Breast and Prostate Cells

PubMed Central

Hu, Dong Gui; McKinnon, Ross A.; Hulin, Julie-Ann; Mackenzie, Peter I.; Meech, Robyn

2016-01-01

Nearly 20 different transcripts of the human androgen receptor (AR) are reported with two currently listed as Refseq isoforms in the NCBI database. Isoform 1 encodes wild-type AR (type 1 AR) and isoform 2 encodes the variant AR45 (type 2 AR). Both variants contain eight exons: they share common exons 2–8 but differ in exon 1 with the canonical exon 1 in isoform 1 and the variant exon 1b in isoform 2. Splicing of exon 1 or exon 1b is reported to be mutually exclusive. In this study, we identified a novel exon 1b (1b/TAG) that contains an additional TAG trinucleotide upstream of exon 1b. Moreover, we identified AR transcripts in both normal and cancerous breast and prostate cells that contained either exon 1b or 1b/TAG spliced between the canonical exon 1 and exon 2, generating nine-exon AR transcripts that we have named isoforms 3a and 3b. The proteins encoded by these new AR variants could regulate androgen-responsive reporters in breast and prostate cancer cells under androgen-depleted conditions. Analysis of type 3 AR-GFP fusion proteins showed partial nuclear localization in PC3 cells under androgen-depleted conditions, supporting androgen-independent activation of the AR. Type 3 AR proteins inhibited androgen-induced growth of LNCaP cells. Microarray analysis identified a small set of type 3a AR target genes in LNCaP cells, including genes known to modulate growth and proliferation of prostate cancer (PCGEM1, PEG3, EPHA3, and EFNB2) or other types of human cancers (TOX3, ST8SIA4, and SLITRK3), and genes that are diagnostic/prognostic biomarkers of prostate cancer (GRINA3, and BCHE). PMID:28035996

Androgen Receptor Functional Analyses by High Throughput Imaging: Determination of Ligand, Cell Cycle, and Mutation-Specific Effects

PubMed Central

Szafran, Adam T.; Szwarc, Maria; Marcelli, Marco; Mancini, Michael A.

2008-01-01

Background Understanding how androgen receptor (AR) function is modulated by exposure to steroids, growth factors or small molecules can have important mechanistic implications for AR-related disease therapies (e.g., prostate cancer, androgen insensitivity syndrome, AIS), and in the analysis of environmental endocrine disruptors. Methodology/Principal Findings We report the development of a high throughput (HT) image-based assay that quantifies AR subcellular and subnuclear distribution, and transcriptional reporter gene activity on a cell-by-cell basis. Furthermore, simultaneous analysis of DNA content allowed determination of cell cycle position and permitted the analysis of cell cycle dependent changes in AR function in unsynchronized cell populations. Assay quality for EC50 coefficients of variation were 5–24%, with Z' values reaching 0.91. This was achieved by the selective analysis of cells expressing physiological levels of AR, important because minor over-expression resulted in elevated nuclear speckling and decreased transcriptional reporter gene activity. A small screen of AR-binding ligands, including known agonists, antagonists, and endocrine disruptors, demonstrated that nuclear translocation and nuclear “speckling” were linked with transcriptional output, and specific ligands were noted to differentially affect measurements for wild type versus mutant AR, suggesting differing mechanisms of action. HT imaging of patient-derived AIS mutations demonstrated a proof-of-principle personalized medicine approach to rapidly identify ligands capable of restoring multiple AR functions. Conclusions/Significance HT imaging-based multiplex screening will provide a rapid, systems-level analysis of compounds/RNAi that may differentially affect wild type AR or clinically relevant AR mutations. PMID:18978937

Variation in the terrestrial isotopic composition and atomic weight of argon

USGS Publications Warehouse

Böhlke, John Karl

2014-01-01

The isotopic composition and atomic weight of argon (Ar) are variable in terrestrial materials. Those variations are a source of uncertainty in the assignment of standard properties for Ar, but they provide useful information in many areas of science. Variations in the stable isotopic composition and atomic weight of Ar are caused by several different processes, including (1) isotope production from other elements by radioactive decay (radiogenic isotopes) or other nuclear transformations (e.g., nucleogenic isotopes), and (2) isotopic fractionation by physical-chemical processes such as diffusion or phase equilibria. Physical-chemical processes cause correlated mass-dependent variations in the Ar isotope-amount ratios (40Ar/36Ar, 38Ar/36Ar), whereas nuclear transformation processes cause non-mass-dependent variations. While atmospheric Ar can serve as an abundant and homogeneous isotopic reference, deviations from the atmospheric isotopic ratios in other Ar occurrences limit the precision with which a standard atomic weight can be given for Ar. Published data indicate variation of Ar atomic weights in normal terrestrial materials between about 39.7931 and 39.9624. The upper bound of this interval is given by the atomic mass of 40Ar, as some samples contain almost pure radiogenic 40Ar. The lower bound is derived from analyses of pitchblende (uranium mineral) containing large amounts of nucleogenic 36Ar and 38Ar. Within this interval, measurements of different isotope ratios (40Ar/36Ar or 38Ar/36Ar) at various levels of precision are widely used for studies in geochronology, water–rock interaction, atmospheric evolution, and other fields.

Inhibitor of p52 NF-κB subunit and androgen receptor (AR) interaction reduces growth of human prostate cancer cells by abrogating nuclear translocation of p52 and phosphorylated ARser81

PubMed Central

Mehraein-Ghomi, Farideh; Church, Dawn R.; Schreiber, Cynthia L.; Weichmann, Ashley M.; Basu, Hirak S.; Wilding, George

2015-01-01

Accumulating evidence shows that androgen receptor (AR) activation and signaling plays a key role in growth and progression in all stages of prostate cancer, even under low androgen levels or in the absence of androgen in the castration-resistant prostate cancer. Sustained activation of AR under androgen-deprived conditions may be due to its interaction with co-activators, such as p52 NF-κB subunit, and/or an increase in its stability by phosphorylation that delays its degradation. Here we identified a specific inhibitor of AR/p52 interaction, AR/p52-02, via a high throughput screen based on the reconstitution of Gaussia Luciferase. We found that AR/p52-02 markedly inhibited growth of both castration-resistant C4-2 (IC50 ∼6 μM) and parental androgen-dependent LNCaP (IC50 ∼4 μM) human prostate cancer cells under low androgen conditions. Growth inhibition was associated with significantly reduced nuclear p52 levels and DNA binding activity, as well as decreased phosphorylation of AR at serine 81, increased AR ubiquitination, and decreased AR transcriptional activity as indicated by decreased prostate-specific antigen (PSA) mRNA levels in both cell lines. AR/p52-02 also caused a reduction in levels of p21WAF/CIP1, which is a direct AR targeted gene in that its expression correlates with androgen stimulation and mitogenic proliferation in prostate cancer under physiologic levels of androgen, likely by disrupting the AR signaling axis. The reduced level of cyclinD1 reported previously for this compound may be due to the reduction in nuclear presence and activity of p52, which directly regulates cyclinD1 expression, as well as the reduction in p21WAF/CIP1, since p21WAF/CIP1 is reported to stabilize nuclear cyclinD1 in prostate cancer. Overall, the data suggest that specifically inhibiting the interaction of AR with p52 and blocking activity of p52 and pARser81 may be an effective means of reducing castration-resistant prostate cancer cell growth. PMID:26622945

A Treatise on the Measurement of Radioactive Argon in the Atmosphere.

DTIC Science & Technology

1984-03-01

and 39Ar are produced continuously by cosmic - *" ray interactions with the atmosphere. The half-lives of these isotopes (35.02 days and 269 years...spectively) are long enough so that the specific activity pro- duced by cosmic - rays is at a steady-state level in the atmos- phere. These levels have been...In addition to the natural cosmic - ray production, 3 7Ar and 39Ar can also be produced artificially in nuclear reactors and nuclear explosions

Medical countermeasures for unwanted CBRN exposures: part II radiological and nuclear threats with review of recent countermeasure patents

PubMed Central

Singh, Vijay K.; Romaine, Patricia L.P.; Newman, Victoria L.; Seed, Thomas M.

2016-01-01

ABSTRACT Introduction: The global threat of a chemical, biological, radiological, or nuclear (CBRN) disaster is an important priority for all government agencies involved in domestic security and public health preparedness. Radiological/nuclear (RN) attacks or accidents have become a larger focus of the United States Food and Drug administration (US FDA) over time because of their increased likeliness. Clinical signs and symptoms of a developing acute radiation syndrome (ARS) are grouped into three sub-syndromes named for the dominant organ system affected, namely the hematopoietic (H-ARS), gastrointestinal (GI-ARS), and neurovascular systems. The availability of safe and effective countermeasures against radiological/nuclear threats currently represents a significant unmet medical need. Areas covered: This article reviews the development of RN threat medical countermeasures and highlights those specific countermeasures that have been recently patented and approved following the FDA Animal Rule. Patents for such agents from 2015 have been presented. Expert opinion: Two granulocyte colony-stimulating factor (G-CSF)-based radiation countermeasures (Neupogen® (Amgen, Thousand Oaks, CA) and Neulasta® (Amgen, Thousand Oaks, CA)) have recently been approved by the FDA for treatment of H-ARS and both these agents are radiomitigators, used after radiation exposure. To date, there are no FDA-approved radioprotectors for ARS. PMID:27610458

Bisphenol A affects androgen receptor function via multiple mechanisms.

PubMed

Teng, Christina; Goodwin, Bonnie; Shockley, Keith; Xia, Menghang; Huang, Ruili; Norris, John; Merrick, B Alex; Jetten, Anton M; Austin, Christopher P; Tice, Raymond R

2013-05-25

Bisphenol A (BPA), is a well-known endocrine disruptor compound (EDC) that affects the normal development and function of the female and male reproductive system, however the mechanisms of action remain unclear. To investigate the molecular mechanisms of how BPA may affect ten different nuclear receptors, stable cell lines containing individual nuclear receptor ligand binding domain (LBD)-linked to the β-Gal reporter were examined by a quantitative high throughput screening (qHTS) format in the Tox21 Screening Program of the NIH. The results showed that two receptors, estrogen receptor alpha (ERα) and androgen receptor (AR), are affected by BPA in opposite direction. To confirm the observed effects of BPA on ERα and AR, we performed transient transfection experiments with full-length receptors and their corresponding response elements linked to luciferase reporters. We also included in this study two BPA analogs, bisphenol AF (BPAF) and bisphenol S (BPS). As seen in African green monkey kidney CV1 cells, the present study confirmed that BPA and BPAF act as ERα agonists (half maximal effective concentration EC50 of 10-100 nM) and as AR antagonists (half maximal inhibitory concentration IC50 of 1-2 μM). Both BPA and BPAF antagonized AR function via competitive inhibition of the action of synthetic androgen R1881. BPS with lower estrogenic activity (EC50 of 2.2 μM), did not compete with R1881 for AR binding, when tested at 30 μM. Finally, the effects of BPA were also evaluated in a nuclear translocation assays using EGPF-tagged receptors. Similar to 17β-estradiol (E2) which was used as control, BPA was able to enhance ERα nuclear foci formation but at a 100-fold higher concentration. Although BPA was able to bind AR, the nuclear translocation was reduced. Furthermore, BPA was unable to induce functional foci in the nuclei and is consistent with the transient transfection study that BPA is unable to activate AR. Published by Elsevier Ireland Ltd.

Simultaneous inhibition of aryl hydrocarbon receptor (AhR) and Src abolishes androgen receptor signaling.

PubMed

Ghotbaddini, Maryam; Cisse, Keyana; Carey, Alexis; Powell, Joann B

2017-01-01

Altered c-Src activity has been strongly implicated in the development, growth, progression, and metastasis of human cancers including prostate cancer. Src is known to regulate several biological functions of tumor cells, including proliferation. There are several Src inhibitors under evaluation for clinical effectiveness but have shown little activity in monotherapy trials of solid tumors. Combination studies are being explored by in vitro analysis and in clinical trials. Here we investigate the effect of simultaneous inhibition of the aryl hydrocarbon receptor (AhR) and Src on androgen receptor (AR) signaling in prostate cancer cells. AhR has also been reported to interact with the Src signaling pathway during prostate development. c-Src protein kinase is associated with the AhR complex in the cytosol and upon ligand binding to AhR, c-Src is activated and released from the complex. AhR has also been shown to regulate AR signaling which remains functionally important in the development and progression of prostate cancer. We provide evidence that co-inhibition of AhR and Src abolish AR activity. Evaluation of total protein and cellular fractions revealed decreased pAR expression and AR nuclear localization. Assays utilizing an androgen responsive element (ARE) and qRT-PCR analysis of AR genes revealed decreased AR promoter activity and transcriptional activity in the presence of both AhR and Src inhibitors. Furthermore, co-inhibition of AhR and Src reduced the growth of prostate cancer cells compared to individual treatments. Several studies have revealed that AhR and Src individually inhibit cellular proliferation. However, this study is the first to suggest simultaneous inhibition of AhR and Src to inhibit AR signaling and prostate cancer cell growth.

NF-κB and androgen receptor variant expression correlate with human BPH progression.

PubMed

Austin, David C; Strand, Douglas W; Love, Harold L; Franco, Omar E; Jang, Alex; Grabowska, Magdalena M; Miller, Nicole L; Hameed, Omar; Clark, Peter E; Fowke, Jay H; Matusik, Robert J; Jin, Ren J; Hayward, Simon W

2016-04-01

Benign prostatic hyperplasia (BPH) is a common, chronic progressive disease. Inflammation is associated with prostatic enlargement and resistance to 5α-reductase inhibitor (5ARI) therapy. Activation of the nuclear factor-kappa B (NF-κB) pathway is linked to both inflammation and ligand-independent prostate cancer progression. NF-κB activation and androgen receptor variant (AR-V) expression were quantified in transition zone tissue samples from patients with a wide range of AUASS from incidental BPH in patients treated for low grade, localized peripheral zone prostate cancer to advanced disease requiring surgical intervention. To further investigate these pathways, human prostatic stromal and epithelial cell lines were transduced with constitutively active or kinase dead forms of IKK2 to regulate canonical NF-κB activity. The effects on AR full length (AR-FL) and androgen-independent AR-V expression as well as cellular growth and differentiation were assessed. Canonical NF-κB signaling was found to be upregulated in late versus early stage BPH, and to be strongly associated with non-insulin dependent diabetes mellitus. Elevated expression of AR-variant 7 (AR-V7), but not other AR variants, was found in advanced BPH samples. Expression of AR-V7 significantly correlated with the patient AUASS and TRUS volume. Forced activation of canonical NF-κB in human prostatic epithelial and stromal cells resulted in elevated expression of both AR-FL and AR-V7, with concomitant ligand-independent activation of AR reporters. Activation of NF-κB and over expression of AR-V7 in human prostatic epithelial cells maintained cell viability in the face of 5ARI treatment. Activation of NF-κB and AR-V7 in the prostate is associated with increased disease severity. AR-V7 expression is inducible in human prostate cells by forced activation of NF-κB resulting in resistance to 5ARI treatment, suggesting a potential mechanism by which patients may become resistant to 5ARI therapy. © 2015 Wiley Periodicals, Inc.

(234)U/(238)U signatures associated with uranium ore bodies: part 3 Koongarra.

PubMed

Lowson, Richard T

2013-04-01

The Koongarra ore body is an early Proterozoic U ore body in the Alligator Rivers U province, Northern Territory, Australia. It has surface expression with a redox front located ∼30 m below the surface. The (234)U/(238)U activity ratios (AR) for the ground water and the amorphous phase of the solid have been analysed for the ore zone and dispersion halo as a function of depth. The results display a (234)U/(238)U AR signature with depth which may be common to all U ore bodies. The (234)U/(238)U AR is depressed below secular equilibrium in the weathered material above the redox front; rises significantly above secular equilibrium in the vicinity of the redox front; and is followed by a gradual decrease with depth below the redox front. The amplitude of the profile is a function of local conditions. A model is proposed for the signature in which oxidising waters preferentially leach the (234)U sites at the redox front due to preconditioning of the (234)U sites by α recoil during the decay of (23)(8)U to (23)(4)U. Mass balance requires the solid material left behind the redox front to have a (234)U/(238)U AR reduced below 1. Local second order effects may be superimposed on the signature. The signature may have application to calibrating scenarios for nuclear waste repositories, assisting in understanding historical climates, economic evaluation of U ore bodies and U exploration. Copyright © 2012 Elsevier Ltd. All rights reserved.

Natural ³⁷Ar concentrations in soil air: implications for monitoring underground nuclear explosions.

PubMed

Riedmann, Robin A; Purtschert, Roland

2011-10-15

For on-site inspections (OSI) under the Comprehensive Nuclear-Test-Ban Treaty (CTBT) measurement of the noble gas ³⁷Ar is considered an important technique. ³⁷Ar is produced underground by neutron activation of Calcium by the reaction ⁴⁰Ca(n,α)³⁷Ar. The naturally occurring equilibrium ³⁷Ar concentration balance in soil air is a function of an exponentially decreasing production rate from cosmic ray neutrons with increasing soil depth, diffusive transport in the soil air, and radioactive decay (T(1/2): 35 days). In this paper for the first time, measurements of natural ³⁷Ar activities in soil air are presented. The highest activities of ~100 mBq m⁻³ air are 2 orders of magnitude larger than in the atmosphere and are found in 1.5-2.5 m depth. At depths > 8 m ³⁷Ar activities are < 20 mBq m⁻³ air. After identifying the main ³⁷Ar production and gas transport factors the expected global activity range distribution of ³⁷Ar in shallow subsoil (0.7 m below the surface) was estimated. In high altitude soils, with large amounts of Calcium and with low gas permeability, ³⁷Ar activities may reach values up to 1 Bq m⁻³.

The RNA-editing deaminase ADAR is involved in stress resistance of Artemia diapause embryos.

PubMed

Dai, Li; Liu, Xue-Chen; Ye, Sen; Li, Hua-Wei; Chen, Dian-Fu; Yu, Xiao-Jian; Huang, Xue-Ting; Zhang, Li; Yang, Fan; Yang, Jin-Shu; Yang, Wei-Jun

2016-11-01

The most widespread type of RNA editing, conversion of adenosine to inosine (A→I), is catalyzed by two members of the adenosine deaminase acting on RNA (ADAR) family, ADAR1 and ADAR2. These enzymes edit transcripts for neurotransmitter receptors and ion channels during adaption to changes in the physical environment. In the primitive crustacean Artemia, when maternal adults are exposed to unfavorable conditions, they release diapause embryos to withstand harsh environments. The aim of the current study was therefore to elucidate the role of ADAR of Artemia diapause embryos in resistance to stress. Here, we identified Artemia ADAR (Ar-ADAR), which harbors a putative nuclear localization sequence (NLS) and two double-stranded RNA-binding motifs (dsRBMs) in the amino-terminal region and an adenosine deaminase (AD) domain in the carboxyl-terminal region. Western blot and immunofluorescence analysis revealed that Ar-ADAR is expressed abundantly in post-diapause embryos. Artemia (n = 200, three replicates) were tested under basal and stress conditions. We found that Ar-ADAR was significantly induced in response to the stresses of salinity and heat-shock. Furthermore, in vivo knockdown of Ar-ADAR (n = 100, three replicates) by RNA interference induced formation of pseudo-diapause embryos, which lack resistance to the stresses and exhibit high levels of apoptosis. These results indicate that Ar-ADAR contributes to resistance to stress in Artemia diapause embryos.

Primary retention following nuclear recoil in β-decay: Proposed synthesis of a metastable rare gas oxide ((38)ArO4) from ((38)ClO4(-)) and the evolution of chemical bonding over the nuclear transmutation reaction path.

PubMed

Timm, Matthew J; Matta, Chérif F

2014-12-01

Argon tetroxide (ArO4) is the last member of the N=50 e(-) isoelectronic and isosteric series of ions: SiO4(4-), PO4(3-), SO4(2-), and ClO4(-). A high level computational study demonstrated that while ArO4 is kinetically stable it has a considerable positive enthalpy of formation (of ~298kcal/mol) (Lindh et al., 1999. J. Phys. Chem. A 103, pp. 8295-8302) confirming earlier predictions by Pyykkö (1990. Phys. Scr. 33, pp. 52-53). ArO4 can be expected to be difficult to synthesize by traditional chemistry due to its metastability and has not yet been synthesized at the time of writing. A computational investigation of the changes in the chemical bonding of chlorate (ClO4(-)) when the central chlorine atom undergoes a nuclear transmutation from the unstable artificial chlorine isotope (38)Cl to the stable rare argon isotope (38)Ar through β-decay, hence potentially leading to the formation of ArO4, is reported. A mathematical model is presented that allows for the prediction of yields following the recoil of a nucleus upon ejecting a β-electron. It is demonstrated that below a critical angle between the ejected β-electron and that of the accompanying antineutrino their respective linear momentums can cancel to such an extent as imparting a recoil to the daughter atom insufficient for breaking the Ar-O bond. As a result, a primary retention yield of ~1% of ArO4 is predicted following the nuclear disintegration. The study is conducted at the quadratic configuration interaction with single and double excitations [QCISD/6-311+G(3df)] level of theory followed by an analysis of the electron density by the quantum theory of atoms in molecules (QTAIM). Crossed potential energy surfaces (PES) were used to construct a PES from the metastable ArO4 ground singlet state to the Ar-O bond dissociation product ArO3+O((3)P) from which the predicted barrier to dissociation is ca. 22kcal/mol and the exothermic reaction energy is ca. 28kcal/mol [(U)MP2/6-311+G(d)]. Copyright © 2014 Elsevier Ltd. All rights reserved.

Timing of strain localization in high-pressure low-temperature shear zones: The argon isotopic record

NASA Astrophysics Data System (ADS)

Laurent, Valentin; Scaillet, Stéphane; Jolivet, Laurent; Augier, Romain

2017-04-01

The complex interplay between rheology, temperature and deformation profoundly influences how crustal-scale shear zones form and then evolve across a deforming lithosphere. Understanding early exhumation processes in subduction zones requires quantitative age constraints on the timing of strain localization within high-pressure shear zones. Using both the in situ laser ablation and conventional step-heating 40Ar/39Ar dating (on phengite single grains and populations) methods, this study aims at quantifying the duration of ductile deformation and the timing of strain localization within HP-LT shear zones of the Cycladic Blueschist Unit (CBU, Greece). The rate of this progressive strain localization is unknown, and in general, poorly known in similar geological contexts. Critical to retrieve realistic estimates of rates of strain localization during exhumation, dense 40Ar/39Ar age transects were sampled along shear zones recently identified on Syros and Sifnos islands. There, field observations suggest that deformation progressively localized downward in the CBU during exhumation. In parallel, these shear zones are characterized by different degrees of retrogression from blueschist-facies to greenschist-facies P-T conditions overprinting eclogite-facies record throughout the CBU. Results show straightforward correlations between the degree of retrogression, the finite strain intensity and 40Ar/39Ar ages; the most ductilely deformed and retrograded rocks yielded the youngest 40Ar/39Ar ages. The possible effects of strain localization during exhumation on the record of the argon isotopic system in HP-LT shear zones are addressed. Our results show that strain has localized in shear zones over a 30 Ma long period and that individual shear zones evolve during 7-15 Ma. We also discuss these results at small-scale to see whether deformation and fluid circulations, channelled within shear bands, can homogenize chemical compositions and reset the 40Ar/39Ar isotopic record. This study brings new perspective on the process of strain localization through the dating of structures along strain gradients, especially on possible variation of rates of localisation through the entire exhumation history.

Nuclear Data Sheets for A = 230

DOE Office of Scientific and Technical Information (OSTI.GOV)

Browne, E.; Tuli, J. K.

The evaluators present in this publication spectroscopic data and level schemes from radioactive decay and nuclear reactions for all isobars with mass number A=230. This evaluation includes the first experimental evidence of 230Am, produced through the 197Au(40Ar,3n)234Bk (α decay to 230Am) reaction, E(40Ar)=188.4 MeV (2003MoZX).

Aldose reductase mediates retinal microglia activation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chang, Kun-Che; Shieh, Biehuoy; Petrash, J. Mark, E-mail: mark.petrash@ucdenver.edu

Retinal microglia (RMG) are one of the major immune cells in charge of surveillance of inflammatory responses in the eye. In the absence of an inflammatory stimulus, RMG reside predominately in the ganglion layer and inner or outer plexiform layers. However, under stress RMG become activated and migrate into the inner nuclear layer (INL) or outer nuclear layer (ONL). Activated RMG in cell culture secrete pro-inflammatory cytokines in a manner sensitive to downregulation by aldose reductase inhibitors. In this study, we utilized CX3CR1{sup GFP} mice carrying AR mutant alleles to evaluate the role of AR on RMG activation and migrationmore » in vivo. When tested on an AR{sup WT} background, IP injection of LPS induced RMG activation and migration into the INL and ONL. However, this phenomenon was largely prevented by AR inhibitors or in AR null mice, or was exacerbated in transgenic mice that over-express AR. LPS-induced increases in ocular levels of TNF-α and CX3CL-1 in WT mice were substantially lower in AR null mice or were reduced by AR inhibitor treatment. These studies demonstrate that AR expression in RMG may contribute to the proinflammatory phenotypes common to various eye diseases such as uveitis and diabetic retinopathy. - Highlights: • AR inhibition prevents retinal microglial activation. • Endotoxin-induced ocular cytokine production is reduced in AR null mice. • Overexpression of AR spontaneously induces retinal microglial activation.« less

The Role of Tropical Moisture Export on Atmospheric River Intensity

NASA Astrophysics Data System (ADS)

Hu, H.; Dominguez, F.

2017-12-01

There has been considerable debate regarding the relative importance of tropical moisture export (TME) and local evapotranspiration on the total moisture associated with atmospheric rivers (ARs). While case studies have related TME signatures with some extreme ARs affecting the U.S. West Coast, no robust relationship between them has been established. In this study, our goal is to quantify the role of TME on AR-related precipitation intensity. From a total of 244 identified ARs that have affected the U.S. Northwest Coast in winters of 1979 to 2016, we are focusing on a subset of 37 ARs with TME features (TME-ARs). These TME-ARs are identified using vapor-weighted wind vectors to back-track ARs 3 days before they reach the Northwest Coast. If their back-trajectories reach latitudes south of 25°N, the AR is labeled as a TME-AR. Compared with the rest of ARs without TME features, TME-ARs are associated with higher vertically integrated vapor transport (IVT) and greater precipitation intensity. At the same time, they also span a wide range of precipitation intensity and thus allow an examination of the TME effect on a full spectrum of AR intensity. To quantify the effect of TME on AR-related precipitable water and precipitation, we simulate the 37 TME-ARs using the tool of water vapor tracer in WRF model (WRF-WVT) to tag the moisture evaporated from latitudes lower than 25°N. Consequently, the total moisture can be separated into that from TME and that from midlatitude evaporation. Our analysis shows that as the AR gets stronger in terms of total precipitable water and precipitation, there is a significant increase of the contribution from TME to total precipitable water. Similarly, the contribution from TME to AR precipitation also increases but with a weaker correlation. Both of them suggest an increasing role of TME on more intense ARs. We also find a higher efficiency of TME moisture being converted to precipitation than that from local sources. However, this efficiency decreases when AR precipitation intensity increases, suggesting an increasing role of local (midlatitude) evaporation in generating precipitation. This is probably due to the thermodynamic changes associated with TME, which enhances local circulation and thus local moisture recycling.

Augmented reality in gynecologic surgery: evaluation of potential benefits for myomectomy in an experimental uterine model.

PubMed

Bourdel, Nicolas; Collins, Toby; Pizarro, Daniel; Bartoli, Adrien; Da Ines, David; Perreira, Bruno; Canis, Michel

2017-01-01

Augmented Reality (AR) is a technology that can allow a surgeon to see subsurface structures. This works by overlaying information from another modality, such as MRI and fusing it in real time with the endoscopic images. AR has never been developed for a very mobile organ like the uterus and has never been performed for gynecology. Myomas are not always easy to localize in laparoscopic surgery when they do not significantly change the surface of the uterus, or are at multiple locations. To study the accuracy of myoma localization using a new AR system compared to MRI-only localization. Ten residents were asked to localize six myomas (on a uterine model into a laparoscopic box) when either using AR or in conditions that simulate a standard method (only the MRI was available). Myomas were randomly divided in two groups: the control group (MRI only, AR not activated) and the AR group (AR activated). Software was used to automatically measure the distance between the point of contact on the uterine surface and the myoma. We compared these distances to the true shortest distance to obtain accuracy measures. The time taken to perform the task was measured, and an assessment of the complexity was performed. The mean accuracy in the control group was 16.80 mm [0.1-52.2] versus 0.64 mm [0.01-4.71] with AR. In the control group, the mean time to perform the task was 18.68 [6.4-47.1] s compared to 19.6 [3.9-77.5] s with AR. The mean score of difficulty (evaluated for each myoma) was 2.36 [1-4] versus 0.87 [0-4], respectively, for the control and the AR group. We developed an AR system for a very mobile organ. This is the first user study to quantitatively evaluate an AR system for improving a surgical task. In our model, AR improves localization accuracy.

Regulation of AR Degradation and Function by Ubiquitylation

DTIC Science & Technology

2015-10-01

ubiquitylation and degradation remain to be established. Newly synthesized AR associates with an HSP90 chaperone complex, and an HSP90 associated E3 ubiquitin ...clearly additional cytoplasmic and/or nuclear ubiquitin ligases that regulate the normal turnover and degradation of the liganded AR. Indeed, multiple... ubiquitin ligases have been reported to interact with AR and regulate its transcriptional activities and/or degradation. Moreover, previous studies

Nuclear Data Sheets for A = 230

DOE Office of Scientific and Technical Information (OSTI.GOV)

Browne, E.; Tuli, J.K.

The evaluators present in this publication spectroscopic data and level schemes from radioactive decay and nuclear reactions for all isobars with mass number A=230. This evaluation includes the first experimental evidence of {sup 230}Am, produced through the {sup 197}Au({sup 40}Ar,3n){sup 234}Bk ({alpha} decay to {sup 230}Am) reaction, E({sup 40}Ar)=188.4 MeV (2003MoZX).

The RNA binding protein Ars2 supports hematopoiesis at multiple levels.

PubMed

Elahi, Seerat; Egan, Shawn M; Holling, G Aaron; Kandefer, Rachel L; Nemeth, Michael J; Olejniczak, Scott H

2018-05-15

Recent biochemical characterization of Arsenic resistance protein 2 (Ars2) has established it as central to determining the fate of nascent RNA polymerase II (RNAPII) transcripts. Through interactions with the nuclear 5'-7-methylguanosine (7mG) cap binding complex (CBC), Ars2 promotes co-transcriptional processing coupled with nuclear export or degradation of several classes of RNAPII transcripts, allowing for gene expression programs that facilitate rapid and sustained proliferation of immortalized cells in culture. However, rapidly dividing cells in culture do not represent the physiological condition of the vast majority of cells in an adult mammal. To examine functions of Ars2 in a physiological setting we generated inducible Ars2 knockout mice and found that deletion of Ars2 from adult mice resulted in defective hematopoiesis in bone marrow and thymus. Importantly, only some of this defect could be explained by the requirement of Ars2 for rapid proliferation, which we found to be cell-type specific in vivo. Rather Ars2 was required for survival of developing thymocytes and for limiting differentiation of bone marrow resident long-term hematopoietic stem cells (LT-HSCs). As a result, Ars2 knockout led to rapid thymic involution and loss of the ability of mice to regenerate peripheral blood following myeloablation. These in vivo data demonstrate that Ars2 expression is important at several steps of hematopoiesis, likely because Ars2 acts on gene expression programs underlying essential cell fate decisions such as the decision to die, to proliferate, or to differentiate. Copyright © 2018. Published by Elsevier Inc.

TBECH, 1,2-dibromo-4-(1,2 dibromoethyl) cyclohexane, alters androgen receptor regulation in response to mutations associated with prostate cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kharlyngdoh, Joubert Banjop; Asnake, Solomon; Prad

Point mutations in the AR ligand-binding domain (LBD) can result in altered AR structures leading to changes of ligand specificity and functions. AR mutations associated to prostate cancer (PCa) have been shown to result in receptor activation by non-androgenic substances and anti-androgenic drugs. Two AR mutations known to alter the function of anti-androgens are the AR{sub T877A} mutation, which is frequently detected mutation in PCa tumors and the AR{sub W741C} that is rare and has been derived in vitro following exposure of cells to the anti-androgen bicalutamide. AR activation by non-androgenic environmental substances has been suggested to affect PCa progression.more » In the present study we investigated the effect of AR mutations (AR{sub W741C} and AR{sub T877A}) on the transcriptional activation following exposure of cells to an androgenic brominated flame retardant, 1,2-dibromo-4-(1,2 dibromoethyl) cyclohexane (TBECH, also named DBE-DBCH). The AR mutations resulted in higher interaction energies and increased transcriptional activation in response to TBECH diastereomer exposures. The AR{sub T877A} mutation rendered AR highly responsive to low levels of DHT and TBECH and led to increased AR nuclear translocation. Gene expression analysis showed a stronger induction of AR target genes in LNCaP cells (AR{sub T877A}) compared to T-47D cells (AR{sub WT}) following TBECH exposure. Furthermore, AR knockdown experiments confirmed the AR dependency of these responses. The higher sensitivity of AR{sub T877A} and AR{sub W741C} to low levels of TBECH suggests that cells with these AR mutations are more susceptible to androgenic endocrine disrupters. - Highlights: • TBECH, is an endocrine disrupting compound that differ in activity depending on AR structure and sequence. • TBECH interaction with the human AR-LBD containing the mutations W741C and T877A is increased compared to the wild type receptor • The mutations, W741C and T877A, are more potent than the wild type receptor at inducing AR nuclear translocation and transcriptional activation following TBECH exposure. • TBECH mediates action on androgen response genes via AR signaling.« less

Positron Annihilation Ratio Spectroscopy (PsARS) Applied to Positronium Formation Studies

DTIC Science & Technology

2010-03-01

POSITRON ANNIHILATION RATIO SPECTROSCOPY (PsARS) APPLIED TO POSITRONIUM FORMATION STUDIES THESIS...AFIT/GNE/ENP/10-M07 POSITRON ANNIHILATION RATIO SPECTROSCOPY (PsARS) APPLIED TO POSITRONIUM FORMATION STUDIES ...lifetime studies in local electric field experiments. High local electric fields can polarize a positron -electron pair, which may result in an extended

LaRC results on nuclear pumped noble gas lasers

NASA Technical Reports Server (NTRS)

Deyoung, R. J.

1979-01-01

The recent experiment and theoretical results obtained for noble gas nuclear laser systems are presented. It is shown that the noble gas lasers are among the easiest systems to pump by nuclear excitation and as a result, all of the noble gases except He have lased under nuclear excitation. The noble gas systems are not ideal for high-power applications but they do give valuable insight into the operation and pumping mechanisms associated with nuclear lasers. At present, the Ar-Xe system is the best noble gas candidate for (U-235)F6 pumping. It appears that the quenching of Ar-Xe lasing is a result of the fluorine and not the uranium or fission fragments themselves. Thus, to achieve lasing with UF6, a fluorine compatible system must be found.

Adenosine A2A Receptor in the Monkey Basal Ganglia: Ultrastructural Localization and Colocalization With the Metabotropic Glutamate Receptor 5 in the Striatum

PubMed Central

Bogenpohl, James W.; Ritter, Stefanie L.; Hall, Randy A.; Smith, Yoland

2012-01-01

The adenosine A2A receptor (A2AR) is a potential drug target for the treatment of Parkinson’s disease and other neurological disorders. In rodents, the therapeutic efficacy of A2AR modulation is improved by concomitant modulation of the metabotropic glutamate receptor 5 (mGluR5). To elucidate the anatomical substrate(s) through which these therapeutic benefits could be mediated, pre-embedding electron microscopy immunohistochemistry was used to conduct a detailed, quantitative ultrastructural analysis of A2AR localization in the primate basal ganglia and to assess the degree of A2AR/mGluR5 colocalization in the striatum. A2AR immunoreactivity was found at the highest levels in the striatum and external globus pallidus (GPe). However, the monkey, but not the rat, substantia nigra pars reticulata (SNr) also harbored a significant level of neuropil A2AR immunoreactivity. At the electron microscopic level, striatal A2AR labeling was most commonly localized in postsynaptic elements (58% ± 3% of labeled elements), whereas, in the GPe and SNr, the labeling was mainly presynaptic (71% ± 5%) or glial (27% ± 6%). In both striatal and pallidal structures, putative inhibitory and excitatory terminals displayed A2AR immunoreactivity. Striatal A2AR/mGluR5 colocalization was commonly found; 60–70% of A2AR-immunoreactive dendrites or spines in the monkey striatum coexpress mGluR5. These findings provide the first detailed account of the ultrastructural localization of A2AR in the primate basal ganglia and demonstrate that A2AR and mGluR5 are located to interact functionally in dendrites and spines of striatal neurons. Together, these data foster a deeper understanding of the substrates through which A2AR could regulate primate basal ganglia function and potentially mediate its therapeutic effects in parkinsonism. PMID:21858817

Mantle rare gas relative abundances in a steady-state mass transport model

NASA Technical Reports Server (NTRS)

Porcelli, D.; Wasserburg, G. J.

1994-01-01

A model for He and Xe was presented previously which incorporates mass transfer of rare gases from an undegassed lower mantle (P) and the atmosphere into a degassed upper mantle (D). We extend the model to include Ne and Ar. Model constraints on rare gas relative abundances within P are derived. Discussions of terrestrial volatile acquisition have focused on the rare gas abundance pattern of the atmosphere relative to meteoritic components, and the pattern of rare gases still trapped in the Ear,th is important in identifying volatile capture and loss processes operating during Earth formation. The assumptions and principles of the model are discussed in Wasserburg and Porcelli (this volume). For P, the concentrations in P of the decay/nuclear products 4 He, 21 Ne, 40 Ar, and 136 Xe can be calculated from the concentrations of the parent elements U, Th, K, and Pu. The total concentration of the daughter element in P is proportional to the isotopic shifts in P. For Ar, ((40)Ar/(36)Ar)p - ((40)Ar/(36)Ar)o =Delta (exp 40) p= 40 Cp/(exp 36)C where(i)C(sub j) the concentration of isotope i in j. In D, isotope compositions are the result of mixing rare gases from P, decay/nuclear products generated in the upper mantle, and subducted rare gases (for Ar and Xe).

Mathematical simulation of the amplification of 1790-nm laser radiation in a nuclear-excited He - Ar plasma containing nanoclusters of uranium compounds

NASA Astrophysics Data System (ADS)

Kosarev, V. A.; Kuznetsova, E. E.

2014-02-01

The possibility of applying dusty active media in nuclearpumped lasers has been considered. The amplification of 1790-nm radiation in a nuclear-excited dusty He - Ar plasma is studied by mathematical simulation. The influence of nanoclusters on the component composition of the medium and the kinetics of the processes occurring in it is analysed using a specially developed kinetic model, including 72 components and more than 400 reactions. An analysis of the results indicates that amplification can in principle be implemented in an active laser He - Ar medium containing 10-nm nanoclusters of metallic uranium and uranium dioxide.

Alteration of natural (37)Ar activity concentration in the subsurface by gas transport and water infiltration.

PubMed

Guillon, Sophie; Sun, Yunwei; Purtschert, Roland; Raghoo, Lauren; Pili, Eric; Carrigan, Charles R

2016-05-01

High (37)Ar activity concentration in soil gas is proposed as a key evidence for the detection of underground nuclear explosion by the Comprehensive Nuclear Test-Ban Treaty. However, such a detection is challenged by the natural background of (37)Ar in the subsurface, mainly due to Ca activation by cosmic rays. A better understanding and improved capability to predict (37)Ar activity concentration in the subsurface and its spatial and temporal variability is thus required. A numerical model integrating (37)Ar production and transport in the subsurface is developed, including variable soil water content and water infiltration at the surface. A parameterized equation for (37)Ar production in the first 15 m below the surface is studied, taking into account the major production reactions and the moderation effect of soil water content. Using sensitivity analysis and uncertainty quantification, a realistic and comprehensive probability distribution of natural (37)Ar activity concentrations in soil gas is proposed, including the effects of water infiltration. Site location and soil composition are identified as the parameters allowing for a most effective reduction of the possible range of (37)Ar activity concentrations. The influence of soil water content on (37)Ar production is shown to be negligible to first order, while (37)Ar activity concentration in soil gas and its temporal variability appear to be strongly influenced by transient water infiltration events. These results will be used as a basis for practical CTBTO concepts of operation during an OSI. Copyright © 2016 Elsevier Ltd. All rights reserved.

Control of cytoplasmic and nuclear protein kinase A by phosphodiesterases and phosphatases in cardiac myocytes

PubMed Central

Haj Slimane, Zeineb; Bedioune, Ibrahim; Lechêne, Patrick; Varin, Audrey; Lefebvre, Florence; Mateo, Philippe; Domergue-Dupont, Valérie; Dewenter, Matthias; Richter, Wito; Conti, Marco; El-Armouche, Ali; Zhang, Jin; Fischmeister, Rodolphe; Vandecasteele, Grégoire

2014-01-01

Aims The cAMP-dependent protein kinase (PKA) mediates β-adrenoceptor (β-AR) regulation of cardiac contraction and gene expression. Whereas PKA activity is well characterized in various subcellular compartments of adult cardiomyocytes, its regulation in the nucleus remains largely unknown. The aim of the present study was to compare the modalities of PKA regulation in the cytoplasm and nucleus of cardiomyocytes. Methods and results Cytoplasmic and nuclear cAMP and PKA activity were measured with targeted fluorescence resonance energy transfer probes in adult rat ventricular myocytes. β-AR stimulation with isoprenaline (Iso) led to fast cAMP elevation in both compartments, whereas PKA activity was fast in the cytoplasm but markedly slower in the nucleus. Iso was also more potent and efficient in activating cytoplasmic than nuclear PKA. Similar slow kinetics of nuclear PKA activation was observed upon adenylyl cyclase activation with L-858051 or phosphodiesterase (PDE) inhibition with 3-isobutyl-1-methylxantine. Consistently, pulse stimulation with Iso (15 s) maximally induced PKA and myosin-binding protein C phosphorylation in the cytoplasm, but marginally activated PKA and cAMP response element-binding protein phosphorylation in the nucleus. Inhibition of PDE4 or ablation of the Pde4d gene in mice prolonged cytoplasmic PKA activation and enhanced nuclear PKA responses. In the cytoplasm, phosphatase 1 (PP1) and 2A (PP2A) contributed to the termination of PKA responses, whereas only PP1 played a role in the nucleus. Conclusion Our study reveals a differential integration of cytoplasmic and nuclear PKA responses to β-AR stimulation in cardiac myocytes. This may have important implications in the physiological and pathological hypertrophic response to β-AR stimulation. PMID:24550350

Mitochondrial Fusion and ERK Activity Regulate Steroidogenic Acute Regulatory Protein Localization in Mitochondria

PubMed Central

Duarte, Alejandra; Castillo, Ana Fernanda; Podestá, Ernesto J.; Poderoso, Cecilia

2014-01-01

The rate-limiting step in the biosynthesis of steroid hormones, known as the transfer of cholesterol from the outer to the inner mitochondrial membrane, is facilitated by StAR, the Steroidogenic Acute Regulatory protein. We have described that mitochondrial ERK1/2 phosphorylates StAR and that mitochondrial fusion, through the up-regulation of a fusion protein Mitofusin 2, is essential during steroidogenesis. Here, we demonstrate that mitochondrial StAR together with mitochondrial active ERK and PKA are necessary for maximal steroid production. Phosphorylation of StAR by ERK is required for the maintenance of this protein in mitochondria, observed by means of over-expression of a StAR variant lacking the ERK phosphorylation residue. Mitochondrial fusion regulates StAR levels in mitochondria after hormone stimulation. In this study, Mitofusin 2 knockdown and mitochondrial fusion inhibition in MA-10 Leydig cells diminished StAR mRNA levels and concomitantly mitochondrial StAR protein. Together our results unveil the requirement of mitochondrial fusion in the regulation of the localization and mRNA abundance of StAR. We here establish the relevance of mitochondrial phosphorylation events in the correct localization of this key protein to exert its action in specialized cells. These discoveries highlight the importance of mitochondrial fusion and ERK phosphorylation in cholesterol transport by means of directing StAR to the outer mitochondrial membrane to achieve a large number of steroid molecules per unit of StAR. PMID:24945345

B-DIM impairs radiation-induced survival pathways independently of androgen receptor expression and augments radiation efficacy in prostate cancer.

PubMed

Singh-Gupta, Vinita; Banerjee, Sanjeev; Yunker, Christopher K; Rakowski, Joseph T; Joiner, Michael C; Konski, Andre A; Sarkar, Fazlul H; Hillman, Gilda G

2012-05-01

Increased consumption of cruciferous vegetables is associated with decreased risk in prostate cancer (PCa). The active compound in cruciferous vegetables appears to be the self dimerized product [3,3'-diindolylmethane (DIM)] of indole-3-carbinol (I3C). Nutritional grade B-DIM (absorption-enhanced) has proven safe in a Phase I trial in PCa. We investigated the anti-cancer activity of B-DIM as a new biological approach to improve the effects of radiotherapy for hormone refractory prostate cancer cells, which were either positive or negative for androgen receptor (AR) expression. B-DIM inhibited cell growth in a dose-dependent manner in both PC-3 (AR-) and C4-2B (AR+) cell lines. B-DIM was effective at increasing radiation-induced cell killing in both cell lines, independently of AR expression. B-DIM inhibited NF-κB and HIF-1α DNA activities and blocked radiation-induced activation of these transcription factors in both PC-3 and C4-2B cells. In C4-2B (AR+) cells, AR expression and nuclear localization were significantly increased by radiation. However, B-DIM abrogated the radiation-induced AR increased expression and trafficking to the nucleus, which was consistent with decreased PSA secretion. In vivo, treatment of PC-3 prostate tumors in nude mice with B-DIM and radiation resulted in significant primary tumor growth inhibition and control of metastasis to para-aortic lymph nodes. These studies demonstrate that B-DIM augments radiation-induced cell killing and tumor growth inhibition. B-DIM impairs critical survival signaling pathways activated by radiation, leading to enhanced cell killing. These novel observations suggest that B-DIM could be used as a safe compound to enhance the efficacy of radiotherapy for castrate-resistant PCa. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Androgen receptor and chemokine receptors 4 and 7 form a signaling axis to regulate CXCL12-dependent cellular motility.

PubMed

Hsiao, Jordy J; Ng, Brandon H; Smits, Melinda M; Wang, Jiahui; Jasavala, Rohini J; Martinez, Harryl D; Lee, Jinhee; Alston, Jhullian J; Misonou, Hiroaki; Trimmer, James S; Wright, Michael E

2015-03-31

Identifying cellular signaling pathways that become corrupted in the presence of androgens that increase the metastatic potential of organ-confined tumor cells is critical to devising strategies capable of attenuating the metastatic progression of hormone-naïve, organ-confined tumors. In localized prostate cancers, gene fusions that place ETS-family transcription factors under the control of androgens drive gene expression programs that increase the invasiveness of organ-confined tumor cells. C-X-C chemokine receptor type 4 (CXCR4) is a downstream target of ERG, whose upregulation in prostate-tumor cells contributes to their migration from the prostate gland. Recent evidence suggests that CXCR4-mediated proliferation and metastasis of tumor cells is regulated by CXCR7 through its scavenging of chemokine CXCL12. However, the role of androgens in regulating CXCR4-mediated motility with respect to CXCR7 function in prostate-cancer cells remains unclear. Immunocytochemistry, western blot, and affinity-purification analyses were used to study how androgens influenced the expression, subcellular localization, and function of CXCR7, CXCR4, and androgen receptor (AR) in LNCaP prostate-tumor cells. Moreover, luciferase assays and quantitative polymerase chain reaction (qPCR) were used to study how chemokines CXCL11 and CXCL12 regulate androgen-regulated genes (ARGs) in LNCaP prostate-tumor cells. Lastly, cell motility assays were carried out to determine how androgens influenced CXCR4-dependent motility through CXCL12. Here we show that, in the LNCaP prostate-tumor cell line, androgens coordinate the expression of CXCR4 and CXCR7, thereby promoting CXCL12/CXCR4-mediated cell motility. RNA interference experiments revealed functional interactions between AR and CXCR7 in these cells. Co-localization and affinity-purification experiments support a physical interaction between AR and CXCR7 in LNCaP cells. Unexpectedly, CXCR7 resided in the nuclear compartment and modulated AR-mediated transcription. Moreover, androgen-mediated cell motility correlated positively with the co-localization of CXCR4 and CXCR7 receptors, suggesting that cell migration may be linked to functional CXCR4/CXCR7 heterodimers. Lastly, CXCL12-mediated cell motility was CXCR7-dependent, with CXCR7 expression required for optimal expression of CXCR4 protein. Overall, our results suggest that inhibition of CXCR7 function might decrease the metastatic potential of organ-confined prostate cancers.

Non-cancer effects in acute radiation syndrome survivors in Ukraine.

PubMed

Belyi, David; Kovalenko, Aleksander; Bazyka, Dmitrij; Bebeshko, Vladimir

2010-06-01

The 1986 Chernobyl Nuclear Power Plant accident that occurred is known as the most severe nuclear disaster in the history of humankind. Acute radiation syndrome (ARS) was diagnosed in 237 persons but only 134 of those were confirmed, including 28 patients who died due to lethal total-body gamma-irradiation and severe skin injuries caused by beta/gamma-emitting radionuclides. A small group of ARS survivors offers an interesting observational insight pertinent to the on-going discussions about long-term non-cancer effects of ionizing radiation. This descriptive study summarizes more than 20 y of follow-up, makes attempts to offer a prognosis for the Chernobyl ARS survivors' health, and explores the link between the outcomes of interest and radiation exposure.

Temperature-Sensitive Intracellular Traffic of α2C-Adrenergic Receptor.

PubMed

Filipeanu, Catalin M

2015-01-01

α(2C)-Adrenergic receptor (α(2C)-AR) is the least characterized adrenergic receptor subtype and still very little is known about the intracellular traffic properties and pathophysiological roles of this receptor. α(2C)-AR has an atypical subcellular localization. At 37 °C, in the vascular smooth muscle cells and in fibroblasts, the receptor is poorly localized at the plasma membrane and accumulates inside the cell. Exposure to lower temperatures stimulates α(2C)-AR transport to the cell surface. This particular intracellular trafficking of α(2C)-AR is significant in the pathology of Raynaud phenomenon. In this brief review, I will present general information on the tissue distribution and cellular localization of α(2C)-AR. Also, I will discuss the mechanisms involved in the receptor transport by focusing on the trafficking motifs and on the molecular chaperones. © 2015 Elsevier Inc. All rights reserved.

The Berkeley Instrumental Neutron Generator (BINGE) for 40Ar/39Ar geochronology

NASA Astrophysics Data System (ADS)

Renne, P. R.; Becker, T. A.; Bernstein, L.; Firestone, R. B.; Kirsch, L.; Leung, K. N.; Rogers, A.; Van Bibber, K.; Waltz, C.

2014-12-01

The Berkeley Instrumental Neutron Generator (BINGE) facility is the product of a consortium involving the Berkeley Geochronology Center (BGC), the U.C. Berkeley Nuclear Engineering Dept. (UCB/NE), and Lawrence Berkeley (LBNL) and Lawrence Livermore (LLNL) National Labs. BINGE was initially designed (and funded by NSF) for 40Ar/39Ar geochronology. BINGE uses a plasma-based deuteron ion source and a self-loading Ti-surfaced target to induce deuteron-deuterium (DD) fusion via the reaction 2H(d,n)3He, producing 2.45 MeV neutrons. The limited neutron energy spectrum is aimed at reducing recoil effects, interfering nuclear reactions, and unwanted radioactive byproducts, all of which are undesirable consequences of conventional irradiation with 235U fission spectrum neutrons. Minimization of interfering reactions such as 40Ca(n,na)36Ar greatly reduces penalties for over-irradiation, enabling improved signal/background measurement of e.g. 39Ar. BINGE will also be used for a variety of nuclear physics and engineering experiments that require a high flux of monoenergetic neutrons. Neutron energies lower than 2.45 MeV can be obtained via irradiation ports within and external to polyethylene shielding. Initial commissioning produced a neutron flux of 108 n/sec/cm2 at 1 mA source current and 100 kV anode voltage, as expected. When scaled up to the 1 A source current as planned, this indicates that BINGE will achieve the design objective neutron flux of 1011 n/sec/cm2. Further progress towards this goal will be reported. Supported by NSF (grant #EAR-0960138), BGC, UCB/NE, University of California Office of the President, and DOE through LLNL under contract #DE-AC52-07NA27344 and LBNL under contract #DE-AC02-05CH11231.

A dependence of quasielastic charged-current neutrino-nucleus cross sections

NASA Astrophysics Data System (ADS)

Van Dessel, N.; Jachowicz, N.; González-Jiménez, R.; Pandey, V.; Van Cuyck, T.

2018-04-01

Background: 12C has been and is still widely used in neutrino-nucleus scattering and oscillation experiments. More recently, 40Ar has emerged as an important nuclear target for current and future experiments. Liquid argon time projection chambers (LArTPCs) possess various advantages in measuring electroweak neutrino-nucleus cross sections. Concurrent theoretical research is an evident necessity. Purpose: 40Ar is larger than 12C , and one expects nuclear effects to play a bigger role in reactions. We present inclusive differential and total cross section results for charged-current neutrino scattering on 40Ar and perform a comparison with 12C , 16O , and 56Fe targets, to find out about the A -dependent behavior of model predictions. Method: Our model starts off with a Hartree-Fock description of the nucleus, with the nucleons interacting through a mean field generated by an effective Skyrme force. Long-range correlations are introduced by means of a continuum random phase approximation approach. Further methods to improve the accuracy of model predictions are also incorporated in the calculations. Results: We present calculations for 12C , 16O , 40Ar , and 56Fe , showcasing differential cross sections over a broad range of kinematic values in the quasielastic regime. We furthermore show flux-folded results for 40Ar and we discuss the differences between nuclear responses. Conclusions: At low incoming energies and forward scattering we identify an enhancement in the 40Ar cross section compared to 12C , as well as in the high ω (low Tμ) region across the entire studied Eν range. The contribution to the folded cross section of the reaction strength at values of ω lower than 50 MeV for forward scattering is sizable.

Localization of alpha 1-adrenoceptors in rat and human hearts by immunocytochemistry.

PubMed

Schulze, W; Fu, M L

1996-01-01

The localization of the alpha 1 adrenoceptors (alpha 1-AR) in the heart tissues from rat and human and in the cultured heart cells from neonatal rats was studied by indirect immunofluorescence and postembedding electronmicroscopical immuno-gold technique. With antipeptide antibodies directed against the second extracellular loop of the human alpha 1-AR (AS sequence 192-218), this receptor was found to be localized along the sarcolemma in both human and rat hearts. Similar localization sites were detected in cultivated rat neonatal cardiomyocytes. Beside the localization in cardiomyocytes, alpha 1-AR were identified in endothelial cells of capillaries and smooth muscle cells of coronary vessels, in neuronal endings, in mast cells of cultivated heart cells but not, or in less amount in fibroblasts. Interestingly, in the right atrium of rat heart the localization of alpha 1-AR was found to be near or on atrial natriuretic factor (ANF) granules, providing the basis for the alpha-adrenergic influence on ANF release. The immunocytochemical studies further confirm and complete the findings known by using autoradiographic binding studies with specific ligands.

Immunohistochemical localization of alpha and beta adrenergic receptors in the human nasal turbinate.

PubMed

Shirasaki, Hideaki; Kanaizumi, Etsuko; Himi, Tetsuo

2016-06-01

Adrenergic receptors (ARs) include four general types (α1, α2, β1 and β2), which are found in different target tissues. α-AR agonists are commonly used for decongestant therapy of upper airway diseases. In order to clarify the roles of AR subtypes in the upper airways, we investigated the localization of these receptors by immunohistochemistry. Human turbinates were obtained after turbinectomy from 12 patients with nasal obstruction refractory to medical therapy. The specific cells expressing α- and β-AR proteins were identified by immunostaining using an anti-human AR subtype-specific antibodies (α1A-, α1D-, α2C- and β2-ARs) antibody. Immunohistochemical analysis revealed that immunoreactivities for α1D- and β2-ARs were densely distributed in submucosal glands. In contrast, immunoreactivities for α1A- and 2C-ARs were densely distributed in vascular smooth muscle. Our results suggested that adrenergic receptor (AR) subtypes had different roles in upper airway diseases, such as allergic rhinitis and nonallergic rhinitis. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Application of nuclear pumped laser to an optical self-powered neutron detector

NASA Astrophysics Data System (ADS)

Yamanaka, N.; Takahashi, H.; Iguchi, T.; Nakazawa, M.; Kakuta, T.; Yamagishi, H.; Katagiri, M.

1996-05-01

A Nuclear Pumped Laser (NPL) using 3He/Ne/Ar gas mixture is investigated for a purpose of applying to an optical self-powered neutron detector. Reactor experiments and simulations on lasing mechanism have been made to estimate the best gas pressure and mixture ratios on the threshold input power density (or thermal neutron flux) in 3He/Ne/Ar mixture. Calculational results show that the best mixture pressure is 3He/Ne/Ar=2280/60/100 Torr and thermal neutron flux threshold 5×1012 n/cm2 sec, while the reactor experiments made in the research reactor ``YAYOI'' of the University of Tokyo and ``JRR-4'' of JAERI also demonstrate that excitational efficiency is maximized in a similar gas mixture predicted by the calculation.

Activation of the cholinergic anti-inflammatory pathway ameliorates postoperative ileus in mice.

PubMed

The, Frans O; Boeckxstaens, Guy E; Snoek, Susanne A; Cash, Jenna L; Bennink, Roel; Larosa, Gregory J; van den Wijngaard, Rene M; Greaves, David R; de Jonge, Wouter J

2007-10-01

We previously showed that intestinal inflammation is reduced by electrical stimulation of the efferent vagus nerve, which prevents postoperative ileus in mice. We propose that this cholinergic anti-inflammatory pathway is mediated via alpha7 nicotinic acetylcholine receptors expressed on macrophages. The aim of this study was to evaluate pharmacologic activation of the cholinergic anti-inflammatory pathway in a mouse model for postoperative ileus using the alpha7 nicotinic acetylcholine receptor-agonist AR-R17779. Mice were pretreated with vehicle, nicotine, or AR-R17779 20 minutes before a laparotomy (L) or intestinal manipulation (IM). Twenty-four hours thereafter gastric emptying was determined using scintigraphy and intestinal muscle inflammation was quantified. Nuclear factor-kappaB transcriptional activity and cytokine production was assayed in peritoneal macrophages. Twenty-four hours after surgery IM led to a delayed gastric emptying compared with L (gastric retention: L(saline) 14% +/- 4% vs IM(saline) 38% +/- 10%, P = .04). Pretreatment with AR-R17779 prevented delayed gastric emptying (IM(AR-R17779) 15% +/- 4%, P = .03). IM elicited inflammatory cell recruitment (L(saline) 50 +/- 8 vs IM(saline) 434 +/- 71 cells/mm(2), P = .001) which was reduced by AR-R17779 pretreatment (IM(AR-R17779) 231 +/- 32 cells/mm(2), P = .04). An equimolar dose of nicotine was not tolerated. Subdiaphragmal vagotomy did not affect the anti-inflammatory properties of AR-R17779. In peritoneal macrophages, both nicotinic agonists reduced nuclear factor kappaB transcriptional activity and proinflammatory cytokine production, with nicotine being more effective than AR-R17779. AR-R17779 treatment potently prevents postoperative ileus, whereas toxicity limits nicotine administration to ineffective doses. Our data further imply that nicotinic inhibition of macrophage activation may involve other receptors in addition to alpha7 nicotinic acetylcholine receptor.

Androgen-Induced Cell Migration: Role of Androgen Receptor/Filamin A Association

PubMed Central

Castoria, Gabriella; D'Amato, Loredana; Ciociola, Alessandra; Giovannelli, Pia; Giraldi, Tiziana; Sepe, Leandra; Paolella, Giovanni; Barone, Maria Vittoria; Migliaccio, Antimo; Auricchio, Ferdinando

2011-01-01

Background Androgen receptor (AR) controls male morphogenesis, gametogenesis and prostate growth as well as development of prostate cancer. These findings support a role for AR in cell migration and invasiveness. However, the molecular mechanism involved in AR-mediated cell migration still remains elusive. Methodology/Principal Findings Mouse embryo NIH3T3 fibroblasts and highly metastatic human fibrosarcoma HT1080 cells harbor low levels of transcriptionally incompetent AR. We now report that, through extra nuclear action, AR triggers migration of both cell types upon stimulation with physiological concentrations of the androgen R1881. We analyzed the initial events leading to androgen-induced cell migration and observed that challenging NIH3T3 cells with 10 nM R1881 rapidly induces interaction of AR with filamin A (FlnA) at cytoskeleton. AR/FlnA complex recruits integrin beta 1, thus activating its dependent cascade. Silencing of AR, FlnA and integrin beta 1 shows that this ternary complex controls focal adhesion kinase (FAK), paxillin and Rac, thereby driving cell migration. FAK-null fibroblasts migrate poorly and Rac inhibition by EHT impairs motility of androgen-treated NIH3T3 cells. Interestingly, FAK and Rac activation by androgens are independent of each other. Findings in human fibrosarcoma HT1080 cells strengthen the role of Rac in androgen signaling. The Rac inhibitor significantly impairs androgen-induced migration in these cells. A mutant AR, deleted of the sequence interacting with FlnA, fails to mediate FAK activation and paxillin tyrosine phosphorylation in androgen-stimulated cells, further reinforcing the role of AR/FlnA interaction in androgen-mediated motility. Conclusions/Significance The present report, for the first time, indicates that the extra nuclear AR/FlnA/integrin beta 1 complex is the key by which androgen activates signaling leading to cell migration. Assembly of this ternary complex may control organ development and prostate cancer metastasis. PMID:21359179

Inflammation, Prostate Cancer and Negative Regulation of Androgen Receptor Expression

DTIC Science & Technology

2009-05-01

Chem. 282(32):23716-24 2. Taganov, K.D., Boldin , M.P., Chang, K.J., and Baltimore, D. (2006) NF-kappaB- dependent induction of microRNA miR-146, an...produced by the rat liver nuclear extract revealed four protein-binding sites (Fig. 5A). Site I is especially note- worthy because it includes an NF-B-like...liver nuclear extract . B, Sequence conservation of rat and mouse AR promoters with the human AR promoter at 144 to 204. An NF-B-like element in

Armenian Astronomical Society (ArAS) activities

NASA Astrophysics Data System (ADS)

Mickaelian, A. M.

2016-09-01

A review on the activities and achievements of Armenian Astronomical Society (ArAS) and Armenian astronomy in general during the last years is given. ArAS membership, ArAS electronic newsletters (ArASNews), ArAS webpage, Annual Meetings, Annual Prize for Young Astronomers (Yervant Terzian Prize) and other awards, international relations, presence in international organizations, local and international summer schools, science camps, astronomical Olympiads and other events, matters related to astronomical education, astronomical heritage, amateur astronomy, astronomy outreach and ArAS further projects are described and discussed.

Effects of androgen on immunohistochemical localization of androgen receptor and Connexin 43 in mouse ovary.

PubMed

Yang, Mei; Li, Jianhua; An, Yulin; Zhang, Shuiwen

2015-10-01

Androgens have essential roles in the regulation of follicular development and female fertility. Androgen excess is the leading defect in polycystic ovary syndrome (PCOS) patients and involved in the ovarian dysfunction. The aim of this study was to elucidate the regarding regulatory role of androgen in the follicular development of female mouse. Immunohistochemical staining and Western blot analyses were performed to detect androgen receptor (AR) and Connexin 43 (Cx43) expression in ovaries from both control and testosterone-treated group mice. In this study, localizations of AR and Cx43 were dramatically altered in testosterone-treated mouse ovaries. In addition, AR expression was significantly increased, whereas Cx43 expression was markedly decreased after testosterone treatment. Alterations of AR and Cx43 expression by testosterone with concomitant reduction of MII oocytes. Overall, these results suggest the involvement of androgen in the regulation of AR and Cx43 localizations in mouse ovary. Alterations of AR and Cx43 expression by testosterone may affect normal folliculogenesis. Together these findings will enable us to begin understanding the important roles of AR and Cx43 actions in the regulation of follicular development, as well as providing insights into the role of AR and Cx43 actions in the androgen-associated reproductive diseases such as PCOS. Copyright © 2015 Elsevier Ltd. All rights reserved.

Outreach programs in physics at Hampton University

NASA Astrophysics Data System (ADS)

Pittman, Carlane J.; Temple, Doyle A.

1996-07-01

The Department of Physics at Hampton University generates over 4.5 M dollars of external research funding annually and operates three research centers, the Nuclear High Energy Physics Research Center, the Research Center for Optical Physics, and the Center for Fusion Training and Research. An integral component of these centers is an active outreach and recruitment program led by the Associate Director for Outreach. This program includes summer internships and research mentorships, both at Hampton University and at national laboratories such as CEBAF and NASA Langley. Faculty presentations ar local area elementary schools, middle schools and high schools are also under the auspices of this program.

Vasopressin V1a receptors are present in the carotid body and contribute to the control of breathing in male Sprague-Dawley rats.

PubMed

Żera, Tymoteusz; Przybylski, Jacek; Grygorowicz, Tomasz; Kasarełło, Kaja; Podobińska, Martyna; Mirowska-Guzel, Dagmara; Cudnoch-Jędrzejewska, Agnieszka

2018-04-01

Vasopressin (AVP) maintains body homeostasis by regulating water balance, cardiovascular system and stress response. AVP inhibits breathing through central vasopressin 1a receptors (V1aRs). Chemoreceptors within carotid bodies (CBs) detect chemical and hormonal signals in the bloodstream and provide sensory input to respiratory and cardiovascular centers of the brainstem. In the study we investigated if CBs contain V1aRs and how the receptors are involved in the regulation of ventilation by AVP. We first immunostained CBs for V1aRs and tyrosine hydroxylase, a marker of chemoreceptor type I (glomus) cells. In urethane-anesthetized adult Sprague-Dawley male rats, we then measured hemodynamic and respiratory responses to systemic (intravenous) or local (carotid artery) administration of AVP prior and after systemic blockade of V1aRs. Immunostaining of CBs showed colocalization of V1aRs and tyrosine hydroxylase within glomus cells. Systemic administration of AVP increased mean arterial blood pressure (MABP) and decreased respiratory rate (RR) and minute ventilation (MV). Local administration of AVP increased MV and RR without significant changes in MABP or heart rate. Pretreatment with V1aR antagonist abolished responses to local and intravenous AVP administration. Our findings show that chemosensory cells within CBs express V1aRs and that local stimulation of the CB with AVP increases ventilation, which is contrary to systemic effects of AVP manifested by decreased ventilation. The responses are mediated by V1aRs, as blockade of the receptors prevents changes in ventilation. We hypothesize that excitatory effects of AVP within the CB provide a counterbalancing mechanism for the inhibitory effects of systemically acting AVP on the respiration. Copyright © 2018 Elsevier Inc. All rights reserved.

The Measurement of the Evaporation Residues Excitation Functions in the Fusion Reactions 144Sm (40Ar,xn) and 166Er(40Ar,xn)

NASA Astrophysics Data System (ADS)

Chernysheva, E. V.; Rodin, A. M.; Belozerov, A. V.; Dmitriev, S. N.; Gulyaev, A. V.; Gulyaeva, A. V.; Itkis, M. G.; Novoselov, A. S.; Oganessian, Yu. Ts.; Salamatin, V. S.; Stepantsov, S. V.; Vedeneev, V. Yu.; Yukhimchuk, S. A.; Krupa, L.; Kliman, J.; Motycak, S.; Sivacek, I.

2015-06-01

The evaporation residues excitation functions for the reactions 40Ar+144Sm→184Hg and 40Ar+166Er→206Rn were measured at the energies below and above the Coulomb barrier (Elab=142-207 MeV) using a mass-separator MASHA. The experimental data were compared with theoretical calculations using a Channel Coupling Model. The influence of experimental beam energy spread on the excitation functions was taking into account. It was found that structure of xn-cross sections correlate strongly with the nuclear structure of colliding nuclei.

Gate simulation of Compton Ar-Xe gamma-camera for radionuclide imaging in nuclear medicine

NASA Astrophysics Data System (ADS)

Dubov, L. Yu; Belyaev, V. N.; Berdnikova, A. K.; Bolozdynia, A. I.; Akmalova, Yu A.; Shtotsky, Yu V.

2017-01-01

Computer simulations of cylindrical Compton Ar-Xe gamma camera are described in the current report. Detection efficiency of cylindrical Ar-Xe Compton camera with internal diameter of 40 cm is estimated as1-3%that is 10-100 times higher than collimated Anger’s camera. It is shown that cylindrical Compton camera can image Tc-99m radiotracer distribution with uniform spatial resolution of 20 mm through the whole field of view.

Calibration of an Ultra-Low-Background Proportional Counter for Measuring 37Ar

DOE Office of Scientific and Technical Information (OSTI.GOV)

Seifert, Allen; Aalseth, Craig E.; Bonicalzi, Ricco

Abstract. An ultra-low-background proportional counter (ULBPC) design has been developed at Pacific Northwest National Laboratory (PNNL) using clean materials, primarily electrochemically-purified copper. This detector, along with an ultra-low-background counting system (ULBCS), was developed to complement a new shallow underground laboratory (30 meters water-equivalent) constructed at PNNL. The ULBCS design includes passive neutron and gamma shielding, along with an active cosmic-veto system. This system provides a capability for making ultra-sensitive measurements to support applications like age-dating soil hydrocarbons with 14C/3H, age-dating of groundwater with 39Ar, and soil-gas assay for 37Ar to support On-Site Inspection (OSI). On-Site Inspection is a key componentmore » of the verification regime for the Comprehensive Nuclear-Test-Ban Treaty (CTBT). Measurements of radionuclides created by an underground nuclear explosion are valuable signatures of a Treaty violation. For OSI, the 35-day half-life of 37Ar, produced from neutron interactions with calcium in soil, provides both high specific activity and sufficient time for inspection before decay limits sensitivity. This work describes the calibration techniques and analysis methods developed to enable quantitative measurements of 37Ar samples over a broad range of pressures. These efforts, along with parallel work in progress on gas chemistry separation, are expected to provide a significant new capability for 37Ar soil gas background studies.« less

Acetylation of androgen receptor by ARD1 promotes dissociation from HSP90 complex and prostate tumorigenesis

PubMed Central

Zhang, Guanyi; Qian, Chiping; Zhang, Haitao; Zabaleta, Jovanny; Liu, Wanguo

2016-01-01

Prostate cancer is an androgen receptor (AR)-driven disease and post-translational modification of AR is critical for AR activation. We previously reported that Arrest-defective protein 1 (ARD1) is an oncoprotein in prostate cancer. It acetylates and activates AR to promote prostate tumorigenesis. However, the ARD1-targeted residue within AR and the mechanisms of the acetylation event in prostate tumorigenesis remained unknown. In this study, we show that ARD1 acetylates AR at lysine 618 (K618) in vitro and in vivo. An AR construct with the charged lysine substitution by arginine (AR-618R) reduces RNA Pol II binding, AR transcriptional activity, prostate cancer cell growth, and xenograft tumor formation due to attenuation of AR nuclear translocation, whereas, construct mimicking neutral polar substitution acetylation at K618 by glutamine (AR-618Q) enhanced these effects beyond that of the wild-type AR. Mechanistically, ARD1 forms a ternary complex with AR and HSP90 in vitro and in vivo. Expression of ARD1 increases levels of AR acetylation and AR-HSP90 dissociation in a dose dependent manner. Moreover, the AR acetylation defective K618R mutant is unable to dissociate from HSP90 while the HSP90-dissociated AR is acetylated following ligand exposure. This work identifies a new mechanism for ligand-induced AR-HSP90 dissociation and AR activation. Targeting ARD1-mediated AR acetylation may be a potent intervention for AR-dependent prostate cancer therapy. PMID:27659526

JS-K, a glutathione/glutathione S-transferase-activated nitric oxide releasing prodrug inhibits androgen receptor and WNT-signaling in prostate cancer cells.

PubMed

Laschak, Martin; Spindler, Klaus-Dieter; Schrader, Andres J; Hessenauer, Andrea; Streicher, Wolfgang; Schrader, Mark; Cronauer, Marcus V

2012-03-30

Nitric oxide (NO) and its oxidative reaction products have been repeatedly shown to block steroid receptor function via nitrosation of zinc finger structures in the DNA-binding domain (DBD). In consequence NO-donors could be of special interest for the treatment of deregulated androgen receptor(AR)-signaling in castration resistant prostate cancer (CRPC). Prostate cancer (PCa) cells were treated with JS-K, a diazeniumdiolate derivate capable of generating large amounts of intracellular NO following activation by glutathione S-transferase. Generation of NO was determined indirectly by the detection of nitrate in tissue culture medium or by immunodetection of nitrotyrosine in the cytoplasm. Effects of JS-K on intracellular AR-levels were determined by western blotting. AR-dimerization was analyzed by mammalian two hybrid assay, nuclear translocation of the AR was visualized in PCa cells transfected with a green fluorescent AR-Eos fusion protein using fluorescence microscopy. Modulation of AR- and WNT-signalling by JS-K was investigated using reporter gene assays. Tumor cell proliferation following JS-K treatment was measured by MTT-Assay. The NO-releasing compound JS-K was shown to inhibit AR-mediated reporter gene activity in 22Rv1 CRPC cells. Inhibition of AR signaling was neither due to an inhibition of nuclear import nor to a reduction in AR-dimerization. In contrast to previously tested NO-donors, JS-K was able to reduce the intracellular concentration of functional AR. This could be attributed to the generation of extremely high intracellular levels of the free radical NO as demonstrated indirectly by high levels of nitrotyrosine in JS-K treated cells. Moreover, JS-K diminished WNT-signaling in AR-positive 22Rv1 cells. In line with these observations, castration resistant 22Rv1 cells were found to be more susceptible to the growth inhibitory effects of JS-K than the androgen dependent LNCaP which do not exhibit an active WNT-signaling pathway. Our results suggest that small molecules able to inhibit WNT- and AR-signaling via NO-release represent a promising platform for the development of new compounds for the treatment of CRPC.

JS-K, a glutathione/glutathione S-transferase-activated nitric oxide releasing prodrug inhibits androgen receptor and WNT-signaling in prostate cancer cells

PubMed Central

2012-01-01

Background Nitric oxide (NO) and its oxidative reaction products have been repeatedly shown to block steroid receptor function via nitrosation of zinc finger structures in the DNA-binding domain (DBD). In consequence NO-donors could be of special interest for the treatment of deregulated androgen receptor(AR)-signaling in castration resistant prostate cancer (CRPC). Methods Prostate cancer (PCa) cells were treated with JS-K, a diazeniumdiolate derivate capable of generating large amounts of intracellular NO following activation by glutathione S-transferase. Generation of NO was determined indirectly by the detection of nitrate in tissue culture medium or by immunodetection of nitrotyrosine in the cytoplasm. Effects of JS-K on intracellular AR-levels were determined by western blotting. AR-dimerization was analyzed by mammalian two hybrid assay, nuclear translocation of the AR was visualized in PCa cells transfected with a green fluorescent AR-Eos fusion protein using fluorescence microscopy. Modulation of AR- and WNT-signalling by JS-K was investigated using reporter gene assays. Tumor cell proliferation following JS-K treatment was measured by MTT-Assay. Results The NO-releasing compound JS-K was shown to inhibit AR-mediated reporter gene activity in 22Rv1 CRPC cells. Inhibition of AR signaling was neither due to an inhibition of nuclear import nor to a reduction in AR-dimerization. In contrast to previously tested NO-donors, JS-K was able to reduce the intracellular concentration of functional AR. This could be attributed to the generation of extremely high intracellular levels of the free radical NO as demonstrated indirectly by high levels of nitrotyrosine in JS-K treated cells. Moreover, JS-K diminished WNT-signaling in AR-positive 22Rv1 cells. In line with these observations, castration resistant 22Rv1 cells were found to be more susceptible to the growth inhibitory effects of JS-K than the androgen dependent LNCaP which do not exhibit an active WNT-signaling pathway. Conclusions Our results suggest that small molecules able to inhibit WNT- and AR-signaling via NO-release represent a promising platform for the development of new compounds for the treatment of CRPC. PMID:22462810

The role of DAB2IP in androgen receptor activation during prostate cancer progression.

PubMed

Wu, K; Liu, J; Tseng, S-F; Gore, C; Ning, Z; Sharifi, N; Fazli, L; Gleave, M; Kapur, P; Xiao, G; Sun, X; Oz, O K; Min, W; Alexandrakis, G; Yang, C-R; Hsieh, C-L; Wu, H-C; He, D; Xie, D; Hsieh, J-T

2014-04-10

Altered androgen-receptor (AR) expression and/or constitutively active AR are commonly associated with prostate cancer (PCa) progression. Targeting AR remains a focal point for designing new strategy of PCa therapy. Here, we have shown that DAB2IP, a novel tumor suppressor in PCa, can inhibit AR-mediated cell growth and gene activation in PCa cells via distinct mechanisms. DAB2IP inhibits the genomic pathway by preventing AR nuclear translocation or phosphorylation and suppresses the non-genomic pathway via its unique functional domain to inactivate c-Src. Also, DAB2IP is capable of suppressing AR activation in an androgen-independent manner. In addition, DAB2IP can inhibit several AR splice variants showing constitutive activity in PCa cells. In DAB2IP(-/-) mice, the prostate gland exhibits hyperplastic epithelia, in which AR becomes more active. Consistently, DAB2IP expression inversely correlates with AR activation status particularly in recurrent or metastatic PCa patients. Taken together, DAB2IP is a unique intrinsic AR modulator in normal cells, and likely can be further developed into a therapeutic agent for PCa.

Registration of BTx623ms8 - a new and easily identifiable nuclear male sterile mutant in sorghum

USDA-ARS?s Scientific Manuscript database

The USDA-ARS has released a new nuclear male sterile sorghum mutant BTx623ms8 (Registration No.xxxx, PIxxxxx). Previously, seven nuclear male sterile mutants have been reported but three are no longer available for sorghum. Here we register a new nuclear male sterile mutant from a mutagenized BTx62...

Orphan nuclear receptor TLX contributes to androgen insensitivity in castration-resistant prostate cancer via its repression of androgen receptor transcription.

PubMed

Jia, Lin; Wu, Dinglan; Wang, Yuliang; You, Wenxing; Wang, Zhu; Xiao, Lijia; Cai, Ganhui; Xu, Zhenyu; Zou, Chang; Wang, Fei; Teoh, Jeremy Yuen-Chun; Ng, Chi-Fai; Yu, Shan; Chan, Franky L

2018-03-20

The metastatic castration-resistant prostate cancer (CRPC) is a lethal form of prostate cancer, in which the expression of androgen receptor (AR) is highly heterogeneous. Indeed, lower AR expression and attenuated AR signature activity is shown in CRPC tissues, especially in the subset of neuroendocrine prostate cancer (NEPC) and prostate cancer stem-like cells (PCSCs). However, the significance of AR downregulation in androgen insensitivity and de-differentiation of tumor cells in CRPC is poorly understood and much neglected. Our previous study shows that the orphan nuclear receptor TLX (NR2E1), which is upregulated in prostate cancer, plays an oncogenic role in prostate carcinogenesis by suppressing oncogene-induced senescence. In the present study, we further established that TLX exhibited an increased expression in metastatic CRPC. Further analyses showed that overexpression of TLX could confer resistance to androgen deprivation and anti-androgen in androgen-dependent prostate cancer cells in vitro and in vivo, whereas knockdown of endogenous TLX could potentiate the sensitivity to androgen deprivation and anti-androgen in prostate cancer cells. Our study revealed that the TLX-induced resistance to androgen deprivation and anti-androgen was mediated through its direct suppression of AR gene transcription and signaling in both androgen-stimulated and -unstimulated prostate cancer cells. We also characterized that TLX could bind directly to AR promoter and repress AR transcription by recruitment of histone modifiers, including HDAC1, HDAC3, and LSD1. Together, our present study shows, for the first time, that TLX can contribute to androgen insensitivity in CRPC via repression of AR gene transcription and signaling, and also implicates that targeting the druggable TLX may have a potential therapeutic significance in CRPC management, particularly in NEPC and PCSCs.

Melatonin Inhibits Androgen Receptor Splice Variant-7 (AR-V7)-Induced Nuclear Factor-Kappa B (NF-κB) Activation and NF-κB Activator-Induced AR-V7 Expression in Prostate Cancer Cells: Potential Implications for the Use of Melatonin in Castration-Resistant Prostate Cancer (CRPC) Therapy.

PubMed

Liu, Vincent Wing Sun; Yau, Wing Lung; Tam, Chun Wai; Yao, Kwok-Ming; Shiu, Stephen Yuen Wing

2017-05-31

A major current challenge in the treatment of advanced prostate cancer, which can be initially controlled by medical or surgical castration, is the development of effective, safe, and affordable therapies against progression of the disease to the stage of castration resistance. Here, we showed that in LNCaP and 22Rv1 prostate cancer cells transiently overexpressing androgen receptor splice variant-7 (AR-V7), nuclear factor-kappa B (NF-κB) was activated and could result in up-regulated interleukin ( IL ) -6 gene expression, indicating a positive interaction between AR-V7 expression and activated NF-κB/IL-6 signaling in castration-resistant prostate cancer (CRPC) pathogenesis. Importantly, both AR-V7-induced NF-κB activation and IL-6 gene transcription in LNCaP and 22Rv1 cells could be inhibited by melatonin. Furthermore, stimulation of AR-V7 mRNA expression in LNCaP cells by betulinic acid, a pharmacological NF-κB activator, was reduced by melatonin treatment. Our data support the presence of bi-directional positive interactions between AR-V7 expression and NF-κB activation in CRPC pathogenesis. Of note, melatonin, by inhibiting NF-κB activation via the previously-reported MT₁ receptor-mediated antiproliferative pathway, can disrupt these bi-directional positive interactions between AR-V7 and NF-κB and thereby delay the development of castration resistance in advanced prostate cancer. Apparently, this therapeutic potential of melatonin in advanced prostate cancer/CRPC management is worth translation in the clinic via combined androgen depletion and melatonin repletion.

Melatonin Inhibits Androgen Receptor Splice Variant-7 (AR-V7)-Induced Nuclear Factor-Kappa B (NF-κB) Activation and NF-κB Activator-Induced AR-V7 Expression in Prostate Cancer Cells: Potential Implications for the Use of Melatonin in Castration-Resistant Prostate Cancer (CRPC) Therapy

PubMed Central

Liu, Vincent Wing Sun; Yau, Wing Lung; Tam, Chun Wai; Yao, Kwok-Ming; Shiu, Stephen Yuen Wing

2017-01-01

A major current challenge in the treatment of advanced prostate cancer, which can be initially controlled by medical or surgical castration, is the development of effective, safe, and affordable therapies against progression of the disease to the stage of castration resistance. Here, we showed that in LNCaP and 22Rv1 prostate cancer cells transiently overexpressing androgen receptor splice variant-7 (AR-V7), nuclear factor-kappa B (NF-κB) was activated and could result in up-regulated interleukin (IL)-6 gene expression, indicating a positive interaction between AR-V7 expression and activated NF-κB/IL-6 signaling in castration-resistant prostate cancer (CRPC) pathogenesis. Importantly, both AR-V7-induced NF-κB activation and IL-6 gene transcription in LNCaP and 22Rv1 cells could be inhibited by melatonin. Furthermore, stimulation of AR-V7 mRNA expression in LNCaP cells by betulinic acid, a pharmacological NF-κB activator, was reduced by melatonin treatment. Our data support the presence of bi-directional positive interactions between AR-V7 expression and NF-κB activation in CRPC pathogenesis. Of note, melatonin, by inhibiting NF-κB activation via the previously-reported MT1 receptor-mediated antiproliferative pathway, can disrupt these bi-directional positive interactions between AR-V7 and NF-κB and thereby delay the development of castration resistance in advanced prostate cancer. Apparently, this therapeutic potential of melatonin in advanced prostate cancer/CRPC management is worth translation in the clinic via combined androgen depletion and melatonin repletion. PMID:28561752

Nuclear Mitochondrial DNA Activates Replication in Saccharomyces cerevisiae

PubMed Central

Chatre, Laurent; Ricchetti, Miria

2011-01-01

The nuclear genome of eukaryotes is colonized by DNA fragments of mitochondrial origin, called NUMTs. These insertions have been associated with a variety of germ-line diseases in humans. The significance of this uptake of potentially dangerous sequences into the nuclear genome is unclear. Here we provide functional evidence that sequences of mitochondrial origin promote nuclear DNA replication in Saccharomyces cerevisiae. We show that NUMTs are rich in key autonomously replicating sequence (ARS) consensus motifs, whose mutation results in the reduction or loss of DNA replication activity. Furthermore, 2D-gel analysis of the mrc1 mutant exposed to hydroxyurea shows that several NUMTs function as late chromosomal origins. We also show that NUMTs located close to or within ARS provide key sequence elements for replication. Thus NUMTs can act as independent origins, when inserted in an appropriate genomic context or affect the efficiency of pre-existing origins. These findings show that migratory mitochondrial DNAs can impact on the replication of the nuclear region they are inserted in. PMID:21408151

Nuclear mitochondrial DNA activates replication in Saccharomyces cerevisiae.

PubMed

Chatre, Laurent; Ricchetti, Miria

2011-03-08

The nuclear genome of eukaryotes is colonized by DNA fragments of mitochondrial origin, called NUMTs. These insertions have been associated with a variety of germ-line diseases in humans. The significance of this uptake of potentially dangerous sequences into the nuclear genome is unclear. Here we provide functional evidence that sequences of mitochondrial origin promote nuclear DNA replication in Saccharomyces cerevisiae. We show that NUMTs are rich in key autonomously replicating sequence (ARS) consensus motifs, whose mutation results in the reduction or loss of DNA replication activity. Furthermore, 2D-gel analysis of the mrc1 mutant exposed to hydroxyurea shows that several NUMTs function as late chromosomal origins. We also show that NUMTs located close to or within ARS provide key sequence elements for replication. Thus NUMTs can act as independent origins, when inserted in an appropriate genomic context or affect the efficiency of pre-existing origins. These findings show that migratory mitochondrial DNAs can impact on the replication of the nuclear region they are inserted in.

North American import? Charting the origins of an enigmatic Trypanosoma cruzi domestic genotype.

PubMed

Zumaya-Estrada, Federico A; Messenger, Louisa A; Lopez-Ordonez, Teresa; Lewis, Michael D; Flores-Lopez, Carlos A; Martínez-Ibarra, Alejandro J; Pennington, Pamela M; Cordon-Rosales, Celia; Carrasco, Hernan V; Segovia, Maikel; Miles, Michael A; Llewellyn, Martin S

2012-10-10

Trypanosoma cruzi, the agent of Chagas disease, is currently recognized as a complex of six lineages or Discrete Typing Units (DTU): TcI-TcVI. Recent studies have identified a divergent group within TcI - TcI(DOM). TcI(DOM). is associated with a significant proportion of human TcI infections in South America, largely absent from local wild mammals and vectors, yet closely related to sylvatic strains in North/Central America. Our aim was to examine hypotheses describing the origin of the TcI(DOM) genotype. We propose two possible scenarios: an emergence of TcI(DOM) in northern South America as a sister group of North American strain progenitors and dispersal among domestic transmission cycles, or an origin in North America, prior to dispersal back into South American domestic cycles. To provide further insight we undertook high resolution nuclear and mitochondrial genotyping of multiple Central American strains (from areas of México and Guatemala) and included them in an analysis with other published data. Mitochondrial sequence and nuclear microsatellite data revealed a cline in genetic diversity across isolates grouped into three populations: South America, North/Central America and TcI(DOM). As such, greatest diversity was observed in South America (A(r) = 4.851, π = 0.00712) and lowest in TcI(DOM) (Ar = 1.813, π = 0.00071). Nuclear genetic clustering (genetic distance based) analyses suggest that TcI(DOM) is nested within the North/Central American clade. Declining genetic diversity across the populations, and corresponding hierarchical clustering suggest that emergence of this important human genotype most likely occurred in North/Central America before moving southwards. These data are consistent with early patterns of human dispersal into South America.

Predicting the Pathogenicity of Aminoacyl-tRNA Synthetase Mutations

PubMed Central

Oprescu, Stephanie N.; Griffin, Laurie B.; Beg, Asim A.; Antonellis, Anthony

2016-01-01

Aminoacyl-tRNA synthetases (ARSs) are ubiquitously expressed, essential enzymes responsible for charging tRNA with cognate amino acids—the first step in protein synthesis. ARSs are required for protein translation in the cytoplasm and mitochondria of all cells. Surprisingly, mutations in 28 of the 37 nuclear-encoded human ARS genes have been linked to a variety of recessive and dominant tissue-specific disorders. Current data sustains that impaired enzyme function is a robust predictor of the pathogenicity of ARS mutations. However, experimental model systems that distinguish between pathogenic and non-pathogenic ARS variants are required for implicating newly identified ARS mutations in disease. Here, we outline strategies to assist in predicting the pathogenicity of ARS variants and urge cautious evaluation of genetic and functional data prior to linking an ARS mutation to a human disease phenotype. PMID:27876679

Localization of androgen receptors and estrogen receptors in the same cells of the songbird brain.

PubMed Central

Gahr, M

1990-01-01

Estrogens and androgens each have unique effects but act together for the neural differentiation and control of sexual behaviors in male vertebrates, such as the canary. The neuronal basis for these synergistic effects is elusive because the spatial relation between estrogen target cells and androgen target cells is unknown. This study localized estrogen receptor (ER)-containing cells by using immunocytochemistry and androgen receptor (AR)-containing cells by using autoradiography in the same sections of the male canary brain. Three cell types, those containing only ER, those containing only AR, and those containing both ER and AR, were found in tissue-specific frequencies. The midbrain nucleus intercollicularis exhibited the highest number of cells expressing both ER and AR, whereas ER and AR are expressed only in disjunctive cell populations in the forebrain nucleus hyperstriatalis ventrale, pars caudale. Synergistic effects of androgens and estrogens for the neural behavorial control could result from cells containing both ER and AR (intracellular) and from neural circuits containing ER and AR in different cells (intercellular). Images PMID:2251286

Increased phospho-AKT is associated with loss of the androgen receptor during the progression of N-methyl-N-nitrosourea-induced prostate carcinogenesis in rats.

PubMed

Liao, Zhiming; Wang, Shihua; Boileau, Thomas W-M; Erdman, John W; Clinton, Steven K

2005-07-01

Characterization of molecular events during N-methyl-N-nitrosourea (MNU)-induced rat prostate carcinogenesis enhances the utility of this model for the preclinical assessment of preventive strategies. Androgen independence is typical of advanced human prostate cancer and may occur through multiple mechanisms including the loss of androgen receptor (AR) expression and the activation of alternative signaling pathways. We examined the interrelationships between AR and p-AKT expression by immunohistochemical staining during MNU-androgen-induced prostate carcinogenesis in male Wistar-Unilever rats. Histone nuclear staining and image analysis was employed to assess parallel changes in chromatin and nuclear structure. The percentage of AR positive nuclei decreased (P < 0.01) as carcinogenesis progressed: hyperplasia (92%), atypical hyperplasia (92%), well-differentiated adenocarcinoma (57%), moderately-differentiated adenocarcinoma (19%), and poorly-differentiated adenocarcinoma (10%). Conversely, p-AKT staining increased significantly during carcinogenesis. Sparse staining was observed in normal tissues (0.2% of epithelial area) and hyperplastic lesions (0.1%), while expression increased significantly (P < 0.001) in atypical hyperplasia (7.6%), well-differentiated adenocarcinoma (16.7%), moderately-differentiated adenocarcinoma (19.6%), and poorly-differentiated adenocarcinoma (17.4%). In parallel, nuclear morphometry revealed increased nuclear size, greater irregularity, and lower DNA compactness as cancers became more poorly differentiated. In the MNU model, the progressive evolution of dominant tumor cell populations showing an increase in p-AKT in parallel with a decline in AR staining suggests that activation of AKT signaling may be one of several mechanisms contributing to androgen insensitivity during prostate cancer progression. Our observations mimic findings suggested by human studies and support the relevance of the MNU model in preclinical studies of preventive strategies. (c) 2005 Wiley-Liss, Inc.

Dye surface coating enables visible light activation of TiO2 nanoparticles leading to degradation of neighboring biological structures.

PubMed

Blatnik, Jay; Luebke, Lanette; Simonet, Stephanie; Nelson, Megan; Price, Race; Leek, Rachael; Zeng, Leyong; Wu, Aiguo; Brown, Eric

2012-02-01

Biologically and chemically modified nanoparticles are gaining much attention as a new tool in cancer detection and treatment. Herein, we demonstrate that an alizarin red S (ARS) dye coating on TiO2 nanoparticles enables visible light activation of the nanoparticles leading to degradation of neighboring biological structures through localized production of reactive oxygen species. Successful coating of nanoparticles with dye is demonstrated through sedimentation, spectrophotometry, and gel electrophoresis techniques. Using gel electrophoresis, we demonstrate that visible light activation of dye-TiO2 nanoparticles leads to degradation of plasmid DNA in vitro. Alterations in integrity and distribution of nuclear membrane associated proteins were detected via fluorescence confocal microscopy in HeLa cells exposed to perinuclear localized ARS-TiO2 nanoparticles that were photoactivated with visible light. This study expands upon previous studies that indicated dye coatings on TiO2 nanoparticles can serve to enhance imaging, by clearly showing that dye coatings on TiO2 nanoparticles can also enhance the photoreactivity of TiO2 nanoparticles by allowing visible light activation. The findings of our study suggest a therapeutic application of dye-coated TiO2 nanoparticles in cancer research; however, at the same time they may reveal limitations on the use of dye assisted visualization of TiO2 nanoparticles in live-cell imaging.

Androgen receptor-dependent and -independent mechanisms driving prostate cancer progression: Opportunities for therapeutic targeting from multiple angles

PubMed Central

Hoang, David T; Iczkowski, Kenneth A; Kilari, Deepak; See, William; Nevalainen, Marja T

2017-01-01

Despite aggressive treatment for localized cancer, prostate cancer (PC) remains a leading cause of cancer-related death for American men due to a subset of patients progressing to lethal and incurable metastatic castrate-resistant prostate cancer (CRPC). Organ-confined PC is treated by surgery or radiation with or without androgen deprivation therapy (ADT), while options for locally advanced and disseminated PC include radiation combined with ADT, or systemic treatments including chemotherapy. Progression to CRPC results from failure of ADT, which targets the androgen receptor (AR) signaling axis and inhibits AR-driven proliferation and survival pathways. The exact mechanisms underlying the transition from androgen-dependent PC to CRPC remain incompletely understood. Reactivation of AR has been shown to occur in CRPC despite depletion of circulating androgens by ADT. At the same time, the presence of AR-negative cell populations in CRPC has also been identified. While AR signaling has been proposed as the primary driver of CRPC, AR-independent signaling pathways may represent additional mechanisms underlying CRPC progression. Identification of new therapeutic strategies to target both AR-positive and AR-negative PC cell populations and, thereby, AR-driven as well as non-AR-driven PC cell growth and survival mechanisms would provide a two-pronged approach to eliminate CRPC cells with potential for synthetic lethality. In this review, we provide an overview of AR-dependent and AR-independent molecular mechanisms which drive CRPC, with special emphasis on the role of the Jak2-Stat5a/b signaling pathway in promoting castrate-resistant growth of PC through both AR-dependent and AR-independent mechanisms. PMID:27741508

Commissioning of the ArDM experiment at the Canfranc underground laboratory: first steps towards a tonne-scale liquid argon time projection chamber for Dark Matter searches

DOE Office of Scientific and Technical Information (OSTI.GOV)

Calvo, J.; Cantini, C.; Crivelli, P.

The Argon Dark Matter (ArDM) experiment consists of a liquid argon (LAr) time projection chamber (TPC) sensitive to nuclear recoils, resulting from scattering of hypothetical Weakly Interacting Massive Particles (WIMPs) on argon targets. With an active target mass of 850 kg ArDM represents an important milestone towards developments for large LAr Dark Matter detectors. Here we present the experimental apparatus currently installed underground at the Laboratorio Subterráneo de Canfranc (LSC), Spain. We show data on gaseous or liquid argon targets recorded in 2015 during the commissioning of ArDM in single phase at zero E-field (ArDM Run I). The data confirmsmore » the overall good and stable performance of the ArDM tonne-scale LAr detector.« less

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20-Aminosteroids as a novel class of selective and complete androgen receptor antagonists and inhibitors of prostate cancer cell growth.

PubMed

Fousteris, Manolis A; Schubert, Undine; Roell, Daniela; Roediger, Julia; Bailis, Nikolaos; Nikolaropoulos, Sotiris S; Baniahmad, Aria; Giannis, Athanassios

2010-10-01

Here, the synthesis and the evaluation of novel 20-aminosteroids on androgen receptor (AR) activity is reported. Compounds 11 and 18 of the series inhibit both the wild type and the T877A mutant AR-mediated transactivation indicating AR antagonistic function. Interestingly, minor structural changes such as stereoisomers of the amino lactame moiety exhibit preferences for antagonism among wild type and mutant AR. Other tested nuclear receptors are only weakly or not affected. In line with this, the prostate cancer cell growth of androgen-dependent but not of cancer cells lacking expression of the AR is inhibited. Further, the expression of the prostate specific antigen used as a diagnostic marker is also repressed. Finally steroid 18 enhances cellular senescence that might explain in part the growth inhibition mediated by this derivative. Steroids 11 and 18 are the first steroids that act as complete AR antagonists and exhibit AR specificity. Copyright © 2010 Elsevier Ltd. All rights reserved.

Radiation Injury After a Nuclear Detonation: Medical Consequences and the Need for Scarce Resources Allocation

PubMed Central

DiCarlo, Andrea L.; Maher, Carmen; Hick, John L.; Hanfling, Dan; Dainiak, Nicholas; Chao, Nelson; Bader, Judith L.; Coleman, C. Norman; Weinstock, David M.

2013-01-01

A 10-kiloton (kT) nuclear detonation within a US city could expose hundreds of thousands of people to radiation. The Scarce Resources for a Nuclear Detonation Project was undertaken to guide community planning and response in the aftermath of a nuclear detonation, when demand will greatly exceed available resources. This article reviews the pertinent literature on radiation injuries from human exposures and animal models to provide a foundation for the triage and management approaches outlined in this special issue. Whole-body doses >2 Gy can produce clinically significant acute radiation syndrome (ARS), which classically involves the hematologic, gastrointestinal, cutaneous, and cardiovascular/central nervous systems. The severity and presentation of ARS are affected by several factors, including radiation dose and dose rate, interindividual variability in radiation response, type of radiation (eg, gamma alone, gamma plus neutrons), partial-body shielding, and possibly age, sex, and certain preexisting medical conditions. The combination of radiation with trauma, burns, or both (ie, combined injury) confers a worse prognosis than the same dose of radiation alone. Supportive care measures, including fluid support, antibiotics, and possibly myeloid cytokines (eg, granulocyte colony-stimulating factor), can improve the prognosis for some irradiated casualties. Finally, expert guidance and surge capacity for casualties with ARS are available from the Radiation Emergency Medical Management Web site and the Radiation Injury Treatment Network. PMID:21402810

Radiation injury after a nuclear detonation: medical consequences and the need for scarce resources allocation.

PubMed

DiCarlo, Andrea L; Maher, Carmen; Hick, John L; Hanfling, Dan; Dainiak, Nicholas; Chao, Nelson; Bader, Judith L; Coleman, C Norman; Weinstock, David M

2011-03-01

A 10-kiloton (kT) nuclear detonation within a US city could expose hundreds of thousands of people to radiation. The Scarce Resources for a Nuclear Detonation Project was undertaken to guide community planning and response in the aftermath of a nuclear detonation, when demand will greatly exceed available resources. This article reviews the pertinent literature on radiation injuries from human exposures and animal models to provide a foundation for the triage and management approaches outlined in this special issue. Whole-body doses >2 Gy can produce clinically significant acute radiation syndrome (ARS), which classically involves the hematologic, gastrointestinal, cutaneous, and cardiovascular/central nervous systems. The severity and presentation of ARS are affected by several factors, including radiation dose and dose rate, interindividual variability in radiation response, type of radiation (eg, gamma alone, gamma plus neutrons), partial-body shielding, and possibly age, sex, and certain preexisting medical conditions. The combination of radiation with trauma, burns, or both (ie, combined injury) confers a worse prognosis than the same dose of radiation alone. Supportive care measures, including fluid support, antibiotics, and possibly myeloid cytokines (eg, granulocyte colony-stimulating factor), can improve the prognosis for some irradiated casualties. Finally, expert guidance and surge capacity for casualties with ARS are available from the Radiation Emergency Medical Management Web site and the Radiation Injury Treatment Network.

Histone demethylase JMJD1A promotes alternative splicing of AR variant 7 (AR-V7) in prostate cancer cells.

PubMed

Fan, Lingling; Zhang, Fengbo; Xu, Songhui; Cui, Xiaolu; Hussain, Arif; Fazli, Ladan; Gleave, Martin; Dong, Xuesen; Qi, Jianfei

2018-05-15

Formation of the androgen receptor splicing variant 7 (AR-V7) is one of the major mechanisms by which resistance of prostate cancer to androgen deprivation therapy occurs. The histone demethylase JMJD1A (Jumonji domain containing 1A) functions as a key coactivator for AR by epigenetic regulation of H3K9 methylation marks. Here, we describe a role for JMJD1A in AR-V7 expression. While JMJD1A knockdown had no effect on full-length AR (AR-FL), it reduced AR-V7 levels in prostate cancer cells. Reexpression of AR-V7 in the JMJD1A-knockdown cells elevated expression of select AR targets and partially rescued prostate cancer cell growth in vitro and in vivo. The AR-V7 protein level correlated positively with JMJD1A in a subset of human prostate cancer specimens. Mechanistically, we found that JMJD1A promoted alternative splicing of AR-V7 through heterogeneous nuclear ribonucleoprotein F (HNRNPF), a splicing factor known to regulate exon inclusion. Knockdown of JMJD1A or HNRNPF inhibited splicing of AR-V7, but not AR-FL, in a minigene reporter assay. JMJD1A was found to interact with and promote the recruitment of HNRNPF to a cryptic exon 3b on AR pre-mRNA for the generation of AR-V7. Taken together, the role of JMJD1A in AR-FL coactivation and AR-V7 alternative splicing highlights JMJD1A as a potentially promising target for prostate cancer therapy.

Regulation of androgen receptor and histone deacetylase 1 by Mdm2-mediated ubiquitylation.

PubMed

Gaughan, Luke; Logan, Ian R; Neal, David E; Robson, Craig N

2005-01-01

The androgen receptor (AR) is a member of the nuclear hormone receptor family of transcription factors and plays a critical role in regulating the expression of genes involved in androgen-dependent and -independent tumour formation. Regulation of the AR is achieved by alternate binding of either histone acetyltransferase (HAT)-containing co-activator proteins, or histone deacetylase 1 (HDAC1). Factors that control AR stability may also constitute an important regulatory mechanism, a notion that has been confirmed with the finding that the AR is a direct target for Mdm2-mediated ubiquitylation and proteolysis. Using chromatin immunoprecipitation (ChIP) and re-ChIP analyses, we show that Mdm2 associates with AR and HDAC1 at the active androgen-responsive PSA promoter in LNCaP prostate cancer cells. Furthermore, we demonstrate that Mdm2-mediated modification of AR and HDAC1 catalyses protein destabilization and attenuates AR sactivity, suggesting that ubiquitylation of the AR and HDAC1 may constitute an additional mechanism for regulating AR function. We also show that HDAC1 and Mdm2 function co-operatively to reduce AR-mediated transcription that is attenuated by the HAT activity of the AR co-activator Tip60, suggesting interplay between acetylation status and receptor ubiquitylation in AR regulation. In all, our data indicates a novel role for Mdm2 in regulating components of the AR transcriptosome.

Baicalein suppresses the androgen receptor (AR)-mediated prostate cancer progression via inhibiting the AR N-C dimerization and AR-coactivators interaction.

PubMed

Xu, Defeng; Chen, Qiulu; Liu, Yalin; Wen, Xingqiao

2017-12-01

Androgen receptor (AR) plays a critical role in prostate cancer (PCa) development and progression. Androgen deprivation therapy with antiandrogens to reduce androgen biosynthesis or prevent androgens from binding to AR are widely used to suppress AR-mediated PCa growth. However, most of ADT may eventually fail with development of the castration resistance after 12-24 months. Here we found that a natural product baicalein can effectively suppress the PCa progression via targeting the androgen-induced AR transactivation with little effect to AR protein expression. PCa cells including LNCaP, CWR22Rv1, C4-2, PC-3, and DU145, were treated with baicalein and luciferase assay was used to evaluate their effect on the AR transactivation. Cell growth and IC 50 were determined by MTT assay after 48 hrs treatment. RT-PCR was used to evaluate the mRNA levels of AR target genes including PSA, TMPRSS2, and TMEPA1. Western blot was used to determine AR and PSA protein expression. The natural product of baicalein can selectively inhibit AR transactivation with little effect on the other nuclear receptors, including ERα, and GR. At a low concentration, 2.5 μM of baicalein effectively suppresses the growth of AR-positive PCa cells, and has little effect on AR-negative PCa cells. Mechanism dissection suggest that baicalein can suppress AR target genes (PSA, TMPRSS2, and TMEPA1) expression in both androgen responsive LNCaP cells and castration resistant CWR22Rv1 cells, that may involve the inhibiting the AR N/C dimerization and AR-coactivators interaction. Baicalein may be developed as an effective anti-AR therapy via its ability to inhibit AR transactivation and AR-mediated PCa cell growth.

Identification of the C-terminal domain of Daxx acts as a potential regulator of intracellular cholesterol synthesis in HepG2 cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sun, Shaowei; Medical School, Hunan University of Chinese Medicine, Changsha 410208, Hunan; Wen, Juan

Daxx is a highly conserved nuclear transcriptional factor, which has been implicated in many nuclear processes including transcription and cell cycle regulation. Our previous study demonstrated Daxx also plays a role in regulation of intracellular cholesterol content. Daxx contains several domains that are essential for interaction with a growing number of proteins. To delineate the underlying mechanism of hypocholesterolemic activity of Daxx, we constructed a set of plasmids which can be used to overexpress different fragments of Daxx and transfected to HepG2 cells. We found that the C- terminal region Daxx626–740 clearly reduced intracellular cholesterol levels and inhibited the expressionmore » of SREBPs and SCAP. In GST pull-down experiments and Double immunofluorescence assays, Daxx626–740 was demonstrated to bind directly to androgen receptor (AR). Our findings suggest that the interaction of Daxx626-740 and AR abolishes the AR-mediated activation of SCAP/SREBPs pathway, which suppresses the de novo cholesterol synthesis. Thus, C-terminal domain of Daxx acts as a potential regulator of intracellular cholesterol content in HepG2 cells. - Highlights: • Daxx C-terminal domain reduces cholesterol levels. • Daxx C-terminal domain binds directly to AR. • The interaction of Daxx C-terminal domain and AR suppresses cholesterol synthesis.« less

Compounds from Cynomorium songaricum with Estrogenic and Androgenic Activities Suppress the Oestrogen/Androgen-Induced BPH Process.

PubMed

Wang, Xueni; Tao, Rui; Yang, Jing; Miao, Lin; Wang, Yu; Munyangaju, Jose Edouard; Wichai, Nuttapong; Wang, Hong; Zhu, Yan; Liu, Erwei; Chang, Yanxu; Gao, Xiumei

2017-01-01

To investigate the phytoestrogenic and phytoandrogenic activities of compounds isolated from CS and uncover the role of CS in prevention of oestrogen/androgen-induced BPH. Cells were treated with CS compounds, and immunofluorescence assay was performed to detect the nuclear translocation of ER α or AR in MCF-7 or LNCaP cells; luciferase reporter assay was performed to detect ERs or AR transcriptional activity in HeLa or AD293 cells; MTT assay was performed to detect the cell proliferation of MCF-7 or LNCaP cells. Oestrogen/androgen-induced BPH model was established in rat and the anti-BPH, anti-estrogenic, and anti-androgenic activities of CS in vivo were further investigated. The nuclear translocation of ER α was stimulated by nine CS compounds, three of which also stimulated AR translocation. The transcriptional activities of ER α and ER β were induced by five compounds, within which only ECG induced AR transcriptional activity as well. Besides, ECG stimulated the proliferation of both MCF-7 cells and LNCaP cells. CS extract suppressed oestrogen/androgen-induced BPH progress in vivo by downregulation of E2 and T level in serum and alteration of the expressions of ER α , ER β , and AR in the prostate. Our data demonstrates that compounds from CS exhibit phytoestrogenic and phytoandrogenic activities, which may contribute to inhibiting the oestrogen/androgen-induced BPH development.

Novel Mechanisms in the Regulation of G Protein-coupled Receptor Trafficking to the Plasma Membrane*

PubMed Central

Tholanikunnel, Baby G.; Joseph, Kusumam; Kandasamy, Karthikeyan; Baldys, Aleksander; Raymond, John R.; Luttrell, Louis M.; McDermott, Paul J.; Fernandes, Daniel J.

2010-01-01

β2-Adrenergic receptors (β2-AR) are low abundance, integral membrane proteins that mediate the effects of catecholamines at the cell surface. Whereas the processes governing desensitization of activated β2-ARs and their subsequent removal from the cell surface have been characterized in considerable detail, little is known about the mechanisms controlling trafficking of neo-synthesized receptors to the cell surface. Since the discovery of the signal peptide, the targeting of the integral membrane proteins to plasma membrane has been thought to be determined by structural features of the amino acid sequence alone. Here we report that localization of translationally silenced β2-AR mRNA to the peripheral cytoplasmic regions is critical for receptor localization to the plasma membrane. β2-AR mRNA is recognized by the nucleocytoplasmic shuttling RNA-binding protein HuR, which silences translational initiation while chaperoning the mRNA-protein complex to the cell periphery. When HuR expression is down-regulated, β2-AR mRNA translation is initiated prematurely in perinuclear polyribosomes, leading to overproduction of receptors but defective trafficking to the plasma membrane. Our results underscore the importance of the spatiotemporal relationship between β2-AR mRNA localization, translation, and trafficking to the plasma membrane, and establish a novel mechanism whereby G protein-coupled receptor (GPCR) responsiveness is regulated by RNA-based signals. PMID:20739277

Clinical Features and Management of Acquired Resistance to PD-1 Axis Inhibitors in 26 Patients With Advanced Non-Small Cell Lung Cancer.

PubMed

Gettinger, Scott N; Wurtz, Anna; Goldberg, Sarah B; Rimm, David; Schalper, Kurt; Kaech, Susan; Kavathas, Paula; Chiang, Anne; Lilenbaum, Rogerio; Zelterman, Daniel; Politi, Katerina; Herbst, Roy S

2018-06-01

With expanding indications for programmed death 1 (PD-1) axis inhibitors in non-small cell lung cancer (NSCLC), acquired resistance (AR) to these therapies is increasingly being encountered. We sought to characterize clinical patterns of AR to PD-1 axis inhibitors in patients with advanced NSCLC, and evaluate subsequent outcome and management strategies for such patients. Patients with NSCLC who developed AR to PD-1 axis inhibitor therapy initiated between December 2009 and February 2016 at one institution were identified and examined by clinical and radiographic features. AR was defined as progressive disease after initial response by either Response Evaluation Criteria in Solid Tumors v1.1 or immune-related response criteria. Twenty-six patients with AR to PD-1 axis inhibitor therapy were identified and evaluated. Median time to AR was 313 days; the 2-year survival rate from AR was 70% (95% confidence interval: 0.53-0.92). Twenty patients (77%) experienced AR in lymph nodes (LNs), including 11 patients with LN-only progression. Twenty-three (88%) patients had recurrence limited to one (54%) or two (35%) sites of disease. Fourteen patients (54%) continued PD-1 axis inhibitor therapy beyond progression. Three patients were re-challenged with the same PD-1 axis inhibitor after holiday from and progression off therapy, 2 again responded. Fifteen patients (58%) received local therapy to site(s) of AR, 11 continued respective PD-1 axis inhibitor after local therapy. The 2-year survival rate from AR among these 15 patients was 92% (95% confidence interval: 0.77-1). Acquired resistance to PD-1 axis inhibitors is often limited to one or two sites when local therapy and continuation of PD-1 axis inhibitor therapy can result in prolonged benefit. LN metastases appear to be particularly susceptible sites to AR. When progression of disease following response occurs after holiday from PD-1 axis inhibitor, re-challenge can again lead to tumor regression. Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Transcriptional activation of LON Gene by a new form of mitochondrial stress: A role for the nuclear respiratory factor 2 in StAR overload response (SOR).

PubMed

Bahat, Assaf; Perlberg, Shira; Melamed-Book, Naomi; Isaac, Sara; Eden, Amir; Lauria, Ines; Langer, Thomas; Orly, Joseph

2015-06-15

High output of steroid hormone synthesis in steroidogenic cells of the adrenal cortex and the gonads requires the expression of the steroidogenic acute regulatory protein (StAR) that facilitates cholesterol mobilization to the mitochondrial inner membrane where the CYP11A1/P450scc enzyme complex converts the sterol to the first steroid. Earlier studies have shown that StAR is active while pausing on the cytosolic face of the outer mitochondrial membrane while subsequent import of the protein into the matrix terminates the cholesterol mobilization activity. Consequently, during repeated activity cycles, high level of post-active StAR accumulates in the mitochondrial matrix. To prevent functional damage due to such protein overload effect, StAR is degraded by a sequence of three to four ATP-dependent proteases of the mitochondria protein quality control system, including LON and the m-AAA membranous proteases AFG3L2 and SPG7/paraplegin. Furthermore, StAR expression in both peri-ovulatory ovarian cells, or under ectopic expression in cell line models, results in up to 3-fold enrichment of the mitochondrial proteases and their transcripts. We named this novel form of mitochondrial stress as StAR overload response (SOR). To better understand the SOR mechanism at the transcriptional level we analyzed first the unexplored properties of the proximal promoter of the LON gene. Our findings suggest that the human nuclear respiratory factor 2 (NRF-2), also known as GA binding protein (GABP), is responsible for 88% of the proximal promoter activity, including the observed increase of transcription in the presence of StAR. Further studies are expected to reveal if common transcriptional determinants coordinate the SOR induced transcription of all the genes encoding the SOR proteases. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Enhanced expression of EGFP gene in CHSE-214 cells by an ARS element from mud loach (Misgurnus mizolepis).

PubMed

Kim, Moo-Sang; Lim, Hak-Seob; Ahn, Sang Jung; Jeong, Yong-Kee; Kim, Chul Geun; Lee, Hyung Ho

2007-11-01

The origins of replication are associated with nuclear matrices or are found in close proximity to matrix attachment regions (MARs). In this report, fish MARs were cloned into an autonomously replicating sequence (ARS) cloning vector and were screened for ARS elements in Saccharomyces cerevisiae. Sixteen clones were isolated that were able to grow on the selective plates. In particular, an ARS905 that shows high efficiency among them was selected for this study. Southern hybridization indicated the autonomous replication of the transformation vector containing the ARS905 element. DNA sequences analysis showed that the ARS905 contained two ARS consensus sequences as well as MAR motifs, such as AT tracts, ORI patterns, and ATC tracts. In vitro matrix binding analysis, major matrix binding activity and ARS function coincided in a subfragment of the ARS905. To analyze the effects of ARS905 on expression of a reporter gene, an ARS905(E1158) with ARS activity was inserted into pBaEGFP(+) containing mud loach beta-actin promoter, EGFP as a reporter gene, and SV40 poly(A) signal. The pBaEGFP(+)-ARS905(E1158) was transfected into a fish cell line, CHSE-214. The intensity of EGFP transfected cells was a 7-fold of the control at 11days post-transfection. These results indicate that ARS905 enhances the expression of the EGFP gene and that it should be as a component of expression vectors in further fish biotechnological studies.

Androgen receptor modulation following combination exposure to brominated flame-retardants.

PubMed

Kharlyngdoh, Joubert Banjop; Pradhan, Ajay; Olsson, Per-Erik

2018-03-19

Endocrine disrupting compounds can interfere with androgen receptor (AR) signaling and disrupt steroidogenesis leading to reproductive failure. The brominated flame-retardant (BFR) 1, 2-dibromo-4-(1, 2-dibromoethyl) cyclohexane (TBECH), is an agonist to human, chicken and zebrafish AR. Recently another group of alternative BFRs, allyl 2, 4, 6-tribromophenyl ether (ATE), and 2, 3-dibromopropyl 2, 4, 6-tribromophenyl ether (DPTE) along with its metabolite 2-bromoallyl 2, 4, 6-tribromophenyl ether (BATE) were identified as potent human AR antagonists. These alternative BFRs are present in the environment. The aim of the present study was to determine the effect of mixed exposures to the AR agonist and the AR antagonists at environmentally relevant concentrations. In vitro reporter luciferase assay showed that the AR antagonists, when present at concentration higher than TBECH, were able to inhibit TBECH-mediated AR activity. These AR antagonists also promoted AR nuclear translocation. In vitro gene expression analysis in the non-tumorigenic human prostate epithelial cell RWPE1 showed that TBECH induced AR target genes whereas DPTE repressed these genes. Further analysis of steroidogenic genes showed that TBECH up-regulated most of the genes while DPTE down-regulated the same genes. The results indicate that when TBECH and DPTE are present together they will antagonize each other, thereby reducing their individual effects.

The phosphorylated C-terminus of cAR1 plays a role in cell-type-specific gene expression and STATa tyrosine phosphorylation.

PubMed

Briscoe, C; Moniakis, J; Kim, J Y; Brown, J M; Hereld, D; Devreotes, P N; Firtel, R A

2001-05-01

cAMP receptors mediate some signaling pathways via coupled heterotrimeric G proteins, while others are G-protein-independent. This latter class includes the activation of the transcription factors GBF and STATa. Within the cellular mounds formed by aggregation of Dictyostelium, micromolar levels of cAMP activate GBF function, thereby inducing the transcription of postaggregative genes and initiating multicellular differentiation. Activation of STATa, a regulator of culmination and ecmB expression, results from cAMP receptor-dependent tyrosine phosphorylation and nuclear localization, also in mound-stage cells. During mound development, the cAMP receptor cAR1 is in a low-affinity state and is phosphorylated on multiple serine residues in its C-terminus. This paper addresses possible roles of cAMP receptor phosphorylation in the cAMP-mediated stimulation of GBF activity, STATa tyrosine phosphorylation, and cell-type-specific gene expression. To accomplish this, we have expressed cAR1 mutants in a strain in which the endogenous cAMP receptors that mediate postaggregative gene expression in vivo are deleted. We then examined the ability of these cells to undergo morphogenesis and induce postaggregative and cell-type-specific gene expression and STATa tyrosine phosphorylation. Analysis of cAR1 mutants in which the C-terminal tail is deleted or the ligand-mediated phosphorylation sites are mutated suggests that the cAR1 C-terminus is not essential for GBF-mediated postaggregative gene expression or STATa tyrosine phosphorylation, but may play a role in regulating cell-type-specific gene expression and morphogenesis. A mutant receptor, in which the C-terminal tail is constitutively phosphorylated, exhibits constitutive activation of STATa tyrosine phosphorylation in pulsed cells in suspension and a significantly impaired ability to induce cell-type-specific gene expression. The constitutively phosphorylated receptor also exerts a partial dominant negative effect on multicellular development when expressed in wild-type cells. These findings suggest that the phosphorylated C-terminus of cAR1 may be involved in regulating aspects of receptor-mediated processes, is not essential for GBF function, and may play a role in mediating subsequent development. Copyright 2001 Academic Press.

Immunohistochemical Evaluation of Androgen Receptor and Nerve Structure Density in Human Prepuce from Patients with Persistent Sexual Side Effects after Finasteride Use for Androgenetic Alopecia

PubMed Central

Di Loreto, Carla; La Marra, Francesco; Mazzon, Giorgio; Belgrano, Emanuele; Trombetta, Carlo; Cauci, Sabina

2014-01-01

Finasteride is an inhibitor of 5-α-reductase used against male androgenetic alopecia (AGA). Reported side effects of finasteride comprise sexual dysfunction including erectile dysfunction, male infertility, and loss of libido. Recently these effects were described as persistent in some subjects. Molecular events inducing persistent adverse sexual symptoms are unexplored. This study was designed as a retrospective case-control study to assess if androgen receptor (AR) and nerve density in foreskin prepuce specimens were associated with persistent sexual side effects including loss of sensitivity in the genital area due to former finasteride use against AGA. Cases were 8 males (aged 29–43 years) reporting sexual side effects including loss of penis sensitivity over 6 months after discontinuation of finasteride who were interviewed and clinically visited. After informed consent they were invited to undergo a small excision of skin from prepuce. Controls were 11 otherwise healthy matched men (aged 23–49 years) who undergone circumcision for phimosis, and who never took finasteride or analogues. Differences in AR expression and nerve density in different portions of dermal prepuce were evaluated in the 2 groups. Density of nuclear AR in stromal and epithelial cells was higher in cases (mean 40.0%, and 80.6% of positive cells, respectively) than controls (mean 23.4%, and 65.0% of positive cells, respectively), P = 0.023 and P = 0.043, respectively. Conversely, percentage of vessel smooth muscle cells positive for AR and density of nerves were similar in the 2 groups. The ratio of AR positive stromal cells % to serum testosterone concentrations was 2-fold higher in cases than in controls (P = 0.001). Our findings revealed that modulation of local AR levels might be implicated in long-term side effects of finasteride use. This provides the first evidence of a molecular objective difference between patients with long-term adverse sexual effects after finasteride use versus drug untreated healthy controls in certain tissues. PMID:24959691

Androgen receptor splice variants circumvent AR blockade by microtubule-targeting agents

PubMed Central

Zhang, Guanyi; Liu, Xichun; Li, Jianzhuo; Ledet, Elisa; Alvarez, Xavier; Qi, Yanfeng; Fu, Xueqi; Sartor, Oliver; Dong, Yan; Zhang, Haitao

2015-01-01

Docetaxel-based chemotherapy is established as a first-line treatment and standard of care for patients with metastatic castration-resistant prostate cancer. However, half of the patients do not respond to treatment and those do respond eventually become refractory. A better understanding of the resistance mechanisms to taxane chemotherapy is both urgent and clinical significant, as taxanes (docetaxel and cabazitaxel) are being used in various clinical settings. Sustained signaling through the androgen receptor (AR) has been established as a hallmark of CRPC. Recently, splicing variants of AR (AR-Vs) that lack the ligand-binding domain (LBD) have been identified. These variants are constitutively active and drive prostate cancer growth in a castration-resistant manner. In taxane-resistant cell lines, we found the expression of a major variant, AR-V7, was upregulated. Furthermore, ectopic expression of two clinically relevant AR-Vs (AR-V7 and ARV567es), but not the full-length AR (AR-FL), reduced the sensitivities to taxanes in LNCaP cells. Treatment with taxanes inhibited the transcriptional activity of AR-FL, but not those of AR-Vs. This could be explained, at least in part, due to the inability of taxanes to block the nuclear translocation of AR-Vs. Through a series of deletion constructs, the microtubule-binding activity was mapped to the LBD of AR. Finally, taxane-induced cytoplasm sequestration of AR-FL was alleviated when AR-Vs were present. These findings provide evidence that constitutively active AR-Vs maintain the AR signaling axis by evading the inhibitory effects of microtubule-targeting agents, suggesting that these AR-Vs play a role in resistance to taxane chemotherapy. PMID:26160840

Molecular Determinants of the Human α2C-Adrenergic Receptor Temperature-Sensitive Intracellular Traffic

PubMed Central

Pullikuth, Ashok K.; Guidry, Jessie J.

2015-01-01

The human α2C-adrenergic receptor (α2C-AR) is localized intracellularly at physiologic temperature. Decreasing the environmental temperature strongly stimulates the receptor transport to the cell surface. In contrast, rat and mouse α2C-AR plasma membrane levels are less sensitive to decrease in temperature, whereas the opossum α2C-AR cell surface levels are not changed in these conditions. Structural analysis demonstrated that human α2C-AR has a high number of arginine residues in the third intracellular loop and in the C-terminus, organized as putative RXR motifs. Although these motifs do not affect the receptor subcellular localization at 37°C, deletion of the arginine clusters significantly enhanced receptor plasma membrane levels at reduced temperature. We found that this exaggerated transport of the human receptor is mediated by two functional arginine clusters, one in the third intracellular loop and one in the C-terminus. This effect is mediated by interactions with COPI vesicles, but not by 14-3-3 proteins. In rat α2C-AR, the arginine cluster from the third intracellular loop is shifted to the left due to three missing residues. Reinsertion of these residues in the rat α2C-AR restored the same temperature sensitivity as in the human receptor. Proteomic and coimmunoprecipitation experiments identified pontin as a molecule having stronger interactions with human α2C-AR compared with rat α2C-AR. Inhibition of pontin activity enhanced human receptor plasma membrane levels and signaling at 37°C. Our results demonstrate that human α2C-AR has a unique temperature-sensitive traffic pattern within the G protein–coupled receptor class due to interactions with different molecular chaperones, mediated in part by strict spatial localization of specific arginine residues. PMID:25680754

The argon nuclear quadrupole moments

NASA Astrophysics Data System (ADS)

Sundholm, Dage; Pyykkö, Pekka

2018-07-01

New standard values -116(2) mb and 76(3) mb are suggested for the nuclear quadrupole moments (Q) of the 39Ar and 37Ar nuclei, respectively. The Q values were obtained by combining optical measurements of the quadrupole coupling constant (B or eqQ/h) of the 3s23p54s[3/2]2 (3Po) and 3s23p54p[5/2]3 (3De) states of argon with large scale numerical complete active space self-consistent field and restricted active space self-consistent field calculations of the electric field gradient at the nucleus (q) using the LUCAS code, which is a finite-element based multiconfiguration Hartree-Fock program for atomic structure calculations.

Binding of bisphenol A, bisphenol AF, and bisphenol S on the androgen receptor: Coregulator recruitment and stimulation of potential interaction sites.

PubMed

Perera, Lalith; Li, Yin; Coons, Laurel A; Houtman, Rene; van Beuningen, Rinie; Goodwin, Bonnie; Auerbach, Scott S; Teng, Christina T

2017-10-01

Bisphenol A (BPA), bisphenol AF (BPAF), and bisphenol S (BPS) are well known endocrine disruptors. Previous in vitro studies showed that these compounds antagonize androgen receptor (AR) transcriptional activity; however, the mechanisms of action are unclear. In the present study, we investigated interactions of coregulator peptides with BPA, BPAF, or BPS at the AR complexes using Micro Array for Real-time Coregulator Nuclear Receptor Interaction (MARCoNI) assays and assessed the binding of these compounds on AR by molecular dynamics (MD) simulations. The set of coregulator peptides that are recruited by BPA-bound AR, either positively/or negatively, are different from those recruited by the agonist R1881-bound AR. Therefore, the data indicates that BPA shows no similarities to R1881 and suggests that it may recruit other coregulators to the AR complex. BPAF-bound AR recruits about 70-80% of the same coregulator peptides as BPA-bound AR. Meanwhile, BPS-bound AR interacts with only few peptides compared to BPA or BPAF-bound AR. MD results show that multiple binding sites with varying binding affinities are available on AR for BPA, BPAF, and BPS, indicating the availability of modified binding surfaces on AR for coregulator interactions. These findings help explain some of the distinct AR-related toxicities observed with bisphenol chemicals and raise concern for the use of substitutes for BPA in commercial products. Published by Elsevier Ltd.

Synaptic long-term potentiation and depression in the rat medial vestibular nuclei depend on neural activation of estrogenic and androgenic signals.

PubMed

Scarduzio, Mariangela; Panichi, Roberto; Pettorossi, Vito Enrico; Grassi, Silvarosa

2013-01-01

Estrogenic and androgenic steroids can be synthesised in the brain and rapidly modulate synaptic transmission and plasticity through direct interaction with membrane receptors for estrogens (ERs) and androgens (ARs). We used whole cell patch clamp recordings in brainstem slices of male rats to explore the influence of ER and AR activation and local synthesis of 17β-estradiol (E2) and 5α-dihydrotestosterone (DHT) on the long-term synaptic changes induced in the neurons of the medial vestibular nucleus (MVN). Long-term depression (LTD) and long-term potentiation (LTP) caused by different patterns of high frequency stimulation (HFS) of the primary vestibular afferents were assayed under the blockade of ARs and ERs or in the presence of inhibitors for enzymes synthesizing DHT (5α-reductase) and E2 (P450-aromatase) from testosterone (T). We found that LTD is mediated by interaction of locally produced androgens with ARs and LTP by interaction of locally synthesized E2 with ERs. In fact, the AR block with flutamide prevented LTD while did not affect LTP, and the blockade of ERs with ICI 182,780 abolished LTP without influencing LTD. Moreover, the block of P450-aromatase with letrozole not only prevented the LTP induction, but inverted LTP into LTD. This LTD is likely due to the local activation of androgens, since it was abolished under blockade of ARs. Conversely, LTD was still induced in the presence of finasteride the inhibitor of 5α-reductase demonstrating that T is able to activate ARs and induce LTD even when DHT is not synthesized. This study demonstrates a key and opposite role of sex neurosteroids in the long-term synaptic changes of the MVN with a specific role of T-DHT for LTD and of E2 for LTP. Moreover, it suggests that different stimulation patterns can lead to LTD or LTP by specifically activating the enzymes involved in the synthesis of androgenic or estrogenic neurosteroids.

Roles of steroid receptor coactivator (SRC)-1 and transcriptional intermediary factor (TIF) 2 in androgen receptor activity in mice.

PubMed

Ye, Xiangcang; Han, Sang Jun; Tsai, Sophia Y; DeMayo, Francesco J; Xu, Jianming; Tsai, Ming-Jer; O'Malley, Bert W

2005-07-05

Genetic disruption of the steroid receptor coactivator (SRC)-1 and transcriptional intermediary factor (TIF)2/SRC-2 in mouse resulted in distinctive mutant phenotypes. To quantify their roles in the function of androgen receptor (AR) transcriptional activity in vivo, we generated a unique transgenic AR-reporter mouse and analyzed the cell-specific contributions of SRC-1 and TIF2 to the activity of AR in mouse testis. Transgenic AR-luciferase and transgenic AR-lacZ mice harbor a recombinant mouse AR gene, AR(GAL4DBD), which is functionally coupled with a upstream activation sequence-mediated reporter gene (AR activity indicator). After characterization of these mice in terms of AR function, we further derived bigenic mice by crossing AR activity indicator mice with the SRC-1-/- or TIF2+/- mutant mice. Analyses of the resultant bigenic mice by in vivo imaging and luciferase assays showed that testicular AR activity was decreased significantly in those with the TIF2+/- mutation but not in the SRC-1+/- background, suggesting that TIF2 serves as the preferential coactivator for AR in testis. Immunohistological analysis confirmed that AR and TIF2 coexist in mouse testicular Sertoli cell nuclei under normal conditions. Although SRC-1 concentrates in Sertoli cell nuclei in the absence of TIF2, nuclear SRC-1 is not able to rescue AR activity in the TIF2 mutant background. Interestingly, SRC-1 appears to negatively influence AR activity, thereby counterbalancing the TIF2-stimulated AR activity. Our results provide unique in vivo insights to the multidimensional cell-type-specific interactions between AR and coregulators.

Inhibition of androgen receptor and β-catenin activity in prostate cancer

PubMed Central

Lee, Eugine; Madar, Aviv; David, Gregory; Garabedian, Michael J.; DasGupta, Ramanuj; Logan, Susan K.

2013-01-01

Androgen receptor (AR) is the major therapeutic target in aggressive prostate cancer. However, targeting AR alone can result in drug resistance and disease recurrence. Therefore, simultaneous targeting of multiple pathways could in principle be an effective approach to treating prostate cancer. Here we provide proof-of-concept that a small-molecule inhibitor of nuclear β-catenin activity (called C3) can inhibit both the AR and β-catenin–signaling pathways that are often misregulated in prostate cancer. Treatment with C3 ablated prostate cancer cell growth by disruption of both β-catenin/T-cell factor and β-catenin/AR protein interaction, reflecting the fact that T-cell factor and AR have overlapping binding sites on β-catenin. Given that AR interacts with, and is transcriptionally regulated by β-catenin, C3 treatment also resulted in decreased occupancy of β-catenin on the AR promoter and diminished AR and AR/β-catenin target gene expression. Interestingly, C3 treatment resulted in decreased AR binding to target genes accompanied by decreased recruitment of an AR and β-catenin cofactor, coactivator-associated arginine methyltransferase 1 (CARM1), providing insight into the unrecognized function of β-catenin in prostate cancer. Importantly, C3 inhibited tumor growth in an in vivo xenograft model and blocked renewal of bicalutamide-resistant sphere-forming cells, indicating the therapeutic potential of this approach. PMID:24019458

Differential regulation of the androgen receptor by protein phosphatase regulatory subunits

PubMed Central

Grey, James; Jones, Dominic; Wilson, Laura; Nakjang, Sirintra; Clayton, Jake; Temperley, Richard; Clark, Emma; Gaughan, Luke; Robson, Craig

2018-01-01

The Androgen Receptor (AR) is a key molecule in the development, maintenance and progression of prostate cancer (PC). However, the relationship between the AR and co-regulatory proteins that facilitate AR activity in castrate resistant settings remain understudied. Here we show that protein phosphatase 1 regulatory subunits, identified from a phosphatase RNAi screen, direct PP1 catalytic subunits to a varied yet significant response in AR function. As such, we have characterised the PP1β holoenzyme, myosin phosphatase (MLCP), as a novel ligand independent regulator of the AR. Sustained MLCP activity through down-regulation of the MLCP inhibitory subunit, PPP1R14C, results in impaired AR nuclear translocation, protein stability and transcriptional activity in distinct models of PC progression, culminating in restoration of a non-malignant prostate genotype. Phenotypically, a marked reduction in cell proliferation and migration, characterised by G1 cell cycle arrest is observed, confirming PP1 holoenzyme disruption as a novel treatment approach in PC. PMID:29423094

Relation between Intensity of Biocide Practice and Residues of Anticoagulant Rodenticides in Red Foxes (Vulpes vulpes)

PubMed Central

Geduhn, Anke; Jacob, Jens; Schenke, Detlef; Keller, Barbara; Kleinschmidt, Sven; Esther, Alexandra

2015-01-01

Anticoagulant rodenticides (ARs) are commonly used to control rodent infestations for biocidal and plant protection purposes. This can lead to AR exposure of non-target small mammals and their predators, which is known from several regions of the world. However, drivers of exposure variation are usually not known. To identify environmental drivers of AR exposure in non-targets we analyzed 331 liver samples of red foxes (Vulpes vulpes) for residues of eight ARs and used local parameters (percentage of urban area and livestock density) to test for associations to residue occurrence. 59.8% of samples collected across Germany contained at least one rodenticide, in 20.2% of cases at levels at which biological effects are suspected. Second generation anticoagulants (mainly brodifacoum and bromadiolone) occurred more often than first generation anticoagulants. Local livestock density and the percentage of urban area were good indicators for AR residue occurrence. There was a positive association between pooled ARs and brodifacoum occurrence with livestock density as well as of pooled ARs, brodifacoum and difenacoum occurrence with the percentage of urban area on administrative district level. Pig holding drove associations of livestock density to AR residue occurrence in foxes. Therefore, risk mitigation strategies should focus on areas of high pig density and on highly urbanized areas to minimize non-target risk. PMID:26418154

Application of Optical Diagnosis to Aged Low-Voltage Cable Insulation in Nuclear Plants

NASA Astrophysics Data System (ADS)

Katagiri, Junichi; Takezawa, Yoshitaka; Shouji, Hiroshi

We have developed a novel non-destructive optical diagnosis technique for low-voltage cable insulations used in nuclear power plants. The key features of this diagnosis are the use of two wavelengths to measure the change in reflective absorbance (ΔAR), the use of polarized light to measure crystallinity and the use of element volatilizing to measure fluorescence. Chemical kinetics is used to predict the lifetimes of the cable insulations. When cable insulations darken and harden by time degradation, the ΔAR and depolarization parameters increase. This means that the cross-linking density in the cable insulations increases due to deterioration reactions. When the cross-linking density of insulation increases, its elasticity, corresponding to the material's life, increases. Similarly, as the crystallinity increases due to the change in the high-order structure of the insulating resin caused by irradiation, its elongation property decreases. The elongation property of insulation is one of the most important parameters that can be used to evaluate material lifetimes, because it relates to elasticity. The ΔAR correlated with the elongation property, and the correlation coefficient of an accelerated experiment using model pieces was over 0.9. Thus, we concluded that this optical diagnosis should be applied to evaluate the degradation of cable insulations used in nuclear power plants.

Extension of the nuclear mass surface for neutron-rich isotopes of argon through iron

NASA Astrophysics Data System (ADS)

Meisel, Zachary Paul

Nuclear mass measurement has maintained an important position in the field of nuclear physics for a little over a century. Nuclear masses provide key evidence of the structural transformation of nuclei away from the valley of beta-stability and are essential input for many simulations of extreme astrophysical environments. However, obtaining these masses is often a challenging endeavor due to the low production cross sections and short half-lives of the exotic nuclei which are of particular interest. To this end, the time-of-flight mass measurement technique has been developed to obtain the masses of several nuclei at once to precisions of 1 part in 105 with virtually no half-life limitation. This dissertation contains a description of the experiment, analysis, and results of the second implementation of the time-of-flight nuclear mass measurement technique at the National Superconducting Cyclotron Laboratory. 18 masses were obtained for neutron-rich isotopes of argon through iron, where the masses of 48Ar, 49Ar, 56Sc, 57Sc, 64Cr, 67Mn, and 69Fe were measured for the first time. These newly obtained masses were applied to outstanding problems in nuclear structure and nuclear astrophysics, resulting in significant scientific advances. The measurement results for 48Ar and 49Ar, which were found to have atomic mass excesses of -22.28(31) MeV and -17.8(1.1) MeV, respectively, provide strong evidence for the closed shell nature of neutron number N = 28 in argon. It follows that argon is therefore the lowest even-Z element exhibiting the N = 28 closed shell. The masses of 64Cr, 67 Mn, and 69Fe, which were found to have atomic mass excesses of -33.48(44) MeV, -34.09(62) MeV, and -39.35(60) MeV, respectively, show signs of nuclear deformation occurring around the N = 40 subshell. In addition, we found 64Cr is substantially less bound than predicted by global mass models that are commonly used in nuclear astrophysics simulations, resulting in a significant reduction in the predicted strength and depth of electron capture heating in the accreted neutron star crust due to the rather abundant A = 64 mass-chain. The reported value for the atomic mass excess of 56Sc, -24.85(59)(+0,-54) MeV, which contains an asymmetric systematic uncertainty due to potential isomeric contamination, results in a smaller than expected odd-even mass staggering in the A = 56 mass chain. Depending on the choice of theoretical models for electron capture transition strengths and energies, this could lead to strong Urca cooling in accreted neutron star crusts, due to the large amount of A = 56 material predicted to be present on the surface of accreted neutron stars.

Application of K-Ar Dating to the Chronology of Young Volcanic Centers

NASA Astrophysics Data System (ADS)

Lanphere, M. A.

2003-12-01

K-Ar dating and a derivative technique, 40Ar/39Ar dating, are methods of high-precision chronology applicable to young volcanic centers. Cascade volcanoes studied in detail by several USGS volcanologists, Duane Champion paleomagetist, and me include Mt. Baker, WA; Mt. Rainier, WA; Mt. Adams, WA; Mt. Hood, OR; Crater Lake, OR; and Medicine Lake, CA. For Mt. Adams using detailed geologic mapping by Hildreth and Fierstein and 74 K-Ar ages for 63 mapped units, Hildreth and Lanphere established a detailed chronology for the stratovolcano. Good agreement has been achieved for K-Ar ages and 40Ar/39Ar ages of rocks from Mt. Adams as young as 36 ka. A similar detailed chronology has been established for other Cascade volcanoes using andesites, in particular. These chronologies often take 10 years or more to develop. Major advantages of the 40Ar/39Ar technique are the ability to work with small sample sizes and the possibility to push the technique to very young ages. The Campanian Ignimbrite erupted from the Campi Flegrei crater near Naples, Italy is an example of the use of small samples. Nine incremental-heating ages were determined on samples of sanidine ranging in size from 47 mg to 67 mg. These samples yielded ages for the Campanian Ignimbrite ranging from 37.1 +/- 0.75 ka to 39.5 +/- 0.62 ka and averaging 38.1 +/- 0.8 ka. Other workers have proposed 40Ar/39Ar ages for the Campanian Ignimbrite of 37.1 +/- 0.4 ka and 39.3 +/- 0.1 ka. An example of the use of 40Ar/39Ar dating of very young samples is the Christian Era (CE) age of the Vesuvius eruption of year 79. Eight packets of sanidine weighing 213-296 mg from two localities, Casti Amanti in Pompeii and Villa Poppea in nearby Oplontis, yielded a weighted-mean incremental-heating age of 1924 +/- 66 years. The known age for the CE 79 eruption of Vesuvius is 1924 years. Earlier studies of Vesuvius by other workers yielded an 40Ar/39Ar age for the Villa Poppea locality of 1922 +/- 72 years.

Roles of steroid receptor coactivator (SRC)-1 and transcriptional intermediary factor (TIF) 2 in androgen receptor activity in mice

PubMed Central

Ye, Xiangcang; Han, Sang Jun; Tsai, Sophia Y.; DeMayo, Francesco J.; Xu, Jianming; Tsai, Ming-Jer; O'Malley, Bert W.

2005-01-01

Genetic disruption of the steroid receptor coactivator (SRC)-1 and transcriptional intermediary factor (TIF)2/SRC-2 in mouse resulted in distinctive mutant phenotypes. To quantify their roles in the function of androgen receptor (AR) transcriptional activity in vivo, we generated a unique transgenic AR-reporter mouse and analyzed the cell-specific contributions of SRC-1 and TIF2 to the activity of AR in mouse testis. Transgenic AR-luciferase and transgenic AR-lacZ mice harbor a recombinant mouse AR gene, ARGAL4DBD, which is functionally coupled with a upstream activation sequence-mediated reporter gene (AR activity indicator). After characterization of these mice in terms of AR function, we further derived bigenic mice by crossing AR activity indicator mice with the SRC-1-/- or TIF2+/- mutant mice. Analyses of the resultant bigenic mice by in vivo imaging and luciferase assays showed that testicular AR activity was decreased significantly in those with the TIF2+/- mutation but not in the SRC-1+/- background, suggesting that TIF2 serves as the preferential coactivator for AR in testis. Immunohistological analysis confirmed that AR and TIF2 coexist in mouse testicular Sertoli cell nuclei under normal conditions. Although SRC-1 concentrates in Sertoli cell nuclei in the absence of TIF2, nuclear SRC-1 is not able to rescue AR activity in the TIF2 mutant background. Interestingly, SRC-1 appears to negatively influence AR activity, thereby counterbalancing the TIF2-stimulated AR activity. Our results provide unique in vivo insights to the multidimensional cell-type-specific interactions between AR and coregulators. PMID:15983373

Recycling argon through metamorphic reactions: The record in symplectites

NASA Astrophysics Data System (ADS)

McDonald, Christopher S.; Regis, Daniele; Warren, Clare J.; Kelley, Simon P.; Sherlock, Sarah C.

2018-02-01

The 40Ar/39Ar ages of metamorphic micas that crystallized at high temperatures are commonly interpreted as cooling ages, with grains considered to have lost 40Ar via thermally-driven diffusion into the grain boundary network. Recently reported laser-ablation data suggest that the spatial distribution of Ar in metamorphic micas does not always conform to the patterns predicted by diffusion theory and that despite high metamorphic temperatures, argon was not removed efficiently from the local system during metamorphic evolution. In the Western Gneiss Region (WGR), Norway, felsic gneisses preserve microtextural evidence for the breakdown of phengite to biotite and plagioclase symplectites during near isothermal decompression from c. 20-25 to c. 8-12 kbar at 700 °C. These samples provide an ideal natural laboratory to assess whether the complete replacement of one K-bearing mineral by another at high temperatures completely 'resets' the Ar clock, or whether there is some inheritance of 40Ar in the neocrystallized phase. The timing of the high-temperature portion of the WGR metamorphic cycle has been well constrained in previous studies. However, the timing of cooling following the overprint is still much debated. In-situ laser ablation spot dating in phengite, biotite-plagioclase symplectites and coarser, texturally later biotite yielded 40Ar/39Ar ages that span much of the metamorphic cycle. Together these data show that despite residence at temperatures of 700 °C, Ar is not completely removed by diffusive loss or during metamorphic recrystallization. Instead, Ar released during phengite breakdown appears to be partially reincorporated into the newly crystallizing biotite and plagioclase (or is trapped in fluid inclusions in those phases) within a close system. Our data show that the microtextural and petrographic evolution of the sample being dated provides a critical framework in which local 40Ar recycling can be tracked, thus potentially allowing 40Ar/39Ar dates to be linked more accurately to metamorphic history.

Human sex hormone-binding globulin binding affinities of 125 structurally diverse chemicals and comparison with their binding to androgen receptor, estrogen receptor, and α-fetoprotein.

PubMed

Hong, Huixiao; Branham, William S; Ng, Hui Wen; Moland, Carrie L; Dial, Stacey L; Fang, Hong; Perkins, Roger; Sheehan, Daniel; Tong, Weida

2015-02-01

One endocrine disruption mechanism is through binding to nuclear receptors such as the androgen receptor (AR) and estrogen receptor (ER) in target cells. The concentration of a chemical in serum is important for its entry into the target cells to bind the receptors, which is regulated by the serum proteins. Human sex hormone-binding globulin (SHBG) is the major transport protein in serum that can bind androgens and estrogens and thus change a chemical's availability to enter the target cells. Sequestration of an androgen or estrogen in the serum can alter the chemical elicited AR- and ER-mediated responses. To better understand the chemical-induced endocrine activity, we developed a competitive binding assay using human pregnancy plasma and measured the binding to the human SHBG for 125 structurally diverse chemicals, most of which were known to bind AR and ER. Eighty seven chemicals were able to bind the human SHBG in the assay, whereas 38 chemicals were nonbinders. Binding data for human SHBG are compared with that for rat α-fetoprotein, ER and AR. Knowing the binding profiles between serum and nuclear receptors will improve assessment of a chemical's potential for endocrine disruption. The SHBG binding data reported here represent the largest data set of structurally diverse chemicals tested for human SHBG binding. Utilization of the SHBG binding data with AR and ER binding data could enable better evaluation of endocrine disrupting potential of chemicals through AR- and ER-mediated responses since sequestration in serum could be considered. Published by Oxford University Press on behalf of the Society of Toxicology 2014. This work is written by US Government employees and is in the public domain in the US.

Study on predictive role of AR and EGFR family genes with response to neoadjuvant chemotherapy in locally advanced breast cancer in Indian women.

PubMed

Singh, L C; Chakraborty, Anurupa; Mishra, Ashwani K; Devi, Thoudam Regina; Sugandhi, Nidhi; Chintamani, Chintamani; Bhatnagar, Dinesh; Kapur, Sujala; Saxena, Sunita

2012-06-01

Locally advanced breast cancer (LABC) remains a clinical challenge as the majority of patients with this diagnosis develop distant metastases despite appropriate therapy. We analyzed expression of steroid and growth hormone receptor genes as well as gene associated with metabolism of chemotherapeutic drugs in locally advanced breast cancer before and after neoadjuvant chemotherapy (NACT) to study whether there is a change in gene expression induced by chemotherapy and whether such changes are associated with tumor response or non-response. Fifty patients were included with locally advanced breast cancer treated with cyclophosphamide, adriamycin, 5-fluorouracil (CAF)-based neoadjuvant chemotherapy before surgery. Total RNA was extracted from 50 match samples of pre- and post-NACT tumor tissues. RNA expression levels of epidermal growth factor receptor family genes including EGFR, ERBB2, ERBB3, androgen receptor (AR), and multidrug-resistance gene 1 (MDR1) were determined by quantitative real-time reverse transcriptase-polymerase chain reaction. Responders show significantly high levels of pre-NACT AR gene expression (P = 0.016), which reduces following NACT (P = 0.008), and hence can serve as a useful tool for the prediction of the success of neoadjuvant chemotherapy in individual cancer patients with locally advanced breast carcinoma. Moreover, a significant post-therapeutic increase in the expression levels of EGFR and MDR1 gene in responders (P = 0.026 and P < 0.001) as well as in non-responders (P = 0.055, P = 0.001) suggests that expression of these genes changes during therapy but they do not have any impact on tumor response, whereas a post-therapeutic reduction was observed in AR in responders. This indicates an independent predictive role of AR with response to NACT.

Identification of Androgen Receptor-Specific Enhancer RNAs

DTIC Science & Technology

2016-06-01

Release; Distribution Unlimited The views, opinions and/or findings contained in this report are those of the author(s) and should not be construed as...There are two Tasks in this application. First, we will perform global run-on assay and deep sequencing to identify AR -specific enhancer RNAs. Second...1 Introduction The androgen receptor ( AR ) is a nuclear receptor transcription factor required for normal prostate development and prostate

Fear Conditioning Selectively Disrupts Noradrenergic Facilitation of GABAergic Inhibition in the Basolateral Amygdala

PubMed Central

Skelly, M. J.; Ariwodola, O. J.; Weiner, J. L.

2016-01-01

Inappropriate fear memory formation is symptomatic of many psychopathologies, and delineating the neurobiology of non-pathological fear learning may provide critical insight into treating these disorders. Fear memory formation is associated with decreased inhibitory signaling in the basolateral amygdala (BLA), and disrupted noradrenergic signaling may contribute to this decrease. BLA noradrenergic neurotransmission has been implicated in fear memory formation, and distinct adrenoreceptor (AR) subtypes modulate excitatory and inhibitory neurotransmission in this region. For example, α1-ARs promote GABA release from local inhibitory interneurons, while β3-ARs potentiate neurotransmission at lateral paracapsular (LPC) GABAergic synapses. Conversely, β1/2-ARs amplify excitatory signaling at glutamatergic synapses in the BLA. As increased BLA excitability promotes fear memory formation, we hypothesized that fear learning shifts the balanced regional effects of noradrenergic signaling toward excitation. To test this hypothesis, we used the fear-potentiated startle paradigm in combination with whole cell patch clamp electrophysiology to examine the effects of AR activation on BLA synaptic transmission following fear conditioning in male Long-Evans rats. We first demonstrated that inhibitory neurotransmission is decreased at both local and LPC synapses following fear conditioning. We next measured noradrenergic facilitation of BLA inhibitory signaling at local and LPC synapses using α1- and β3-AR agonists (1μM A61603 and 10μM BRL37344), and found that the ability of these agents to facilitate inhibitory neurotransmission is disrupted following fear conditioning. Conversely, we found that fear learning does not disrupt noradrenergic modulation of glutamatergic signaling via a β1/2-AR agonist (1μM isoproterenol). Taken together, these studies suggest that fear learning increases BLA excitability by selectively disrupting the inhibitory effects of noradrenaline. PMID:27720769

Fear conditioning selectively disrupts noradrenergic facilitation of GABAergic inhibition in the basolateral amygdala.

PubMed

Skelly, M J; Ariwodola, O J; Weiner, J L

2017-02-01

Inappropriate fear memory formation is symptomatic of many psychopathologies, and delineating the neurobiology of non-pathological fear learning may provide critical insight into treating these disorders. Fear memory formation is associated with decreased inhibitory signaling in the basolateral amygdala (BLA), and disrupted noradrenergic signaling may contribute to this decrease. BLA noradrenergic neurotransmission has been implicated in fear memory formation, and distinct adrenoreceptor (AR) subtypes modulate excitatory and inhibitory neurotransmission in this region. For example, α1-ARs promote GABA release from local inhibitory interneurons, while β3-ARs potentiate neurotransmission at lateral paracapsular (LPC) GABAergic synapses. Conversely, β1/2-ARs amplify excitatory signaling at glutamatergic synapses in the BLA. As increased BLA excitability promotes fear memory formation, we hypothesized that fear learning shifts the balanced regional effects of noradrenergic signaling toward excitation. To test this hypothesis, we used the fear-potentiated startle paradigm in combination with whole cell patch clamp electrophysiology to examine the effects of AR activation on BLA synaptic transmission following fear conditioning in male Long-Evans rats. We first demonstrated that inhibitory neurotransmission is decreased at both local and LPC synapses following fear conditioning. We next measured noradrenergic facilitation of BLA inhibitory signaling at local and LPC synapses using α1-and β3-AR agonists (1 μM A61603 and 10 μM BRL37344), and found that the ability of these agents to facilitate inhibitory neurotransmission is disrupted following fear conditioning. Conversely, we found that fear learning does not disrupt noradrenergic modulation of glutamatergic signaling via a β1/2-AR agonist (1 μM isoproterenol). Taken together, these studies suggest that fear learning increases BLA excitability by selectively disrupting the inhibitory effects of noradrenaline. Copyright © 2016 Elsevier Ltd. All rights reserved.

Preoptimised VB: a fast method for the ground and excited states of ionic clusters II. Delocalised preoptimisation for He 2+, Ar 2+, He 3+ and Ar 3+

NASA Astrophysics Data System (ADS)

Archirel, Pierre

1997-09-01

We generalise the preoptimisation of orbitals within VB (Part I of this series) through letting the orbitals delocalise on the neighbouring fragments. The method is more accurate than the local preoptimisation. The method is tested on the rare gas clusters He 2+, Ar 2+, He 3+ and Ar 3+. The results are in good agreement with previously published data on these systems. We complete these data with higher excited states. The binding energies of (ArCO) +, (ArN 2) + and N 4+ are revisited. The simulation of the SCF method is extended to Cu +H 2O.

SMILE upregulated by metformin inhibits the function of androgen receptor in prostate cancer cells.

PubMed

Lee, Seung-Yon; Song, Chin-Hee; Xie, Yuan-Bin; Jung, Chaeyong; Choi, Hueng-Sik; Lee, Keesook

2014-11-28

Metformin, a diabetes drug, has been reported to inhibit the growth of prostate cancer cells. In this study, we investigated the effect and action mechanism of metformin on the function of androgen receptor (AR), a key molecule in the proliferation of prostate cancer cells. Metformin was found to reduce androgen-dependent cell growth and the expression of AR target genes by inhibiting AR function in prostate cancer cells such as LNCaP and C4-2 cells. Interestingly, metformin upregulated the protein level of small heterodimer partner-interacting leucine zipper (SMILE), a coregulator of nuclear receptors, and knockdown of SMILE expression with shRNA abolished the inhibitory effect of metformin on AR function. Further studies revealed that SMILE protein itself suppressed the transactivation of AR, and its ectopic expression resulted in the repressed expression of endogenous AR target genes, PSA and NKX3.1, in LNCaP cells. In addition, SMILE protein physically interacted with AR and competed with the AR coactivator SRC-1 to modulate AR transactivation. As expected, SMILE repressed androgen-dependent growth of LNCaP and C4-2 cells. Taken together, these results suggest that SMILE, which is induced by metformin, functions as a novel AR corepressor and may mediate the inhibitory effect of metformin on androgen-dependent growth of prostate cancer cells. Copyright © 2014. Published by Elsevier Ireland Ltd.

NRIP/DCAF6 stabilizes the androgen receptor protein by displacing DDB2 from the CUL4A-DDB1 E3 ligase complex in prostate cancer.

PubMed

Chen, Hsin-Hsiung; Fan, Ping; Chang, Szu-Wei; Tsao, Yeou-Ping; Huang, Hsiang-Po; Chen, Show-Li

2017-03-28

Both nuclear receptor interaction protein (NRIP) and DNA damage binding protein 2 (DDB2) belong to the Cullin 4 (CUL4)-DDB1 binding protein family and are androgen receptor (AR)-interacting proteins. Here, we investigated the expression patterns of the NRIP, DDB2 and AR proteins in human prostate cancer tissues and found that the expression levels of NRIP and AR were higher, but the DDB2 level was lower, in prostate cancer tissues than in non-neoplastic controls, suggesting NRIP as a candidate tumor promoter and DDB2 as a tumor suppressor in prostate cancer. Furthermore, both NRIP and DDB2 shared the same AR binding domain; they were competitors for the AR, but not for DDB1 binding, in the AR-DDB2-DDB1-CUL4A complex. Conclusively, NRIP stabilizes the AR protein by displacing DDB2 from the AR-DDB2 complex. Consistent with our hypothesis, a specific expression pattern with high levels of NRIP and AR, together with a low level of DDB2, was found more frequently in the human prostate cancer tissues with a cribriform pattern than in non-cribriform tumors, suggesting that disruption of the balance between NRIP and DDB2 may change AR protein homeostasis and contribute to pathogenesis in certain aggressive types of prostate cancer.

Oriental herbs as a source of novel anti-androgen and prostate cancer chemopreventive agents.

PubMed

Lu, Junxuan; Kim, Sung-Hoon; Jiang, Cheng; Lee, HyoJeong; Guo, Junming

2007-09-01

Androgen and androgen receptor (AR) signaling are crucial for the genesis of prostate cancer (PCa), which can often develop into androgen-ligand-independent diseases that are lethal to the patients. Recent studies show that even these hormone-refractory PCa require ligand-independent AR signaling for survival. As current chemotherapy is largely ineffective for PCa and has serious toxic sideeffects, we have initiated a collaborative effort to identify and develop novel, safe and naturally occurring agents that target AR signaling from Oriental medicinal herbs for the chemoprevention and treatment of PCa. We highlight our discovery of decursin from an Oriental formula containing Korean Angelica gigas Nakai (Dang Gui) root as a novel anti-androgen/AR agent. We have identified the following mechanisms to account for the specific anti-AR actions: rapid block of AR nuclear translocation, inhibition of binding of 5alpha-dihydrotestesterone to AR and increased proteasomal degradation of AR protein. Furthermore, decursin lacks the agonist activity of the "pure" anti-androgen bicalutamide and is more potent than bicalutamide in inducing PCa apoptosis. Structure-activity analyses reveal a critical requirement of the side-chain on decursin or its structural isomer decursinol angelate for anti-AR, cell cycle arrest and proapoptotic activities. This work demonstrates the feasibility of using activity-guided fractionation in cell culture assays combined with mechanistic studies to identify novel anti-androgen/ AR agents from complex herbal mixtures.

NRIP/DCAF6 stabilizes the androgen receptor protein by displacing DDB2 from the CUL4A-DDB1 E3 ligase complex in prostate cancer

PubMed Central

Tsao, Yeou-Ping; Huang, Hsiang-Po; Chen, Show-Li

2017-01-01

Both nuclear receptor interaction protein (NRIP) and DNA damage binding protein 2 (DDB2) belong to the Cullin 4 (CUL4)-DDB1 binding protein family and are androgen receptor (AR)-interacting proteins. Here, we investigated the expression patterns of the NRIP, DDB2 and AR proteins in human prostate cancer tissues and found that the expression levels of NRIP and AR were higher, but the DDB2 level was lower, in prostate cancer tissues than in non-neoplastic controls, suggesting NRIP as a candidate tumor promoter and DDB2 as a tumor suppressor in prostate cancer. Furthermore, both NRIP and DDB2 shared the same AR binding domain; they were competitors for the AR, but not for DDB1 binding, in the AR-DDB2-DDB1-CUL4A complex. Conclusively, NRIP stabilizes the AR protein by displacing DDB2 from the AR-DDB2 complex. Consistent with our hypothesis, a specific expression pattern with high levels of NRIP and AR, together with a low level of DDB2, was found more frequently in the human prostate cancer tissues with a cribriform pattern than in non-cribriform tumors, suggesting that disruption of the balance between NRIP and DDB2 may change AR protein homeostasis and contribute to pathogenesis in certain aggressive types of prostate cancer. PMID:28212551

A specific role of iron in promoting meristematic cell division during adventitious root formation.

PubMed

Hilo, Alexander; Shahinnia, Fahimeh; Druege, Uwe; Franken, Philipp; Melzer, Michael; Rutten, Twan; von Wirén, Nicolaus; Hajirezaei, Mohammad-Reza

2017-07-10

Adventitious root (AR) formation is characterized by a sequence of physiological and morphological processes and determined by external factors, including mineral nutrition, the impacts of which remain largely elusive. Morphological and anatomical evaluation of the effects of mineral elements on AR formation in leafy cuttings of Petunia hybrida revealed a striking stimulation by iron (Fe) and a promotive action of ammonium (NH4+). The optimal application period for these nutrients corresponded to early division of meristematic cells in the rooting zone and coincided with increased transcript levels of mitotic cyclins. Fe-localization studies revealed an enhanced allocation of Fe to the nuclei of meristematic cells in AR initials. NH4+ supply promoted AR formation to a lesser extent, most likely by favoring the availability of Fe. We conclude that Fe acts locally by promoting cell division in the meristematic cells of AR primordia. These results highlight a specific biological function of Fe in AR development and point to an unexploited importance of Fe for the vegetative propagation of plants from cuttings. © The Author 2017. Published by Oxford University Press on behalf of the Society for Experimental Biology.

Androgen receptor signaling and mutations in prostate cancer

PubMed Central

Koochekpour, Shahriar

2010-01-01

Normal and neoplastic growth of the prostate gland are dependent on androgen receptor (AR) expression and function. Androgenic activation of the AR, in association with its coregulatory factors, is the classical pathway that leads to transcriptional activity of AR target genes. Alternatively, cytoplasmic signaling crosstalk of AR by growth factors, neurotrophic peptides, cytokines or nonandrogenic hormones may have important roles in prostate carcinogenesis and in metastatic or androgen-independent (AI) progression of the disease. In addition, cross-modulation by various nuclear transcription factors acting through basal transcriptional machinery could positively or negatively affect the AR or AR target genes expression and activity. Androgen ablation leads to an initial favorable response in a significant number of patients; however, almost invariably patients relapse with an aggressive form of the disease known as castration-resistant or hormone-refractory prostate cancer (PCa). Understanding critical molecular events that lead PCa cells to resist androgen-deprivation therapy is essential in developing successful treatments for hormone-refractory disease. In a significant number of hormone-refractory patients, the AR is overexpressed, mutated or genomically amplified. These genetic alterations maintain an active presence for a highly sensitive AR, which is responsive to androgens, antiandrogens or nonandrogenic hormones and collectively confer a selective growth advantage to PCa cells. This review provides a brief synopsis of the AR structure, AR coregulators, posttranslational modifications of AR, duality of AR function in prostate epithelial and stromal cells, AR-dependent signaling, genetic changes in the form of somatic and germline mutations and their known functional significance in PCa cells and tissues. PMID:20711217

Galbanic acid decreases androgen receptor abundance and signaling and induces G1 arrest in prostate cancer cells

PubMed Central

Zhang, Yong; Kim, Kwan-Hyun; Zhang, Wei; Guo, Yinglu; Kim, Sung-Hoon; Lü, Junxuan

2011-01-01

Androgen receptor (AR) signaling is crucial for the genesis and progression of prostate cancer (PCa). We compared the growth responses of AR(+) LNCaP and LNCaP C4-2 vs. AR(−) DU145 and PC-3 PCa cell lines to galbanic acid (GBA) isolated from the resin of medicinal herb Ferula assafoetida and assessed their connection to AR signaling and cell cycle regulatory pathways. Our results showed that GBA preferentially suppressed AR(+) PCa cell growth than AR(−) PCa cells. GBA induced a caspase-mediated apoptosis that was attenuated by a general caspase inhibitor. Subapoptotic GBA down-regulated AR protein in LNCaP cells primarily through promoting its proteasomal degradation, and inhibited AR-dependent transcription without affecting AR nuclear translocation. Whereas docking simulations predicted binding of GBA to the AR ligand binding domain with similarities and differences with the AR antagonist drug bicalutamide, LNCaP cell culture assays did not detect agonist activity of GBA. GBA and bicalutamide exerted greater than additive inhibitory effect on cell growth when used together. Subapoptotic GBA induced G1 arrest associated with an inhibition of cyclin/CDK4/6 pathway, especially cyclin D1 without the causal involvement of CDK inhibitory proteins P21Cip1 and P27Kip1. In summary, the novelty of GBA as an anti-AR compound resides in the distinction between GBA and bicalutamide with respect to AR protein turnover and a lack of agonist effect. Our observations of anti-AR and cell cycle arrest actions plus the anti-angiogenesis effect reported elsewhere suggest GBA as a multi-targeting drug candidate for the prevention and therapy of PCa. PMID:21328348

Androgen receptor activity modulates responses to cisplatin treatment in bladder cancer.

PubMed

Kashiwagi, Eiji; Ide, Hiroki; Inoue, Satoshi; Kawahara, Takashi; Zheng, Yichun; Reis, Leonardo O; Baras, Alexander S; Miyamoto, Hiroshi

2016-08-02

Cisplatin (CDDP)-based combination chemotherapy remains the mainstream treatment for advanced bladder cancer. However, its efficacy is often limited due to the development of resistance for which underlying mechanisms are poorly understood. Meanwhile, emerging evidence has indicated the involvement of androgen-mediated androgen receptor (AR) signals in bladder cancer progression. In this study, we aimed to investigate whether AR signals have an impact on sensitivity to CDDP in bladder cancer cells. UMUC3-control-short hairpin RNA (shRNA) cells with endogenous AR and AR-negative 647V/5637 cells stably expressing AR were significantly more resistant to CDDP treatment at its pharmacological concentrations, compared with UMUC3-AR-shRNA and 647V-vector/5637-vector control cells, respectively. A synthetic androgen R1881 significantly reduced CDDP sensitivity in UMUC3, 647V-AR, or 5637-AR cells, and the addition of an anti-androgen hydroxyflutamide inhibited the effect of R1881. In these AR-positive cells, R1881 treatment also induced the expression levels of NF-κB, which is known to involve CDDP resistance, and its phosphorylated form, as well as nuclear translocation of NF-κB. In CDDP-resistant bladder cancer sublines established following long-term culture with CDDP, the expression levels of AR as well as NF-κB and phospho-NF-κB were considerably elevated, compared with respective control sublines. In bladder cancer specimens, there was a strong trend to correlate between AR positivity and chemoresistance. These results suggest that AR activation correlates with CDDP resistance presumably via modulating NF-κB activity in bladder cancer cells. Targeting AR during chemotherapy may thus be a useful strategy to overcome CDDP resistance in patients with AR-positive bladder cancer.

Reconfiguring the AR-TIF2 Protein–Protein Interaction HCS Assay in Prostate Cancer Cells and Characterizing the Hits from a LOPAC Screen

PubMed Central

Fancher, Ashley T.; Hua, Yun; Camarco, Daniel P.; Close, David A.; Strock, Christopher J.

2016-01-01

Abstract The continued activation of androgen receptor (AR) transcription and elevated expression of AR and transcriptional intermediary factor 2 (TIF2) coactivator observed in prostate cancer (CaP) recurrence and the development of castration-resistant CaP (CRPC) support a screening strategy for small-molecule inhibitors of AR-TIF2 protein–protein interactions (PPIs) to find new drug candidates. Small molecules can elicit tissue selective effects, because the cells of distinct tissues express different levels and cohorts of coregulatory proteins. We reconfigured the AR-TIF2 PPI biosensor (PPIB) assay in the PC-3 CaP cell line to determine whether AR modulators and hits from an AR-TIF2 PPIB screen conducted in U-2 OS cells would behave differently in the CaP cell background. Although we did not observe any significant differences in the compound responses between the assay performed in osteosarcoma and CaP cells, the U-2 OS AR-TIF2 PPIB assay would be more amenable to screening, because both the virus and cell culture demands are lower. We implemented a testing paradigm of counter-screens and secondary hit characterization assays that allowed us to identify and deprioritize hits that inhibited/disrupted AR-TIF2 PPIs and AR transcriptional activation (AR-TA) through antagonism of AR ligand binding or by non-specifically blocking nuclear receptor trafficking. Since AR-TIF2 PPI inhibitor/disruptor molecules act distally to AR ligand binding, they have the potential to modulate AR-TA in a cell-specific manner that is distinct from existing anti-androgen drugs, and to overcome the development of resistance to AR antagonism. We anticipate that the application of this testing paradigm to characterize the hits from an AR-TIF2 PPI high-content screening campaign will enable us to prioritize the AR-TIF2 PPI inhibitor/disruptor leads that have potential to be developed into novel therapeutics for CaP and CRPC. PMID:27606620

SREBF1 Activity is Regulated by an AR/mTOR Nuclear Axis in Prostate Cancer.

PubMed

Audet-Walsh, Etienne; Vernier, Mathieu; Yee, Tracey; Laflamme, Chloe E; Li, Susan; Chen, Yonghong; Giguere, Vincent

2018-05-21

Reprogramming of cellular metabolism is an important feature of prostate cancer (PCa), including altered lipid metabolism. Recently, it was observed that the nuclear fraction of mTOR is essential for the androgen-mediated metabolic reprogramming of PCa cells. Herein, it is demonstrated that the androgen receptor (AR) and mTOR bind to regulatory regions of sterol regulatory element binding transcription factor 1 (SREBF1) to control its expression, while dual activation of these signaling pathways also promotes SREBF1 cleavage and its translocation to the nucleus. Consequently, SREBF1 recruitment to regulatory regions of its target genes is induced upon treatment with the synthetic androgen R1881, an effect abrogated upon inhibition of the mTOR signaling pathway. In turn, pharmacological and genetic inhibition of SREBF1 activity impairs the androgen-mediated induction of the key lipogenic genes fatty acid synthase (FASN) and stearoyl-CoA desaturase (SCD1). Consistent with these observations, the expression of SREBF1, FASN and SCD1 is significantly correlated in human PCa tumor clinical specimens. Functionally, blockade of SREBF1 activity reduces the androgen-driven lipid accumulation. Interestingly, decreased triglyceride accumulation observed upon SREBF1 inhibition is paralleled by an increase in mitochondrial respiration, indicating a potential rewiring of citrate metabolism in PCa cells. Altogether, these data define an AR/mTOR nuclear axis, in the context of PCa, as a novel pathway regulating SREBF1 activity and citrate metabolism. The finding that an AR/mTOR complex promotes SREBP expression and activity enhances our understanding of the metabolic adaptation necessary for prostate cancer cell growth and suggests novel therapeutic approaches to target metabolic vulnerabilities in tumors. Copyright ©2018, American Association for Cancer Research.

Subterranean production of neutrons, 39Ar and 21Ne: Rates and uncertainties

NASA Astrophysics Data System (ADS)

Šrámek, Ondřej; Stevens, Lauren; McDonough, William F.; Mukhopadhyay, Sujoy; Peterson, R. J.

2017-01-01

Accurate understanding of the subsurface production rate of the radionuclide 39Ar is necessary for argon dating techniques and noble gas geochemistry of the shallow and the deep Earth, and is also of interest to the WIMP dark matter experimental particle physics community. Our new calculations of subsurface production of neutrons, 21Ne , and 39Ar take advantage of the state-of-the-art reliable tools of nuclear physics to obtain reaction cross sections and spectra (TALYS) and to evaluate neutron propagation in rock (MCNP6). We discuss our method and results in relation to previous studies and show the relative importance of various neutron, 21Ne , and 39Ar nucleogenic production channels. Uncertainty in nuclear reaction cross sections, which is the major contributor to overall calculation uncertainty, is estimated from variability in existing experimental and library data. Depending on selected rock composition, on the order of 107-1010 α particles are produced in one kilogram of rock per year (order of 1-103 kg-1 s-1); the number of produced neutrons is lower by ∼ 6 orders of magnitude, 21Ne production rate drops by an additional factor of 15-20, and another one order of magnitude or more is dropped in production of 39Ar. Our calculation yields a nucleogenic 21Ne /4He production ratio of (4.6 ± 0.6) ×10-8 in Continental Crust and (4.2 ± 0.5) ×10-8 in Oceanic Crust and Depleted Mantle. Calculated 39Ar production rates span a great range from 29 ± 9 atoms kg-rock-1 yr-1 in the K-Th-U-enriched Upper Continental Crust to (2.6 ± 0.8) × 10-4 atoms kg-rock-1 yr-1 in Depleted Upper Mantle. Nucleogenic 39Ar production exceeds the cosmogenic production below ∼700 m depth and thus, affects radiometric ages of groundwater. The 39Ar chronometer, which fills in a gap between 3H and 14C , is particularly important given the need to tap deep reservoirs of ancient drinking water.

Mechanisms of protein kinase C signaling in the modulation of 3',5'-cyclic adenosine monophosphate-mediated steroidogenesis in mouse gonadal cells.

PubMed

Manna, Pulak R; Huhtaniemi, Ilpo T; Stocco, Douglas M

2009-07-01

The protein kinase C (PKC) signaling pathway plays integral roles in the expression of the steroidogenic acute regulatory (StAR) protein that regulates steroid biosynthesis in steroidogenic cells. PKC can modulate the activity of cAMP/protein kinase A signaling involved in steroidogenesis; however, its mechanism remains obscure. In the present study, we demonstrate that activation of the PKC pathway, by phorbol 12-myristate 13-acetate (PMA), was capable of potentiating dibutyryl cAMP [(Bu)(2)cAMP]-stimulated StAR expression, StAR phosphorylation, and progesterone synthesis in both mouse Leydig (MA-10) and granulosa (KK-1) tumor cells. The steroidogenic potential of PMA and (Bu)(2)cAMP was linked with phosphorylation of ERK 1/2; however, inhibition of the latter demonstrated varying effects on steroidogenesis. Transcriptional activation of the StAR gene by PMA and (Bu)(2)cAMP was influenced by several factors, its up-regulation being dependent on phosphorylation of the cAMP response element binding protein (CREB). An oligonucleotide probe containing a CREB/activating transcription factor binding region in the StAR promoter was found to bind nuclear proteins in PMA and (Bu)(2)cAMP-treated MA-10 and KK-1 cells. Chromatin immunoprecipitation studies revealed that the induction of phosphorylated CREB was tightly correlated with in vivo protein-DNA interactions and recruitment of CREB binding protein to the StAR promoter. Ectopic expression of CREB binding protein enhanced CREB-mediated transcription of the StAR gene, an event that was markedly repressed by the adenovirus E1A oncoprotein. Further studies demonstrated that the activation of StAR expression and steroid synthesis by PMA and (Bu)(2)cAMP was associated with expression of the nuclear receptor Nur77, indicating its essential role in hormone-regulated steroidogenesis. Collectively, these findings provide insight into the mechanisms by which PKC modulates cAMP/protein kinase A responsiveness involved in regulating the steroidogenic response in mouse gonadal cells.

Erratum: Erratum to: A study of vorticity formation in high energy nuclear collisions

NASA Astrophysics Data System (ADS)

Becattini, F.; Inghirami, G.; Rolando, V.; Beraudo, A.; Del Zanna, L.; De Pace, A.; Nardi, M.; Pagliara, G.; Chandra, V.

2018-05-01

Due to an oversight of ours in proofreading and a communication problem with the publisher, the figures published in F. Becattini et al. Eur. Phys. J. C (2015) 75: 406 were not correct. This Erratum contains the correct figures as in arXiv 1501.04468v2, submitted on March 12 2015, and the post-publication version arXiv 1501.04468v3, submitted on August 17 2015.

Smoking-associated lung cancer prevention by blockade of the beta-adrenergic receptor-mediated insulin-like growth factor receptor activation.

PubMed

Min, Hye-Young; Boo, Hye-Jin; Lee, Ho Jin; Jang, Hyun-Ji; Yun, Hye Jeong; Hwang, Su Jung; Smith, John Kendal; Lee, Hyo-Jong; Lee, Ho-Young

2016-10-25

Activation of receptor tyrosine kinases (RTKs) is associated with carcinogenesis, but its contribution to smoking-associated lung carcinogenesis is poorly understood. Here we show that a tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced insulin-like growth factor 1 receptor (IGF-1R) activation via β-adrenergic receptor (β-AR) is crucial for smoking-associated lung carcinogenesis. Treatment with NNK stimulated the IGF-1R signaling pathway in a time- and dose-dependent manner, which was suppressed by pharmacological or genomic blockade of β-AR and the downstream signaling including a Gβγ subunit of β-AR and phospholipase C (PLC). Consistently, β-AR agonists led to increased IGF-1R phosphorylation. The increase in IGF2 transcription via β-AR, signal transducer and activator of transcription 3 (STAT3), and nuclear factor-kappa B (NF-κB) was associated with NNK-induced IGF-1R activation. Finally, treatment with β-AR antagonists suppressed the acquisition of transformed phenotypes in lung epithelial cells and lung tumor formation in mice. These results suggest that blocking β-AR-mediated IGF-1R activation can be an effective strategy for lung cancer prevention in smokers.

A closer look at 40Ar/39Ar systematics of illite, recoil, retention ages, total gas ages, and a new correction method

NASA Astrophysics Data System (ADS)

Fitz-Diaz, E.; Hall, C. M.; van der Pluijm, B.

2013-12-01

One of the fundamentals of 40Ar-39Ar systematics of illite considers the effects of 39Ar recoil (ejection of 39Ar from tiny illite crystallites during the nuclear reaction 39K(n,p)39Ar), for which sample vacuum encapsulation prior to irradiation has been used since the 1990's. This technique separately measures the fraction of recoiled 39Ar and the Ar (39Ar and 40Ar) retained within illite crystals as they degas during step heating in vacuum. Total-gas ages (TGA) are calculated by using both recoiled and retained argon, while retention ages (RA) only involve retained Ar. Observations in numerous natural examples have shown that TGA fit stratigraphic constraints of geological processes when the average illite crystallite thickness (ICT) is smaller than 10nm, and that RA better matches these constrains for larger ICTs. Illite crystals with ICT >50nm show total gas and retention ages within a few My and they are identical, within analytical error, when ICT exceeds 150nm. We propose a new age correction that takes into account the average ICT and corresponding recoil for a sample , with such corrected ages (XCA) lying between the TGA and RA end-member ages. We apply this correction to samples containing one generation of illite and it particularly affects illite populations formed in the anchizone, with typical ICT values between 10-40nm. We analyzed bentonitic samples (S1, S2 and S3) from sites in Cretaceous carbonates in the front of the Monterrey salient in northern Mexico. Four size fractions (<0.05, 0.05-0.2, 0.2-1 & 1-2 μm) were separated, analyzed with XRD and dated by Ar-Ar. XRD analysis provides mineralogic characterization, illite polytype quantification, and illite crystallite thickness (ICT) determination using half-height peak width (illite crystallinity) and the Scherrer equation. All samples contain illite as the main mineral phase, ICT values between 8-27nm, from fine to coarser grain size fractions. Ages show a range in TGA among the different size fractions of S1, S2 and S3, respectively: 46-49, 36-43 and 40-52 My) and RA (54-64, 47-52 and 53-54 My. XCA calculations produce tighter constrained ranges (53-57, 45.5-48.5 and 49-52 My) with an overall average 51.1Ma×3.9 My. In the ICT vs. apparent age plot, authigenic illite grains show a greater slope that is in general slightly positive for TGA, slightly negative for RA, but close to zero for XCA. In the ICT vs. XCA plot thinner crystallites shows more dispersion than thicker ones. In order to test if such dispersion in the age of the finer/thinner illite is due to a different formation history in each site or the result of retention capability, degassing spectra were modeled for site XCA averages and overall XCA average. The modeling shows that local site ages best match the measured spectra, instead of a single age for the combined sites. The closeness between experimental and artificial degassing patterns also supports the hypothesis that each sample preserves a single age population. All illite grains in these samples grew progressively during folding in a time window that is constrained by the three sites. Small and large grains represent the same population in each sample, representing progressive degrees of grain growth (Ostwald ripening).

Targeting AR Variant-Coactivator Interactions to Exploit Prostate Cancer Vulnerabilities.

PubMed

Magani, Fiorella; Peacock, Stephanie O; Rice, Meghan A; Martinez, Maria J; Greene, Ann M; Magani, Pablo S; Lyles, Rolando; Weitz, Jonathan R; Burnstein, Kerry L

2017-11-01

Castration-resistant prostate cancer (CRPC) progresses rapidly and is incurable. Constitutively active androgen receptor splice variants (AR-Vs) represent a well-established mechanism of therapeutic resistance and disease progression. These variants lack the AR ligand-binding domain and, as such, are not inhibited by androgen deprivation therapy (ADT), which is the standard systemic approach for advanced prostate cancer. Signaling by AR-Vs, including the clinically relevant AR-V7, is augmented by Vav3, an established AR coactivator in CRPC. Using mutational and biochemical studies, we demonstrated that the Vav3 Diffuse B-cell lymphoma homology (DH) domain interacted with the N-terminal region of AR-V7 (and full length AR). Expression of the Vav3 DH domain disrupted Vav3 interaction with and enhancement of AR-V7 activity. The Vav3 DH domain also disrupted AR-V7 interaction with other AR coactivators: Src1 and Vav2, which are overexpressed in PC. This Vav3 domain was used in proof-of-concept studies to evaluate the effects of disrupting the interaction between AR-V7 and its coactivators on CRPC cells. This disruption decreased CRPC cell proliferation and anchorage-independent growth, caused increased apoptosis, decreased migration, and resulted in the acquisition of morphological changes associated with a less aggressive phenotype. While disrupting the interaction between FL-AR and its coactivators decreased N-C terminal interaction, disrupting the interaction of AR-V7 with its coactivators decreased AR-V7 nuclear levels. Implications: This study demonstrates the potential therapeutic utility of inhibiting constitutively active AR-V signaling by disrupting coactivator binding. Such an approach is significant, as AR-Vs are emerging as important drivers of CRPC that are particularly recalcitrant to current therapies. Mol Cancer Res; 15(11); 1469-80. ©2017 AACR . ©2017 American Association for Cancer Research.

Synaptic Long-Term Potentiation and Depression in the Rat Medial Vestibular Nuclei Depend on Neural Activation of Estrogenic and Androgenic Signals

PubMed Central

Scarduzio, Mariangela; Panichi, Roberto; Pettorossi, Vito Enrico; Grassi, Silvarosa

2013-01-01

Estrogenic and androgenic steroids can be synthesised in the brain and rapidly modulate synaptic transmission and plasticity through direct interaction with membrane receptors for estrogens (ERs) and androgens (ARs). We used whole cell patch clamp recordings in brainstem slices of male rats to explore the influence of ER and AR activation and local synthesis of 17β-estradiol (E2) and 5α-dihydrotestosterone (DHT) on the long-term synaptic changes induced in the neurons of the medial vestibular nucleus (MVN). Long-term depression (LTD) and long-term potentiation (LTP) caused by different patterns of high frequency stimulation (HFS) of the primary vestibular afferents were assayed under the blockade of ARs and ERs or in the presence of inhibitors for enzymes synthesizing DHT (5α-reductase) and E2 (P450-aromatase) from testosterone (T). We found that LTD is mediated by interaction of locally produced androgens with ARs and LTP by interaction of locally synthesized E2 with ERs. In fact, the AR block with flutamide prevented LTD while did not affect LTP, and the blockade of ERs with ICI 182,780 abolished LTP without influencing LTD. Moreover, the block of P450-aromatase with letrozole not only prevented the LTP induction, but inverted LTP into LTD. This LTD is likely due to the local activation of androgens, since it was abolished under blockade of ARs. Conversely, LTD was still induced in the presence of finasteride the inhibitor of 5α-reductase demonstrating that T is able to activate ARs and induce LTD even when DHT is not synthesized. This study demonstrates a key and opposite role of sex neurosteroids in the long-term synaptic changes of the MVN with a specific role of T-DHT for LTD and of E2 for LTP. Moreover, it suggests that different stimulation patterns can lead to LTD or LTP by specifically activating the enzymes involved in the synthesis of androgenic or estrogenic neurosteroids. PMID:24265837

Coincidence (e,e'p) Scattering on 40Ar and 48Ti to Aid Precision Neutrino Oscillation Experiments

NASA Astrophysics Data System (ADS)

Abrams, Dan; E12-14-012 Collaboration

2017-09-01

Neutrino oscillations are an active area of research, with experiments such as DUNE (Deep Underground Neutrino Experiment). DUNE will make use of large liquid argon detectors to perform a precision measurement of the CP violating phase. Hence, an understanding of the argon nuclear ground state and its response to (anti-)neutrino interactions is of paramount importance. Information about the nuclear ground state is encapsulated in the spectral function, S (k , E) , the joint probability of removing a nucleon of momentum k = |k | from the ground state leaving the residual (A-1) system with excitation energy E. E12-14-012 at Jefferson Lab ran in early 2017 and has measured the argon spectral function through coincidence (e ,e' p) scattering on 40Ar and 48Ti. The results of E12-14-012 are important to both the neutrino and nuclear physics communities. A direct measurement of the coincidence (e ,e' p) cross section from 40Ar and 48Ti will provide valuable information about the argon nucleus, as well as the experimental input necessary to constrain theoretical models used to calculate S (k , E) , paving the way for reliable estimates of the neutrino cross sections. Data from E12-14-012 is currently being analyzed at UVA and Va. Tech. Supported in part by the Department of Energy Grant No: DE-FG02-96ER40950.

Static and Impulsive Models of Solar Active Regions

NASA Technical Reports Server (NTRS)

Patsourakos, S.; Klimchuk, James A.

2008-01-01

The physical modeling of active regions (ARs) and of the global coronal is receiving increasing interest lately. Recent attempts to model ARs using static equilibrium models were quite successful in reproducing AR images of hot soft X-ray (SXR) loops. They however failed to predict the bright EUV warm loops permeating ARs: the synthetic images were dominated by intense footpoint emission. We demonstrate that this failure is due to the very weak dependence of loop temperature on loop length which cannot simultaneously account for both hot and warm loops in the same AR. We then consider time-dependent AR models based on nanoflare heating. We demonstrate that such models can simultaneously reproduce EUV and SXR loops in ARs. Moreover, they predict radial intensity variations consistent with the localized core and extended emissions in SXR and EUV AR observations respectively. We finally show how the AR morphology can be used as a gauge of the properties (duration, energy, spatial dependence, repetition time) of the impulsive heating.

Nuclear and radiological terrorism: continuing education article.

PubMed

Anderson, Peter D; Bokor, Gyula

2013-06-01

Terrorism involving radioactive materials includes improvised nuclear devices, radiation exposure devices, contamination of food sources, radiation dispersal devices, or an attack on a nuclear power plant or a facility/vehicle that houses radioactive materials. Ionizing radiation removes electrons from atoms and changes the valence of the electrons enabling chemical reactions with elements that normally do not occur. Ionizing radiation includes alpha rays, beta rays, gamma rays, and neutron radiation. The effects of radiation consist of stochastic and deterministic effects. Cancer is the typical example of a stochastic effect of radiation. Deterministic effects include acute radiation syndrome (ARS). The hallmarks of ARS are damage to the skin, gastrointestinal tract, hematopoietic tissue, and in severe cases the neurovascular structures. Radiation produces psychological effects in addition to physiological effects. Radioisotopes relevant to terrorism include titrium, americium 241, cesium 137, cobalt 60, iodine 131, plutonium 238, califormium 252, iridium 192, uranium 235, and strontium 90. Medications used for treating a radiation exposure include antiemetics, colony-stimulating factors, antibiotics, electrolytes, potassium iodine, and chelating agents.

Atmospheric Rivers across Multi-scales of the Hydrologic cycle

NASA Astrophysics Data System (ADS)

Hu, H.

2017-12-01

Atmospheric Rivers (ARs) are defined as filamentary structures with strong water vapor transport in the atmosphere, moving as much water as is discharged by the Amazon River. As a large-scale phenomenon, ARs are embedded in the planetary-scale Rossby waves and account for the majority of poleward moisture transport in the midlatitudes. On the other hand, AR is the fundamental physical mechanism leading to extreme basin-scale precipitation and flooding over the U.S. West Coast in the winter season. The moisture transported by ARs is forced to rise and generate precipitation when it impinges on the mountainous coastal lands. My goal is to build the connection between the multi-scale features associated with ARs with their impacts on local hydrology, with particular focus on the U.S. West Coast. Moving across the different scales I have: (1) examined the planetary-scale dynamics in the upper-troposphere, and established a robust relationship between the two regimes of Rossby wave breaking and AR-precipitation and streamflow along the West Coast; (2) quantified the contribution from the tropics/subtropics to AR-related precipitation intensity and found a significant modulation from the large-scale thermodynamics; (3) developed a water tracer tool in a land surface model to track the lifecycle of the water collected from AR precipitation over the terrestrial system, so that the role of catchment-scale factors in modulating ARs' hydrological consequences could be examined. Ultimately, the information gather from these studies will indicate how the dynamic and thermodynamic changes as a response to climate change could affect the local flooding and water resource, which would be helpful in decision making.

FAA Air Traffic Activity: Fiscal Year 1989

DTIC Science & Technology

1990-11-01

TEXARKANA (TXK) N ITINERANT OPERATIONS ............................................................. 35464 6 10125 23032 2301 LOCAL O PERATIO NS...48465 W ACO MUNICIPAL ............ . . ..... TX N 338 62067 TEXARKANA ............... ........................... AR N 378 48059 MISSOULA... TEXARKANA ........................................................ AR N 363 35464 SPOKANE FELTS FIELD ..... ................... A M 324 42975 LAKE

Air and Space Power Journal. Volume 24, Number 2, Summer 2010

DTIC Science & Technology

2010-01-01

25:30 PM Departments 20 ❙ Ricochets and Replies 23 ❙ Views & Analyses Should the United States Maintain the Nuclear Triad...become especially daunting. That is the environment I address in this article by examining a case study of the B-1B bomber nuclear -certification... nuclear certification before describing the situation I faced when I ar- rived at the B-1B System Program Office (SPO) in the summer of 1982. Then, I move

CD147 modulates androgen receptor activity through the Akt/Gsk-3β/β-catenin/AR pathway in prostate cancer cells.

PubMed

Fang, Fang; Qin, Yingxin; Hao, Feng; Li, Qiang; Zhang, Wei; Zhao, Chen; Chen, Shuang; Zhao, Liangzhong; Wang, Liguo; Cai, Jianhui

2016-08-01

The androgen signaling pathway serves an important role in the development of prostate cancer. β-Catenin is an androgen receptor (AR) cofactor and augments AR signaling. Glycogen synthase kinase-3β (GSK-3β), a target of phosphorylated serine/threonine protein kinase B (p-Akt), regulates β-catenin stability. In addition, β-catenin, a coregulator of AR, physically interacts with AR and enhances AR-mediated target gene transcription. The multifunctional glycoprotein cluster of differentiation (CD) 147 is highly expressed on the cell surface of the majority of cancer cells, and it promotes tumor invasion, metastasis and growth. In the present study, the molecular effects of CD147 on the Akt/GSK-3β/β-catenin/AR signaling network were investigated in LNCaP cells. Using short hairpin-mediated RNA knockdown of CD147 in LNCaP cells, it was demonstrated that downregulation of CD147 resulted in inhibitory phosphorylation of GSK-3β, and then promoted degeneration of β-catenin and reduced nuclear accumulation of β-catenin. In addition, immunoprecipitation studies demonstrated that CD147 downregulation decreased the formation of a complex between β-catenin and AR. It was shown that CD147 knockdown suppressed the expression of the AR target gene prostate-specific antigen and the growth of AR-positive LNCaP cells. Furthermore, inhibition of PI3K/Akt with LY294002 augmented CD147-mediated function. The present study indicates that the PI3K/Akt pathway may facilitate CD147-mediated activation of the AR pathway.

OEDGE modeling of plasma contamination efficiency of Ar puffing from different divertor locations in EAST

NASA Astrophysics Data System (ADS)

Pengfei, ZHANG; Ling, ZHANG; Zhenwei, WU; Zong, XU; Wei, GAO; Liang, WANG; Qingquan, YANG; Jichan, XU; Jianbin, LIU; Hao, QU; Yong, LIU; Juan, HUANG; Chengrui, WU; Yumei, HOU; Zhao, JIN; J, D. ELDER; Houyang, GUO

2018-04-01

Modeling with OEDGE was carried out to assess the initial and long-term plasma contamination efficiency of Ar puffing from different divertor locations, i.e. the inner divertor, the outer divertor and the dome, in the EAST superconducting tokamak for typical ohmic plasma conditions. It was found that the initial Ar contamination efficiency is dependent on the local plasma conditions at the different gas puff locations. However, it quickly approaches a similar steady state value for Ar recycling efficiency >0.9. OEDGE modeling shows that the final equilibrium Ar contamination efficiency is significantly lower for the more closed lower divertor than that for the upper divertor.

Contour-Based Corner Detection and Classification by Using Mean Projection Transform

PubMed Central

Kahaki, Seyed Mostafa Mousavi; Nordin, Md Jan; Ashtari, Amir Hossein

2014-01-01

Image corner detection is a fundamental task in computer vision. Many applications require reliable detectors to accurately detect corner points, commonly achieved by using image contour information. The curvature definition is sensitive to local variation and edge aliasing, and available smoothing methods are not sufficient to address these problems properly. Hence, we propose Mean Projection Transform (MPT) as a corner classifier and parabolic fit approximation to form a robust detector. The first step is to extract corner candidates using MPT based on the integral properties of the local contours in both the horizontal and vertical directions. Then, an approximation of the parabolic fit is calculated to localize the candidate corner points. The proposed method presents fewer false-positive (FP) and false-negative (FN) points compared with recent standard corner detection techniques, especially in comparison with curvature scale space (CSS) methods. Moreover, a new evaluation metric, called accuracy of repeatability (AR), is introduced. AR combines repeatability and the localization error (Le) for finding the probability of correct detection in the target image. The output results exhibit better repeatability, localization, and AR for the detected points compared with the criteria in original and transformed images. PMID:24590354

Contour-based corner detection and classification by using mean projection transform.

PubMed

Kahaki, Seyed Mostafa Mousavi; Nordin, Md Jan; Ashtari, Amir Hossein

2014-02-28

Image corner detection is a fundamental task in computer vision. Many applications require reliable detectors to accurately detect corner points, commonly achieved by using image contour information. The curvature definition is sensitive to local variation and edge aliasing, and available smoothing methods are not sufficient to address these problems properly. Hence, we propose Mean Projection Transform (MPT) as a corner classifier and parabolic fit approximation to form a robust detector. The first step is to extract corner candidates using MPT based on the integral properties of the local contours in both the horizontal and vertical directions. Then, an approximation of the parabolic fit is calculated to localize the candidate corner points. The proposed method presents fewer false-positive (FP) and false-negative (FN) points compared with recent standard corner detection techniques, especially in comparison with curvature scale space (CSS) methods. Moreover, a new evaluation metric, called accuracy of repeatability (AR), is introduced. AR combines repeatability and the localization error (Le) for finding the probability of correct detection in the target image. The output results exhibit better repeatability, localization, and AR for the detected points compared with the criteria in original and transformed images.

Global Floods and Water Availability Driven by Atmospheric Rivers

NASA Astrophysics Data System (ADS)

Paltan, Homero; Waliser, Duane; Lim, Wee Ho; Guan, Bin; Yamazaki, Dai; Pant, Raghav; Dadson, Simon

2017-10-01

While emerging regional evidence shows that atmospheric rivers (ARs) can exert strong impacts on local water availability and flooding, their role in shaping global hydrological extremes has not yet been investigated. Here we quantify the relative contribution of ARs variability to both flood hazard and water availability. We find that globally, precipitation from ARs contributes 22% of total global runoff, with a number of regions reaching 50% or more. In areas where their influence is strongest, ARs may increase the occurrence of floods by 80%, while absence of ARs may increase the occurrence of hydrological droughts events by up to 90%. We also find that 300 million people are exposed to additional floods and droughts due the occurrence of ARs. ARs provide a source of hydroclimatic variability whose beneficial or damaging effects depend on the capacity of water resources managers to predict and adapt to them.

Function of beta 2-adrenergic receptors in chronic localized myalgia.

PubMed

Maekawa, Kenji; Kuboki, Takuo; Inoue, Eitoku; Inoue-Minakuchi, Mami; Suzuki, Koji; Yatani, Hirofumi; Clark, Glenn T

2003-01-01

To investigate alteration of beta 2-adrenergic receptor (beta 2 AR) function in chronic localized myalgia subjects by evaluating levels of the beta 2 AR second messenger, cyclic adenosine monophosphate (cAMP), in mononuclear cells after beta AR-agonist stimulation. Eleven chronic localized myalgia subjects and 21 matched healthy controls participated in this study. Peripheral blood (30 cc) was drawn from the subjects' anterocubital vein. Mononuclear cells were isolated from the total blood by using the Ficoll-Hypaque gradient technique. Basal and stimulated intracellular cAMP levels were determined by enzyme immunoassay using a commercially available kit. Aliquots of 5 x 10(6) cells were incubated with or without stimulation of the beta AR-agonist isoproterenol for 5 minutes. Five different concentrations of isoproterenol (10(-3) M to 10(-7) M) were utilized. cAMP levels in both groups were tested statistically by a 2-way repeated-measures ANOVA with 2 predictors, group difference and isoproterenol concentration difference. As with isoproterenol stimulation, the cAMP responses to forskolin, which activates adenylyl cyclase directly and produces cAMP, bypassing the cell surface receptors were also measured. The basal cAMP levels in both groups (myalgia: 0.33 +/- 0.02 pmol/5 x 10(6) cells; control: 0.43 +/- 0.10 pmol/5 x 10(6) cells) were almost identical, and isoproterenol-produced cAMP levels increased dose-dependently in both groups. No significant differences in the mean cAMP levels were observed between the groups (P = .909). Significant increases were observed according to the isoproterenol concentration increase (P < .0001). The cAMP responses to forskolin stimulation also showed no significant group difference (P = .971). These results suggest that beta 2 AR function is not different between localized myalgia subjects and healthy individuals.

Stilbene Induced Inhibition of Androgen Receptor Dimerization: Implications for AR and ARΔLBD-Signalling in Human Prostate Cancer Cells

PubMed Central

Streicher, Wolfgang; Luedeke, Manuel; Azoitei, Anca; Zengerling, Friedemann; Herweg, Alexander; Genze, Felicitas; Schrader, Mark G.; Schrader, Andres J.; Cronauer, Marcus V.

2014-01-01

Background Advanced castration resistant prostate cancer (CRPC) is often characterized by an increase of C-terminally truncated, constitutively active androgen receptor (AR) variants. Due to the absence of a ligand binding domain located in the AR-C-terminus, these receptor variants (also termed ARΔLBD) are unable to respond to all classical forms of endocrine treatments like surgical/chemical castration and/or application of anti-androgens. Methodology In this study we tested the effects of the naturally occurring stilbene resveratrol (RSV) and (E)-4-(2, 6-Difluorostyryl)-N, N-dimethylaniline, a fluorinated dialkylaminostilbene (FIDAS) on AR- and ARΔLBD in prostate cancer cells. The ability of the compounds to modulate transcriptional activity of AR and the ARΔLBD-variant Q640X was shown by reporter gene assays. Expression of endogenous AR and ARΔLBD mRNA and protein levels were determined by qRT-PCR and Western Blot. Nuclear translocation of AR-molecules was analyzed by fluorescence microscopy. AR and ARΔLBD/Q640X homo-/heterodimer formation was assessed by mammalian two hybrid assays. Biological activity of both compounds in vivo was demonstrated using a chick chorioallantoic membrane xenograft assay. Results The stilbenes RSV and FIDAS were able to significantly diminish AR and Q640X-signalling. Successful inhibition of the Q640X suggests that RSV and FIDAS are not interfering with the AR-ligand binding domain like all currently available anti-hormonal drugs. Repression of AR and Q640X-signalling by RSV and FIDAS in prostate cancer cells was caused by an inhibition of the AR and/or Q640X-dimerization. Although systemic bioavailability of both stilbenes is very low, both compounds were also able to downregulate tumor growth and AR-signalling in vivo. Conclusion RSV and FIDAS are able to inhibit the dimerization of AR and ARΔLBD molecules suggesting that stilbenes might serve as lead compounds for a novel generation of AR-inhibitors. PMID:24887556

α1b-Adrenergic Receptor Localization and Relationship to the D1-Dopamine Receptor in the Rat Nucleus Accumbens.

PubMed

Mitrano, Darlene A; Jackson, Kelsey; Finley, Samantha; Seeley, Allison

2018-02-10

The α1-adrenergic receptors (α1ARs) have been implicated in numerous actions of the brain, including attention and wakefulness. Additionally, they have been identified as contributing to disorders of the brain, such as drug addiction, and recent work has shown a role of these receptors in relapse to psychostimulants. While some functionality is known, the actual subcellular localization of the subtypes of the α1ARs remains to be elucidated. Further, their anatomical relationship to receptors for other neurotransmitters, such as dopamine (DA), remains unclear. Therefore, using immunohistochemistry and electron microscopy techniques, this study describes the subcellular localization of the α1b-adrenergic receptor (α1bAR), the subtype most tied to relapse behaviors, as well as its relationship to the D1-dopamine receptor (D1R) in both the shell and core of the rat nucleus accumbens (NAc). Overall, α1bARs were found in unmyelinated axons and axon terminals with some labeling in dendrites. In accordance with other studies of the striatum, the D1R was found mainly in dendrites and spines; therefore, colocalization of the D1R with the α1bAR was rare postsynaptically. However, in the NAc shell, when the receptors were co-expressed in the same neuronal elements there was a trend for both receptors to be found on the plasma membrane, as opposed to the intracellular compartment. This study provides valuable anatomical information about the α1bAR and its relationship to the D1R and the regulation of DA and norepinephrine (NE) neurotransmission in the brain which have been examined previously. Published by Elsevier Ltd.

Central depression of nuclear charge density distribution

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chu Yanyun; Ren Zhongzhou; Center of Theoretical Nuclear Physics, National Laboratory of Heavy-Ion Accelerator, Lanzhou 730000

The center-depressed nuclear charge distributions are investigated with the parametrized distribution and the relativistic mean-field theory, and their corresponding charge form factors are worked out with the phase shift analysis method. The central depression of nuclear charge distribution of {sup 46}Ar and {sup 44}S is supported by the relativistic mean-field calculation. According to the calculation, the valence protons in {sup 46}Ar and {sup 44}S prefer to occupy the 1d{sub 3/2} state rather than the 2s{sub 1/2} state, which is different from that in the less neutron-rich argon and sulfur isotopes. As a result, the central proton densities of {sup 46}Armore » and {sup 44}S are highly depressed, and so are their central charge densities. The charge form factors of some argon and sulfur isotopes are presented, and the minima of the charge form factors shift upward and inward when the central nuclear charge distributions are more depressed. Besides, the effect of the central depression on the charge form factors is studied with a parametrized distribution, when the root-mean-square charge radii remain constant.« less

Presurgical Planning for Supratentorial Lesions with Free Slicer Software and Sina App.

PubMed

Chen, Ji-Gang; Han, Kai-Wei; Zhang, Dan-Feng; Li, Zhen-Xing; Li, Yi-Ming; Hou, Li-Jun

2017-10-01

Neuronavigation systems are used widely in the localization of intracranial lesions with satisfactory accuracy. However, they are expensive and difficult to learn. Therefore, a simple and practical augmented reality (AR) system using mobile devices might be an alternative technique. We introduce a mobile AR system for the localization of supratentorial lesions. Its practicability and accuracy were examined by clinical application in patients and comparison with a standard neuronavigation system. A 3-dimensional (3D) model including lesions was created with 3D Slicer. A 2-dimensional image of this 3D model was obtained and overlapped on the patient's head with the Sina app. Registration was conducted with the assistance of anatomical landmarks and fiducial markers. The center of lesion projected on scalp was identified with our mobile AR system and standard neuronavigation system, respectively. The difference in distance between the centers identified by these 2 systems was measured. Our mobile AR system was simple and accurate in the localization of supratentorial lesions with a mean distance difference of 4.4 ± 1.1 mm. Registration added on an average of 141.7 ± 39 seconds to operation time. There was no statistically significant difference for the required time among 3 registrations (P = 0.646). The mobile AR system presents an alternative technology for image-guided neurosurgery and proves to be practical and reliable. The technique contributes to optimal presurgical planning for supratentorial lesions, especially in the absence of a neuronavigation system. Copyright © 2017 Elsevier Inc. All rights reserved.

Colony-stimulating factors for the treatment of the hematopoietic component of the acute radiation syndrome (H-ARS): a review.

PubMed

Singh, Vijay K; Newman, Victoria L; Seed, Thomas M

2015-01-01

One of the greatest national security threats to the United States is the detonation of an improvised nuclear device or a radiological dispersal device in a heavily populated area. As such, this type of security threat is considered to be of relatively low risk, but one that would have an extraordinary high impact on health and well-being of the US citizenry. Psychological counseling and medical assessments would be necessary for all those significantly impacted by the nuclear/radiological event. Direct medical interventions would be necessary for all those individuals who had received substantial radiation exposures (e.g., >1 Gy). Although no drugs or products have yet been specifically approved by the United States Food and Drug Administration (US FDA) to treat the effects of acute radiation syndrome (ARS), granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage colony-stimulating factor (GM-CSF), and pegylated G-CSF have been used off label for treating radiation accident victims. Recent threats of terrorist attacks using nuclear or radiologic devices makes it imperative that the medical community have up-to-date information and a clear understanding of treatment protocols using therapeutically effective recombinant growth factors and cytokines such as G-CSF and GM-CSF for patients exposed to injurious doses of ionizing radiation. Based on limited human studies with underlying biology, we see that the recombinants, G-CSF and GM-CSF appear to have modest, but significant medicinal value in treating radiation accident victims. In the near future, the US FDA may approve G-CSF and GM-CSF as ‘Emergency Use Authorization’ (EUA) for managing radiation-induced aplasia, an ARS-related pathology. In this article, we review the status of growth factors for the treatment of radiological/nuclear accident victims.

Transcription factor Brn-3α mRNA in cancers, relationship with AR, ER receptors and AKT/m-TOR pathway components

NASA Astrophysics Data System (ADS)

Spirina, L. V.; Gorbunov, A. K.; Chigevskaya, S. Y.; Usynin, Y. A.; Kondakova, I. V.; Slonimskaya, E. M.; Usynin, E. A.; Choinzonov, E. L.; Zaitseva, O. S.

2017-09-01

Transcription factors POU4F1 (neurogenic factor Brn-3α) play a pivotal role in cancers development. The aim of the study was to reveal the Brn-3α expression, AR, ER expression in cancers development, association with AKT/mTOR pathway activation. 30 patients with locally advanced prostate cancer, 20 patients with papillary thyroid cancer, T2-3N0-1M0 stages and 40 patients with renal cell cancer T2-3N0M0-1 were involved into the study. The expressions of Brn-3α, AR, ERα, components of AKT/m-TOR signaling pathway genes were performed by real-time PCR. The dependence of Brn-3α expression on mRNA levels of steroid hormone receptors and components of AKT/m-TOR signaling pathway in studied cancers were shown. High levels of mRNA of nuclear factor, steroid hormone receptors were found followed by the activation of this signaling pathway in prostate cancer tissue. The reduction of transcription factor Brn-3α was accompanied with tumor invasive growth with increasing rates of AR, ER and 4E-BP1 mRNA. Thyroid cancer development happened in a case of a Brn-3α and steroid hormone receptors decrease. The activation of AKT/m-TOR signaling pathway was established in the metastatic renal cancers, accompanied with the increase of ER mRNA. But there was no correlation between the steroid receptor and Brn-3α. One-direction changes of Brn-3α were observed in the development of prostate and thyroid cancer due to its effect on the steroid hormone receptors and the activation of AKT/m-TOR signaling pathway components. The influence of this factor on the development of the kidney cancer was mediated through m-TOR activity modifications, the key enzyme of oncogenesis.

Extracting Spectroscopic Factors of Argon Isotopes from Transfer Reactions

NASA Astrophysics Data System (ADS)

Manfredi, Juan; Tsang, M. B.; Lynch, W. G.; Brown, K. W.; Cerizza, G.; Barney, J.; Estee, J.; Loelius, C.; Sweany, S.; Anderson, C.; Setiawan, H.; Winkelbauer, J.; Smith, K.; Lee, J.; Xu, Z.; Rogers, A.; Pruitt, C.; Chajecki, Z.; Chen, G.; Langer, C.; Xiao, Z.; Li, Z.; Niu, C.

2017-09-01

A spectroscopic factor (SF) quantifies the single particle structure of a given state in a nucleus. There is a discrepancy in extracted SF's between studies that use transfer reactions and those that use knockout reactions. Resolving this discrepancy is important both for understanding reaction probes as well as constraining nuclear structure theory. Kinematically complete measurements of the transfer reactions 34Ar(p,d) and 46Ar(p,d) were performed at the National Superconducting Cyclotron Laboratory. The same beam energy (70 MeV/u) was used as in a previous knockout measurement to account for energy dependence in the relevant optical potentials. Preliminary results will be presented. In addition, findings from measurement of the two-neutron transfer reactions 34Ar(p,t) and 4 6 Ar(p,t) will be discussed. This work was supported by the NSF (PHY 1565546) and the DOE NNSA Stewardship Science Graduate Fellowship.

On current contribution to Fronsdal equations

NASA Astrophysics Data System (ADS)

Misuna, N. G.

2018-03-01

We explore a local form of second-order Vasiliev equations proposed in [arxiv:arXiv:1706.03718] and obtain an explicit expression for quadratic corrections to bosonic Fronsdal equations, generated by gauge-invariant higher-spin currents. Our analysis is performed for general phase factor, and for the case of parity-invariant theory we find the agreement with expressions for cubic vertices available in the literature. This provides an additional indication that local frame proposed in [arxiv:arXiv:1706.03718] is the proper one.

Holographic Methods for the Investigation of Photophysical Properties.

DTIC Science & Technology

1983-04-22

terphenyl doped with 10- 3 mol/mol of pentacene . Obtaining k from decay curves as in * A -Fig. 14a and plotting k as a function of 02 (see Fig. 14b...translation diffusion of molecules in liquid solvents can be used to probe solute conformations, solvent-solute interactions and local solvent structure...eiion of 1.7omoAr WauW by TrArWAOn GFarinP So far, local heating by the absorption of the two interfering light pulses has not been taken into

A Medical Center Network for Optimized Lung Cancer Biospecimen Banking

DTIC Science & Technology

2013-10-01

Carcinoma Stage IIB N N .149 1 8 .132 1 8 .092 1 No - Quit Smoking 50 AR Agent Orange , Nuclear weapons, Second-hand smoke Agent Orange , Nuclear weapons...Smoking 30 None Agent Orange , Asbestos, Second-hand smoke Agent Orange , Asbestos, Second-hand smoke S0159 Squamous Cell Carcinoma Stage IIB Y N...2.560 100 80 25 6 7 0.670 4 4 0.370 1 No - Quit Smoking 30 NV Agent Orange , Asbestos, Nuclear weapons, Second- hand smoke Agent Orange , Asbestos

nCTEQ15 - Global analysis of nuclear parton distributions with uncertainties

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kusina, A.; Kovarik, Karol; Jezo, T.

2015-09-01

We present the first official release of the nCTEQ nuclear parton distribution functions with errors. The main addition to the previous nCTEQ PDFs is the introduction of PDF uncertainties based on the Hessian method. Another important addition is the inclusion of pion production data from RHIC that give us a handle on constraining the gluon PDF. This contribution summarizes our results from arXiv:1509.00792 and concentrates on the comparison with other groups providing nuclear parton distributions.

nCTEQ15 - Global analysis of nuclear parton distributions with uncertainties

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kusina, A.; Kovarik, K.; Jezo, T.

2015-09-04

We present the first official release of the nCTEQ nuclear parton distribution functions with errors. The main addition to the previous nCTEQ PDFs is the introduction of PDF uncertainties based on the Hessian method. Another important addition is the inclusion of pion production data from RHIC that give us a handle on constraining the gluon PDF. This contribution summarizes our results from arXiv:1509.00792, and concentrates on the comparison with other groups providing nuclear parton distributions.

THE NUCLEAR RAMJET PROPULSION SYSTEM

DOE Office of Scientific and Technical Information (OSTI.GOV)

Merkle, T.C.

1959-06-30

The most practical nuclear ramjet systems consist of a suituble inlet diffusor system followed by a singlepass, straight-through heat exchanger (reactor) which couples into a typical exhaust nozzle. Within this framework, possibilities ars governed by the aerodynamic requirements of flight, the nuclear requirements of the reactor, the chemical problems associated with breathing air, and the mechanical properties of materials at elevated temperatures. The major research and development areas which must be entered in the actual production of such an engine are discussed. (W.D.M.)

Multiplicities of secondaries in nuclear interactions, induced by 20Ne, 40Ar and 56Fe nuclei at 0.1-0.5 GeV/nucleon

NASA Technical Reports Server (NTRS)

Dudkin, V. E.; Kovalev, E. E.; Nefedov, N. A.; Antonchik, V. A.; Bogdanov, S. D.; Kosmach, V. F.; Hassan, J.; Benton, E. V.; Crawford, H. J.

1994-01-01

Multiplicities of various species of charged secondaries produced in inelastic interactions of 20Ne, 40Ar and 56Fe nuclei with emulsion nuclei at 0.1-0.5 GeV/nucleon have been measured. The data obtained are compared with the results for interactions of higher energy nuclei with emulsion nuclei. The dependences of the nucleus-nucleus interaction parameters on masses and energies of colliding nuclei are examined.

Novel therapy in Parkinson's disease: adenosine A(2A) receptor antagonists.

PubMed

Szabó, Nikoletta; Kincses, Zsigmond Tamás; Vécsei, László

2011-04-01

Parkinson's disease (PD) is a progressive neurodegenerative disorder. To date, most of the currently available therapies in PD target the dopaminergic system and none of these therapeutic approaches have been proven to modify the course of the disease. To various extents, these drugs can also cause motor and non-motor complications. A novel target, the adenosine A(2A) receptor (AA2AR), was recently identified, blockade of which may alleviate Parkinsonian symptoms, reduce motor fluctuations and potentially afford neuroprotection. This review is based on a PubMed search covering the relationship of the adenosine receptors and PD. The role of the AA2AR is reviewed and the results of preclinical investigations of antagonists are assessed. A synopsis of current drug development is provided, with a special focus on the pharmacokinetics and relevant clinical trials. The localization of the AA2AR in the central nervous system, the ultra structural localization and the molecular mechanism of its action reveal the potential importance of the AA2AR in movement disorders. The theoretical background and experimental data indicate that AA2AR antagonists may have a potential therapeutic effect in Parkinson's disease. More importantly, the putative neuroprotective effect needs further investigation.

Molecular biology of castration-resistant prostate cancer: basis for the novel therapeutic targets.

PubMed

Mellado, Begoña; Marin Aguilera, Mercedes; Pereira, Maria Veronica

2013-06-01

Prostate cancer cells express the androgen receptor (AR) and need the presence of androgens to survive. Androgen suppression is the gold standard first-line therapy for metastatic disease. Almost all prostate cancer patients initially respond to hormonal therapy, but most of them gradually develop castration-resistant progression. Recent evidence has shown that progression at the castration resistant prostate cancer (CRPC) stage is often mediated by AR signalling. Importantly, subsequent AR androgen inhibition, by abiraterone acetate or enzalutamide, has shown to improve patients' survival. Several mechanisms that enhance AR signalling in an androgen-depleted environment have been elucidated:(1) AR mutations that allow activation by low androgen levels or by other endogenous steroids, (2) AR amplification and/or overexpression,(3)increased local intracrine synthesis of androgens, (4) changes in AR cofactors and (5) cross-talk with cytokines and growth factors. Today, there are under development a number of novel agents targeting the AR signaling pathway. This article reviews the postulated mechanisms of AR-driven resistance to androgen suppression that have contributed to the development of new hormonal therapeutic strategies in prostate cancer.

Tissue-specific distribution of the androgen receptor (AR) in the porcine fetus.

PubMed

Burek, Małgorzata; Duda, Małgorzata; Knapczyk, Katarzyna; Koziorowski, Marek; Słomczyńska, Maria

2007-01-01

The aim of this study was to investigate androgen receptor (AR) expression in developing porcine fetuses. The localization of AR was examined on embryos obtained at different days of gestation: days 18, 32, 50, 71, 90 post coitum (p.c.), and in the several tissues collected from the newborn piglets of both sexes. AR expression was first observed on day 32 p.c. in the mesonephron region. RT-PCR did not show AR mRNA on day18 p.c., but the message was present starting from day 32. In the male differentiating gonads and in the male genital ducts AR protein was present at 50, 71 and 90 days of gestation. AR protein was also detected in the cords of stromal cells within the medulla of the ovary and in stromal cells investing the oogonial nests. Pregranulosa cells on day 90 of gestation and on day 1 post partum (p.p.) immunolabelled positively for AR. In the kidney, a number of AR-positive tubules were visible while the mesenchyme in the kidney was AR-negative. Immunoreactive AR was detected predominantly in the nuclei of epithelial cells of the budding component at different stages of gestation of porcine lung. The presence of AR during gestation in non-gonadal tissues suggests a role of androgen in these tissues.

Ar-40/Ar-39 Studies of Martian Meteorite RBT 04262 and Terrestrial Standards

NASA Technical Reports Server (NTRS)

Park, J.; Herzog, G. F.; Turrin, B.; Lindsay, F. N.; Delaney, J. S.; Swisher, C. C., III; Nagao, K.; Nyquist, L. E.

2014-01-01

Park et al. recently presented an Ar-40/Ar-39 dating study of maskelynite separated from the Martian meteorite RBT 04262. Here we report an additional study of Ar-40/Ar-39 patterns for smaller samples, each consisting of only a few maskelynite grains. Considered as a material for Ar-40/Ar-39 dating, the shock-produced glass maskelynite has both an important strength (relatively high K concentration compared to other mineral phases) and some potentially problematic weaknesses. At Rutgers, we have been analyzing small grains consisting of a single phase to explore local effects that might be averaged and remain hidden in larger samples. Thus, to assess the homogeneity of the RBT maskelynite and for comparison with the results of, we analyzed six approx. 30 microgram samples of the same maskelynite separate they studied. Furthermore, because most Ar-40/Ar-39 are calculated relative to the age of a standard, we present new Ar-40/Ar-39 age data for six standards. Among the most widely used standards are sanidine from Fish Canyon (FCs) and various hornblendes (hb3gr, MMhb-1, NL- 25), which are taken as primary standards because their ages have been determined by independent, direct measurements of K and A-40.

Development of a Low-Level Ar-37 Calibration Standard

DOE Office of Scientific and Technical Information (OSTI.GOV)

Williams, Richard M.; Aalseth, Craig E.; Bowyer, Ted W.

Argon-37 is an important environmental signature of an underground nuclear explosion. Producing and quantifying low-level 37Ar standards is an important step in the development of sensitive field measurement instruments for use during an On-Site Inspection, a key provision of the Comprehensive Nuclear-Test-Ban Treaty. This paper describes progress at Pacific Northwest National Laboratory (PNNL) in the development of a process to generate and quantify low-level 37Ar standard material, which can then be used to calibrate sensitive field systems at activities consistent with soil background levels. The 37Ar used for our work was generated using a laboratory-scale, high-energy neutron source to irradiatemore » powdered samples of calcium carbonate. Small aliquots of 37Ar were then extracted from the head space of the irradiated samples. The specific activity of the head space samples, mixed with P10 (90% stable argon:10% methane by mole fraction) count gas, is then derived using the accepted Length-Compensated Internal-Source Proportional Counting method. Due to the low activity of the samples, a set of three Ultra-Low Background Proportional-Counters designed and fabricated at PNNL from radio-pure electroformed copper was used to make the measurements in PNNL’s shallow underground counting laboratory. Very low background levels (<10 counts/day) have been observed in the spectral region near the 37Ar emission feature at 2.8 keV. Two separate samples from the same irradiation were measured. The first sample was counted for 12 days beginning 28 days after irradiation, the second sample was counted for 24 days beginning 70 days after irradiation (the half-life of 37Ar is 35.0 days). Both sets of measurements were analyzed and yielded very similar results for the starting activity (~0.1 Bq) and activity concentration (0.15 mBq/ccSTP argon) after P10 count gas was added. A detailed uncertainty model was developed based on the ISO Guide to the Expression of Uncertainty in Measurement. This paper presents a discussion of the measurement analysis, along with assumptions and uncertainty estimates.« less

Docosahexaenoic acid inhibits IL-6 expression via PPARγ-mediated expression of catalase in cerulein-stimulated pancreatic acinar cells.

PubMed

Song, Eun Ah; Lim, Joo Weon; Kim, Hyeyoung

2017-07-01

Cerulein pancreatitis mirrors human acute pancreatitis. In pancreatic acinar cells exposed to cerulein, reactive oxygen species (ROS) mediate inflammatory signaling by Janus kinase (JAK) 2/signal transducer and activator of transcription (STAT) 3, and cytokine induction. Docosahexaenoic acid (DHA) acts as an agonist of peroxisome proliferator activated receptor γ (PPARγ), which mediates the expression of some antioxidant enzymes. We hypothesized that DHA may induce PPARγ-target catalase expression and reduce ROS levels, leading to the inhibition of JAK2/STAT3 activation and IL-6 expression in cerulein-stimulated acinar cells. Pancreatic acinar AR42J cells were treated with DHA in the presence or absence of the PPARγ antagonist GW9662, or treated with the PPARγ agonist troglitazone, and then stimulated with cerulein. Expression of IL-6 and catalase, ROS levels, JAK2/STAT3 activation, and nuclear translocation of PPARγ were assessed. DHA suppressed the increase in ROS, JAK2/STAT3 activation, and IL-6 expression induced nuclear translocation of PPARγ and catalase expression in cerulein-stimulated AR42J cells. Troglitazone inhibited the cerulein-induced increase in ROS and IL-6 expression, but induced catalase expression similar to DHA in AR42J cells. GW9662 abolished the inhibitory effect of DHA on cerulein-induced increase in ROS and IL-6 expression in AR42J cells. DHA-induced expression of catalase was suppressed by GW9662 in cerulein-stimulated AR42J cells. Thus, DHA induces PPARγ activation and catalase expression, which inhibits ROS-mediated activation of JAK2/STAT3 and IL-6 expression in cerulein-stimulated pancreatic acinar cells. Copyright © 2017. Published by Elsevier Ltd.

The pluripotency factor Nanog is directly upregulated by the androgen receptor in prostate cancer cells.

PubMed

Kregel, Steven; Szmulewitz, Russell Z; Vander Griend, Donald J

2014-11-01

The Androgen Receptor (AR) is a nuclear hormone receptor that functions as a critical oncogene in all stages of prostate cancer progression, including progression to castration-resistance following androgen-deprivation therapy. Thus, identifying and targeting critical AR-regulated genes is one potential method to block castration-resistant cancer proliferation. Of particular importance are transcription factors that regulate stem cell pluripotency; many of these genes are emerging as critical oncogenes in numerous tumor cell types. Of these, Nanog has been previously shown to increase the self-renewal and stem-like properties of prostate cancer cells. Thus, we hypothesized that Nanog is a candidate AR target gene that may impart castration-resistance. We modulated AR signaling in LNCaP prostate cancer cells and assayed for Nanog expression. Direct AR binding to the NANOG promoter was tested using AR Chromatin Immunoprecipation (ChIP) and analyses of publically available AR ChIP-sequencing data-sets. Nanog over-expressing cells were analyzed for cell growth and cytotoxicity in response to the AR antagonist enzalutamide and the microtubule stabilizing agent docetaxel. AR signaling upregulates Nanog mRNA and protein. AR binds directly to the NANOG promoter, and was not identified within 75 kb of the NANOGP8 pseudogene, suggesting the NANOG gene locus was preferentially activated. Nanog overexpression in LNCaP cells increases overall growth, but does not increase resistance to enzalutamide or docetaxel. Nanog is a novel oncogenic AR target gene in prostate cancer cells, and stable expression of Nanog increases proliferation and growth of prostate cancer cells, but not resistance to enzalutamide or docetaxel. © 2014 Wiley Periodicals, Inc.

Targeting Androgen Receptor-Driven Resistance to CYP17A1 Inhibitors

DTIC Science & Technology

2016-11-01

unlimited The views, opinions and/or findings contained in this report are those of the author(s) and should not be construed as an official Department of...chemo- and radiotherapies that are efficacious against primary, androgen sensitive (AS)-CaP. CR-CaP progresses to metastatic disease in local lymph... AR ) protein, called AR -V, is directly responsible for malignancy of CR-CaP, and moreover, that ENZ or ABI treatment actually enhances production of AR

Chronobiology and chronotherapy of allergic rhinitis and bronchial asthma.

PubMed

Smolensky, Michael H; Lemmer, Bjoern; Reinberg, Alain E

2007-08-31

Study of the chronobiology of allergic rhinitis (AR) and bronchial asthma (BA) and the chronopharmacology and chronotherapy of the medications used in their treatment began five decades ago. AR is an inflammatory disease of the upper airway tissue with hypersensitivity to specific environmental antigens, resulting in further local inflammation, vasomotor changes, and mucus hypersecretion. Symptoms include sneezing, nasal congestion, and runny and itchy nose. Approximately 25% of children and 40% of adults in USA are affected by AR during one or more seasons of the year. The manifestation and severity of AR symptoms exhibit prominent 24-h variation; in most persons they are worse overnight or early in the morning and often comprise nighttime sleep, resulting in poor daytime quality of life, compromised school and work performance, and irritability and moodiness. BA is also an inflammatory medical condition of the lower airways characterized by hypersensitivity to specific environmental antigens, resulting in greater local inflammation as well as bronchoconstriction, vasomotor change, and mucus hypersecretion. In USA an estimated 6.5 million children and 15.7 million adults have BA. The onset and worsening of BA are signaled by chest wheeze and/or croupy cough and difficult and labored breathing. Like AR, BA is primarily a nighttime medical condition. AR is treated with H1-antagonist, decongestant, and anti-inflammatory (glucocorticoid and leukotriene receptor antagonist and modifier) medications. Only H1-antagonist AR medications have been studied for their chronopharmacology and potential chronotherapy. BA is treated with some of the same medications and also theophylline and beta2-agonists. The chronopharmacology and chronotherapy of many classes of BA medications have been explored. This article reviews the rather extensive knowledge of the chronobiology of AR and BA and the chronopharmacology and chronotherapy of the various medications used in their treatment.

Quantification of transcription factor-DNA binding affinity in a living cell

PubMed Central

Belikov, Sergey; Berg, Otto G.; Wrange, Örjan

2016-01-01

The apparent dissociation constant (Kd) for specific binding of glucocorticoid receptor (GR) and androgen receptor (AR) to DNA was determined in vivo in Xenopus oocytes. The total nuclear receptor concentration was quantified as specifically retained [3H]-hormone in manually isolated oocyte nuclei. DNA was introduced by nuclear microinjection of single stranded phagemid DNA, chromatin is then formed during second strand synthesis. The fraction of DNA sites occupied by the expressed receptor was determined by dimethylsulphate in vivo footprinting and used for calculation of the receptor-DNA binding affinity. The forkhead transcription factor FoxA1 enhanced the DNA binding by GR with an apparent Kd of ∼1 μM and dramatically stimulated DNA binding by AR with an apparent Kd of ∼0.13 μM at a composite androgen responsive DNA element containing one FoxA1 binding site and one palindromic hormone receptor binding site known to bind one receptor homodimer. FoxA1 exerted a weak constitutive- and strongly cooperative DNA binding together with AR but had a less prominent effect with GR, the difference reflecting the licensing function of FoxA1 at this androgen responsive DNA element. PMID:26657626

Improved gas tagging and cover gas combination for nuclear reactor

DOEpatents

Gross, K.C.; Laug, M.T.

1983-09-26

The invention discloses the use of stable isotopes of neon and argon, sealed as tags in different cladding nuclear fuel elements to be used in a liquid metal fast breeder reactor. Cladding failure allows fission gases and these tag isotopes to escape and to combine with the cover gas. The isotopes are Ne/sup 20/, Ne/sup 21/ and Ne/sup 22/ and Ar/sup 36/, Ar/sup 38/ and Ar/sup 40/, and the cover gas is He. Serially connected cryogenically operated charcoal beds are used to clean the cover gas and to separate out the tags. The first or cover gas cleanup bed is held between 0 and -25/sup 0/C to remove the fission gases from the cover gas and tags, and the second or tag recovery system bed between -170 and -185/sup 0/C to isolate the tags from the cover gas. Spectrometric analysis is used to identify the specific tags that are recovered, and thus the specific leaking fuel element. By cataloging the fuel element tags to the location of the fuel elements in the reactor, the location of the leaking fuel element can then be determined.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ding, Ying; Adachi, Hiroaki, E-mail: hadachi-ns@umin.org; Department of Neurology, University of Occupational and Environmental Health School of Medicine, 1-1 Iseigaoka, Yahata-nishi-ku, Kitakyushu 807-8555

Spinal and bulbar muscular atrophy (SBMA) is an inherited motor neuron disease caused by the expansion of a polyglutamine (polyQ)-encoding tract within the androgen receptor (AR) gene. The pathologic features of SBMA are motor neuron loss in the spinal cord and brainstem and diffuse nuclear accumulation and nuclear inclusions of mutant AR in residual motor neurons and certain visceral organs. Hepatocyte growth factor (HGF) is a polypeptide growth factor which has neuroprotective properties. To investigate whether HGF overexpression can affect disease progression in a mouse model of SBMA, we crossed SBMA transgenic model mice expressing an AR gene with anmore » expanded CAG repeat with mice overexpressing HGF. Here, we report that high expression of HGF induces Akt phosphorylation and modestly ameliorated motor symptoms in an SBMA transgenic mouse model treated with or without castration. These findings suggest that HGF overexpression can provide a potential therapeutic avenue as a combination therapy with disease-modifying therapies in SBMA. - Highlights: • HGF overexpression ameliorates the motor phenotypes of the SBMA mouse model. • HGF overexpression induces Akt phosphorylation in the SBMA mouse model. • This is the first report of combination therapy in a mouse model of polyQ diseases.« less

Superconductivity switch from spin-singlet to -triplet pairing in a topological superconducting junction.

PubMed

Tao, Ze; Chen, F J; Zhou, L Y; Li, Bin; Tao, Y C; Wang, J

2018-06-06

The interedge coupling is the cardinal characteristic of the narrow quantum spin Hall (QSH) insulator, and thus could bring about exotic transport phenomena. Herein, we present a theoretical investigation of the spin-resolved Andreev reflection (AR) in a QSH insulator strip touching on two neighbouring ferromagnetic insulators and one s-wave superconductor. It is demonstrated that, due to the interplay of the interedge coupling and ferromagnetic configuration, there could be not only usual local ARs leading to the spin-singlet pairing with the incident electron and Andreev-reflected hole from different spin subbands, but also novel local ARs giving rise to the spin-triplet pairing from the same spin subband. However, only the latter exists in the absence of the interedge coupling, and therefore the two pairings in turn testify the helical spin texture of the edge states. By proper tuning of the band structures of the ferromagnetic layers, under the resonance bias voltage, the usual and novel local ARs of [Formula: see text] can be all exhibited, resulting in fully spin-polarized pure spin-singlet superconductivity and pure spin-triplet superconductivity, respectively, which suggests a superconductivity switch from spin-singlet to -triplet pairing by electrical control. The results can be experimentally confirmed by the tunneling conductance and the noise power.

Superconductivity switch from spin-singlet to -triplet pairing in a topological superconducting junction

NASA Astrophysics Data System (ADS)

Tao, Ze; Chen, F. J.; Zhou, L. Y.; Li, Bin; Tao, Y. C.; Wang, J.

2018-06-01

The interedge coupling is the cardinal characteristic of the narrow quantum spin Hall (QSH) insulator, and thus could bring about exotic transport phenomena. Herein, we present a theoretical investigation of the spin-resolved Andreev reflection (AR) in a QSH insulator strip touching on two neighbouring ferromagnetic insulators and one s-wave superconductor. It is demonstrated that, due to the interplay of the interedge coupling and ferromagnetic configuration, there could be not only usual local ARs leading to the spin-singlet pairing with the incident electron and Andreev-reflected hole from different spin subbands, but also novel local ARs giving rise to the spin-triplet pairing from the same spin subband. However, only the latter exists in the absence of the interedge coupling, and therefore the two pairings in turn testify the helical spin texture of the edge states. By proper tuning of the band structures of the ferromagnetic layers, under the resonance bias voltage, the usual and novel local ARs of can be all exhibited, resulting in fully spin-polarized pure spin-singlet superconductivity and pure spin-triplet superconductivity, respectively, which suggests a superconductivity switch from spin-singlet to -triplet pairing by electrical control. The results can be experimentally confirmed by the tunneling conductance and the noise power.

Androgen receptor is overexpressed in boys with severe hypospadias, and ZEB1 regulates androgen receptor expression in human foreskin cells

PubMed Central

Qiao, Liang; Tasian, Gregory E.; Zhang, Haiyang; Cao, Mei; Ferretti, Max; Cunha, Gerald R.; Baskin, Laurence S.

2012-01-01

INTRODUCTION ZEB1 is overexpressed in patients with severe hypospadias. We examined the interaction between ZeB1 and the androgen receptor (AR) in vitro and the expression of AR in boys with hypospadias. RESULTS ZEB1 and AR colocalize to the nucleus. Estrogen upregulated ZEB1 and AR expression. Chromatin immunoprecipitation (ChIP) demonstrated that ZEB1 binds to an E-box sequence in the AR gene promoter. AR expression is higher in subjects with severe hypospadias than those with mild hypospadias and control subjects (P < 0.05). ZEB1 physically interacts with AR in human foreskin cells. DISCUSSION AR is overexpressed in patients with severe hypospadias. Environmental estrogenic compounds may increase the risk of hypospadias by facilitating the interaction between ZEB1 and AR. METHODS Hs68 cells, a fibroblast cell line derived from neonatal human foreskin, were exposed to 0, 10, and 100 nmol/l of estrogen, after which the cellular localization of ZEB1 and AR was assessed using immunocytochemistry. To determine if ZEB1 interacted with the AR gene, ChIP was performed using ZEB1 antibody and polymerase chain reaction (PCR) for AR. Second, AR expression was quantified using real-time PcR and western blot in normal subjects (n = 32), and subjects with mild (n = 16) and severe hypospadia (n = 16). PMID:22391641

Optimization of immunolocalization of cell cycle proteins in human corneal endothelial cells.

PubMed

He, Zhiguo; Campolmi, Nelly; Ha Thi, Binh-Minh; Dumollard, Jean-Marc; Peoc'h, Michel; Garraud, Olivier; Piselli, Simone; Gain, Philippe; Thuret, Gilles

2011-01-01

En face observation of corneal endothelial cells (ECs) using flat-mounted whole corneas is theoretically much more informative than observation of cross-sections that show only a few cells. Nevertheless, it is not widespread for immunolocalization (IL) of proteins, probably because the endothelium, a superficial monolayer, behaves neither like a tissue in immunohistochemistry (IHC) nor like a cell culture in immunocytochemistry (ICC). In our study we optimized IL for ECs of flat-mounted human corneas to study the expression of cell cycle-related proteins. We systematically screened 15 fixation and five antigen retrieval (AR) methods on 118 human fresh or stored corneas (organ culture at 31 °C), followed by conventional immunofluorescence labeling. First, in an attempt to define a universal protocol, we selected combinations able to correctly localize four proteins that are perfectly defined in ECs (zonula occludens-1 [ZO-1] and actin) or ubiquitous (heterogeneous nuclear ribonucleoprotein L [hnRNP L] and histone H3). Second, we screened protocols adapted to the revelation of 9 cell cycle proteins: Ki67, proliferating cell nuclear antigen (PCNA), minichromosome maintenance protein 2 (MCM2), cyclin D1, cyclin E, cyclin A, p16(Ink4a), p21(Cip1) and p27(Kip1). Primary antibody controls (positive controls) were performed on both epithelial cells of the same, simultaneously-stained whole corneas, and by ICC on human ECs in in vitro non-confluent cultures. Both controls are known to contain proliferating cells. IL efficiency was evaluated by two observers in a masked fashion. Correct localization at optical microscopy level in ECs was define as clear labeling with no background, homogeneous staining, agreement with previous works on ECs and/or protein functions, as well as a meaningful IL in proliferating cells of both controls. The common fixation with 4% formaldehyde (gold standard for IHC) failed to reveal 12 of the 13 proteins. In contrast, they were all revealed using either 0.5% formaldehyde at room temperature (RT) during 30 min alone or followed by AR with sodium dodecyl sulfate or trypsin, or pure methanol for 30 min at RT. Individual optimization was nevertheless often required to optimize the labeling. Ki67 was absent in both fresh and stored corneas, whereas PCNA was found in the nucleus, and MCM2 in the cytoplasm, of all ECs. Cyclin D1 was found in the cytoplasm in a paranuclear pattern much more visible after corneal storage. Cyclin E and cyclin A were respectively nuclear and cytoplasmic, unmodified by storage. P21 was not found in ECs with three different antibodies. P16 and p27 were exclusively nuclear, unmodified by storage. IL in ECs of flat-mounted whole human corneas requires a specific sample preparation, especially to avoid overfixation with aldehydes that probably easily masks epitopes. En face observation allows easy analysis of labeling pattern within the endothelial layer and clear subcellular localization, neither of which had previously been described for PCNA, MCM2, or cyclin D1.

32 CFR 635.14 - Accounting for military police record disclosure.

Code of Federal Regulations, 2014 CFR

2014-07-01

... Emergency Services will develop local procedures to ensure that disclosure data requirements by AR 340-21... 32 National Defense 4 2014-07-01 2013-07-01 true Accounting for military police record disclosure... § 635.14 Accounting for military police record disclosure. (a) AR 340-21 prescribes accounting policies...

32 CFR 635.14 - Accounting for military police record disclosure.

Code of Federal Regulations, 2013 CFR

2013-07-01

... Emergency Services will develop local procedures to ensure that disclosure data requirements by AR 340-21... 32 National Defense 4 2013-07-01 2013-07-01 false Accounting for military police record disclosure... § 635.14 Accounting for military police record disclosure. (a) AR 340-21 prescribes accounting policies...

32 CFR 635.14 - Accounting for military police record disclosure.

Code of Federal Regulations, 2011 CFR

2011-07-01

... Emergency Services will develop local procedures to ensure that disclosure data requirements by AR 340-21... 32 National Defense 4 2011-07-01 2011-07-01 false Accounting for military police record disclosure... § 635.14 Accounting for military police record disclosure. (a) AR 340-21 prescribes accounting policies...

32 CFR 635.14 - Accounting for military police record disclosure.

Code of Federal Regulations, 2012 CFR

2012-07-01

... Emergency Services will develop local procedures to ensure that disclosure data requirements by AR 340-21... 32 National Defense 4 2012-07-01 2011-07-01 true Accounting for military police record disclosure... § 635.14 Accounting for military police record disclosure. (a) AR 340-21 prescribes accounting policies...

Measurement of the argon-38(n,2n)argon-37 and calcium- 40(n,alpha)argon-37 cross sections, and National Ignition Facility concrete activation using the rotating target neutron source. The design of an experiment to measure the beryllium-9(n,gamma)beryllium-10 cross section at 14 MeV

NASA Astrophysics Data System (ADS)

Belian, Anthony Paul

The Rotating Target Neutron Source (RTNS) was used in experiments to measure neutron induced cross sections at 14 MeV, and the activation properties of a specific mix of concrete. The RTNS is an accelerator based DT fusion neutron source located at the University of California, Berkeley. Two of the experiments performed for this thesis were specifically of interest for the construction and operation of the National Ignition Facility (NIF), they were the 38Ar(n,2n)37Ar cross section measurement, and the concrete activation measurement. The NIF is a large multi-beam laser facility that will study the effects of age on the nation's stockpile of nuclear weapons. The NIF, when fully operational, will focus the energy of 192 Neodymium glass lasers onto a 1 mm diameter pellet filled with deuterium and tritium fuel. This pellet is compressed by the laser energy giving some of the individual atoms of deuterium and tritium enough kinetic energy to overcome the coulomb barrier and fuse. The energy output from these pellet implosions will be in the range of tens of mega-joules (MJ). The 38Ar(n,2n)37Ar reaction will be useful to NIF scientists to measure important parameters such as target energy yield and areal density. In order to make these measurements precise, an accurate 38Ar(n,2n)37Ar cross section was necessary. The cross sections measured were: 74.9 +/- 3.8 millibarns (mb) at 13.3 +/- 0.01 MeV, 89.2 +/- 4.0 mb at 14.0 +/- 0.03 MeV, and 123.57 +/- 6.4 mb at 15.0 +/- 0.06 MeV. With anticipated energy yields in the tens of mega-joules per pellet implosion, the number of neutrons released is in the range of 1019 to 1020 neutrons per implosion. With such a large number of neutrons, minimizing the activation of the surrounding structure is very much of interest for the sake of personnel radiation safety. To benchmark the computer codes used to calculate the anticipated neutron activation of target bay concrete, samples were irradiated at the RTNS. Dose rates from each sample were recorded as a function of time after irradiation. These dose rates were compared to those calculated using the Monte Carlo code TART and the activation code ACAB. It was found that 95.8% of the comparisons agreed within the experimental uncertainty. The 40Ca(n,α)37Ar reaction was of interest for the detection of clandestine underground nuclear detonations. Since calcium is naturally abundant in the earth's crust, and since 37Ar is an inert gas and is not found naturally, the 40Ca(n, α) 37Ar reaction is a good candidate for detecting a nuclear detonation. An accurate cross section is needed to estimate the yield of the nuclear device. The average cross sections measured were: 175.6 +/- 9.2 millibarns (mb) at 13.2 +/- 0.6 MeV and 122.1 +/- 4.6 mb at 15.2 +/- 0.12 MeV. One of the current NIF pellet designs uses beryllium as the ablation layer, and the target positioner will be made of a beryllium/copper alloy. The reaction product, 10Be, from the 9Be(n,γ) 10Be reaction will be generated, although probably in very small quantities, during the lifetime of the NIF. This cross section has not been measured at 14 MeV, but should be measured to estimate the amount of 10Be produced at the NIF.

Multimodal actions of the phytochemical sulforaphane suppress both AR and AR-V7 in 22Rv1 cells: Advocating a potent pharmaceutical combination against castration-resistant prostate cancer.

PubMed

Khurana, Namrata; Kim, Hogyoung; Chandra, Partha K; Talwar, Sudha; Sharma, Pankaj; Abdel-Mageed, Asim B; Sikka, Suresh C; Mondal, Debasis

2017-11-01

Prostate cancer (PCa) cells expressing full-length androgen receptor (AR-FL) are susceptible to androgen deprivation therapy (ADT). However, outgrowth of castration-resistant prostate cancer (CRPC) can occur due to the expression of constitutively active (ligand-independent) AR splice variants, particularly AR-V7. We previously demonstrated that sulforaphane (SFN), an isothiocyanate phytochemical, can decrease AR-FL levels in the PCa cell lines, LNCaP and C4-2B. Here, we examined the efficacy of SFN in targeting both AR-FL and AR-V7 in the CRPC cell line, CWR22Rv1 (22Rv1). MTT cell viability, wound-heal assay, and colony forming unit (CFU) measurements revealed that 22Rv1 cells are resistant to the anti-androgen, enzalutamide (ENZ). However, co-exposure to SFN sensitized these cells to the potent anticancer effects of ENZ (P<0.05). Immunoblot analyses showed that SFN (5-20 µM) rapidly decreases both AR-FL and AR-V7 levels, and immunofluorescence microscopy (IFM) depicted decreased AR in both cytoplasm and nucleus with SFN treatment. SFN increased both ubiquitination and proteasomal activity in 22Rv1 cells. Studies using a protein synthesis inhibitor (cycloheximide) or a proteasomal inhibitor (MG132) indicated that SFN increases both ubiquitin-mediated aggregation and subsequent proteasomal-degradation of AR proteins. Previous studies reported that SFN inhibits the chaperone activity of heat-shock protein 90 (Hsp90) and induces the nuclear factor erythroid-2-like 2 (Nrf2) transcription factor. Therefore, we investigated whether the Hsp90 inhibitor, ganetespib (G) or the Nrf2 activator, bardoxolone methyl (BM) can similarly suppress AR levels in 22Rv1 cells. Low doses of G and BM, alone or in combination, decreased both AR-FL and AR-V7 levels, and combined exposure to G+BM sensitized 22Rv1 cells to ENZ. Therefore, adjunct treatment with the phytochemical SFN or a safe pharmaceutical combination of G+BM may be effective against CRPC cells, especially those expressing AR-V7.

Multimodal actions of the phytochemical sulforaphane suppress both AR and AR-V7 in 22Rv1 cells: Advocating a potent pharmaceutical combination against castration-resistant prostate cancer

PubMed Central

Khurana, Namrata; Kim, Hogyoung; Chandra, Partha K.; Talwar, Sudha; Sharma, Pankaj; Abdel-Mageed, Asim B.; Sikka, Suresh C.; Mondal, Debasis

2017-01-01

Prostate cancer (PCa) cells expressing full-length androgen receptor (AR-FL) are susceptible to androgen deprivation therapy (ADT). However, outgrowth of castration-resistant prostate cancer (CRPC) can occur due to the expression of constitutively active (ligand-independent) AR splice variants, particularly AR-V7. We previously demonstrated that sulforaphane (SFN), an isothiocyanate phytochemical, can decrease AR-FL levels in the PCa cell lines, LNCaP and C4-2B. Here, we examined the efficacy of SFN in targeting both AR-FL and AR-V7 in the CRPC cell line, CWR22Rv1 (22Rv1). MTT cell viability, wound-heal assay, and colony forming unit (CFU) measurements revealed that 22Rv1 cells are resistant to the anti-androgen, enzalutamide (ENZ). However, co-exposure to SFN sensitized these cells to the potent anticancer effects of ENZ (P<0.05). Immunoblot analyses showed that SFN (5–20 µM) rapidly decreases both AR-FL and AR-V7 levels, and immunofluorescence microscopy (IFM) depicted decreased AR in both cytoplasm and nucleus with SFN treatment. SFN increased both ubiquitination and proteasomal activity in 22Rv1 cells. Studies using a protein synthesis inhibitor (cycloheximide) or a proteasomal inhibitor (MG132) indicated that SFN increases both ubiquitin-mediated aggregation and subsequent proteasomal-degradation of AR proteins. Previous studies reported that SFN inhibits the chaperone activity of heat-shock protein 90 (Hsp90) and induces the nuclear factor erythroid-2-like 2 (Nrf2) transcription factor. Therefore, we investigated whether the Hsp90 inhibitor, ganetespib (G) or the Nrf2 activator, bardoxolone methyl (BM) can similarly suppress AR levels in 22Rv1 cells. Low doses of G and BM, alone or in combination, decreased both AR-FL and AR-V7 levels, and combined exposure to G+BM sensitized 22Rv1 cells to ENZ. Therefore, adjunct treatment with the phytochemical SFN or a safe pharmaceutical combination of G+BM may be effective against CRPC cells, especially those expressing AR-V7. PMID:28901514

Zebrafish (Danio rerio) androgen receptor: sequence homology and up-regulation by the fungicide vinclozolin.

PubMed

Smolinsky, Amanda N; Doughman, Jennifer M; Kratzke, Liên-Thành C; Lassiter, Christopher S

2010-03-01

Steroid hormones regulate gene expression in organisms by binding to receptor proteins. These hormones include the androgens, which signal through androgen receptors (ARs). Endocrine disrupters (EDCs) are chemicals in the environment that adversely affect organisms by binding to nuclear receptors, including ARs. Vinclozolin, a fungicide used on fruit and vegetable crops, is a known anti-androgen, a type of EDC that blocks signals from testosterone and its derivatives. In order to better understand the effects of EDCs, further research on androgen receptors and other hormone signaling pathways is necessary. In this study, we demonstrate the evolutionary conservation between the genomic structure of the human and zebrafish ar genes and find that ar mRNA expression increases in zebrafish embryos exposed to vinclozolin, which may be evolutionarily conserved as well. At 48 and 72 h post-fertilization, vinclozolin-treated embryos express ar mRNA 8-fold higher than the control level. These findings suggest that zebrafish embryos attempt to compensate for the presence of an anti-androgen by increasing the number of androgen receptors available.

Pre-folding IkappaBalpha alters control of NF-kappaB signaling.

PubMed

Truhlar, Stephanie M E; Mathes, Erika; Cervantes, Carla F; Ghosh, Gourisankar; Komives, Elizabeth A

2008-06-27

Transcription complex components frequently show coupled folding and binding but the functional significance of this mode of molecular recognition is unclear. IkappaBalpha binds to and inhibits the transcriptional activity of NF-kappaB via its ankyrin repeat (AR) domain. The beta-hairpins in ARs 5-6 in IkappaBalpha are weakly-folded in the free protein, and their folding is coupled to NF-kappaB binding. Here, we show that introduction of two stabilizing mutations in IkappaBalpha AR 6 causes ARs 5-6 to fold cooperatively to a conformation similar to that in NF-kappaB-bound IkappaBalpha. Free IkappaBalpha is degraded by a proteasome-dependent but ubiquitin-independent mechanism, and this process is slower for the pre-folded mutants both in vitro and in cells. Interestingly, the pre-folded mutants bind NF-kappaB more weakly, as shown by both surface plasmon resonance and isothermal titration calorimetry in vitro and immunoprecipitation experiments from cells. One consequence of the weaker binding is that resting cells containing these mutants show incomplete inhibition of NF-kappaB activation; they have significant amounts of nuclear NF-kappaB. Additionally, the weaker binding combined with the slower rate of degradation of the free protein results in reduced levels of nuclear NF-kappaB upon stimulation. These data demonstrate clearly that the coupled folding and binding of IkappaBalpha is critical for its precise control of NF-kappaB transcriptional activity.

Inducible nuclear translocation of a STAT protein in Dictyostelium prespore cells: implications for morphogenesis and cell-type regulation.

PubMed

Dormann, D; Abe, T; Weijer, C J; Williams, J

2001-04-01

Dd-STATa, the Dictyostelium STAT (signal transducer and activator of transcription) protein, is selectively localised in the nuclei of a small subset of prestalk cells located in the slug tip. Injection of cAMP into the extracellular spaces in the rear of the slug induces rapid nuclear translocation of a Dd-GFP:STATa fusion protein in prespore cells surrounding the site of injection. This suggests that cAMP signals that emanate from the tip direct the localised nuclear accumulation of Dd-STATa. It also shows that prespore cells are competent to respond to cAMP, by Dd-STATa activation, and it implies that cAMP signalling is in some way limiting in the rear of the slug. Co-injection of a specific inhibitor of the cAR1 serpentine cAMP receptor almost completely prevents the cAMP-induced nuclear translocation, showing that most or all of the cAMP signal is transduced by cAR1. Dd-GFP:STATa also rapidly translocates into the nuclei of cells adjoining the front and back cut edges when a slug is bisected. Less severe mechanical disturbances, such as pricking the rear of a slug with an unfilled micropipette, also cause a more limited nuclear translocation of Dd-GFP:STATa. We propose that these signalling events form part of a repair mechanism that is activated when the migrating slug suffers mechanical damage.

Correlation between local hemodynamics and lesion distribution in a novel aortic regurgitation murine model of atherosclerosis.

PubMed

Hoi, Yiemeng; Zhou, Yu-Qing; Zhang, Xiaoli; Henkelman, R Mark; Steinman, David A

2011-05-01

Following surgical induction of aortic valve regurgitation (AR), extensive atherosclerotic plaque development along the descending thoracic and abdominal aorta of Ldlr⁻/⁻ mice has been reported, with distinct spatial distributions suggestive of a strong local hemodynamic influence. The objective of this study was to test, using image-based computational fluid dynamics (CFD), whether this is indeed the case. The lumen geometry was reconstructed from micro-CT scanning of a control Ldlr⁻/⁻ mouse, and CFD simulations were carried out for both AR and control flow conditions derived from Doppler ultrasound measurements and literature data. Maps of time-averaged wall shear stress magnitude (TAWSS), oscillatory shear index (OSI) and relative residence time (RRT) were compared against the spatial distributions of plaque stained with oil red O, previously acquired in a group of AR and control mice. Maps of OSI and RRT were found to be consistent with plaque distributions in the AR mice and the absence of plaque in the control mice. TAWSS was uniformly lower under control vs. AR flow conditions, suggesting that levels (> 100 dyn/cm²) exceeded those required to alone induce a pro-atherogenic response. Simulations of a straightened CFD model confirmed the importance of anatomical curvature for explaining the spatial distribution of lesions in the AR mice. In summary, oscillatory and retrograde flow induced in the AR mice, without concomitant low shear, may exacerbate or accelerate lesion formation, but the distinct anatomical curvature of the mouse aorta is responsible for the spatial distribution of lesions.

Adenosine A2B and A3 receptor location at the mouse neuromuscular junction.

PubMed

Garcia, Neus; Priego, Mercedes; Hurtado, Erica; Obis, Teresa; Santafe, Manel M; Tomàs, Marta; Lanuza, Maria Angel; Tomàs, Josep

2014-07-01

To date, four subtypes of adenosine receptors have been cloned (A(1)R, A(2A)R, A(2B)R, and A(3)R). In a previous study we used confocal immunocytochemistry to identify A(1)R and A(2A)R receptors at mouse neuromuscular junctions (NMJs). The data shows that these receptors are localized differently in the three cells (muscle, nerve and glia) that configure the NMJs. A(1)R localizes in the terminal teloglial Schwann cell and nerve terminal, whereas A(2A)R localizes in the postsynaptic muscle and in the axon and nerve terminal. Here, we use Western blotting to investigate the presence of A(2B)R and A(3)R receptors in striated muscle and immunohistochemistry to localize them in the three cells of the adult neuromuscular synapse. The data show that A(2B)R and A(3)R receptors are present in the nerve terminal and muscle cells at the NMJs. Neither A(2B)R nor A(3)R receptors are localized in the Schwann cells. Thus, the four subtypes of adenosine receptors are present in the motor endings. The presence of these receptors in the neuromuscular synapse allows the receptors to be involved in the modulation of transmitter release. © 2014 Anatomical Society.

The androgen receptor malignancy shift in prostate cancer.

PubMed

Copeland, Ben T; Pal, Sumanta K; Bolton, Eric C; Jones, Jeremy O

2018-05-01

Androgens and the androgen receptor (AR) are necessary for the development, function, and homeostatic growth regulation of the prostate gland. However, once prostate cells are transformed, the AR is necessary for the proliferation and survival of the malignant cells. This change in AR function appears to occur in nearly every prostate cancer. We have termed this the AR malignancy shift. In this review, we summarize the current knowledge of the AR malignancy shift, including the DNA-binding patterns that define the shift, the transcriptome changes associated with the shift, the putative drivers of the shift, and its clinical implications. In benign prostate epithelial cells, the AR primarily binds consensus AR binding sites. In carcinoma cells, the AR cistrome is dramatically altered, as the AR associates with FOXA1 and HOXB13 motifs, among others. This shift leads to the transcription of genes associated with a malignant phenotype. In model systems, some mutations commonly found in localized prostate cancer can alter the AR cistrome, consistent with the AR malignancy shift. Current evidence suggests that the AR malignancy shift is necessary but not sufficient for transformation of prostate epithelial cells. Reinterpretation of prostate cancer genomic classification systems in light of the AR malignancy shift may improve our ability to predict clinical outcomes and treat patients appropriately. Identifying and targeting the molecular factors that contribute to the AR malignancy shift is not trivial but by doing so, we may be able to develop new strategies for the treatment or prevention of prostate cancer. © 2018 Wiley Periodicals, Inc.

In vitro study on the agonistic and antagonistic activities of bisphenol-S and other bisphenol-A congeners and derivatives via nuclear receptors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Molina-Molina, José-Manuel, E-mail: molinajm@ugr.es; Amaya, Esperanza; Grimaldi, Marina

Bisphenols are a group of chemicals structurally similar to bisphenol-A (BPA) in current use as the primary raw material in the production of polycarbonate and epoxy resins. Some bisphenols are intended to replace BPA in several industrial applications. This is the case of bisphenol-S (BPS), which has an excellent stability at high temperature and resistance to sunlight. Studies on the endocrine properties of BPS have focused on its interaction with human estrogen receptor alpha (hERα), but information on its interaction with other nuclear receptors is scarce. The aim of this study was to investigate interactions of BPS, BPF, BPA andmore » its halogenated derivatives, tetrachlorobisphenol A (TCBPA), and tetrabromobisphenol A (TBBPA), with human estrogen receptors (hERα and hERβ), androgen receptor (hAR), and pregnane X receptor (hPXR), using a panel of in vitro bioassays based on competitive binding to nuclear receptors (NRs), reporter gene expression, and cell proliferation assessment. BPS, BPF, and BPA efficiently activated both ERs, while TCBPA behaved as weak hERα agonist. Unlike BPF and BPA, BPS was more active in the hERβ versus hERα assay. BPF and BPA were full hAR antagonists (BPA > BPF), whereas BPA and BPS were weak hAR agonists. Only BPA, TCBPA, and TBBPA, were hPXR agonists (TCBPA > TBBPA > BPA). These findings provide evidence that BPA congeners and derivatives disrupt multiple NRs and may therefore interfere with the endocrine system. Hence, further research is needed to evaluate the potential endocrine-disrupting activity of putative BPA substitutes. - Highlights: • We investigated the agonist/antagonist activities of BPS, BPF, BPA, TCBPA and TBBPA. • The direct interaction of these compounds with hERα, hERβ, hAR and hPXR was studied. • BPA congeners and derivatives were found to disrupt multiple NRs. • Further evaluation of their role as endocrine-disrupting chemicals is needed.« less

Androgen receptor status is highly conserved during tumor progression of breast cancer.

PubMed

Grogg, André; Trippel, Mafalda; Pfaltz, Katrin; Lädrach, Claudia; Droeser, Raoul A; Cihoric, Nikola; Salhia, Bodour; Zweifel, Martin; Tapia, Coya

2015-11-09

With the advent of new and more efficient anti-androgen drugs targeting androgen receptor (AR) in breast cancer (BC) is becoming an increasingly important area of investigation. This would potentially be most useful in triple negative BC (TNBC), where better therapies are still needed. The assessment of AR status is generally performed on the primary tumor even if the tumor has already metastasized. Very little is known regarding discrepancies of AR status during tumor progression. To determine the prevalence of AR positivity, with emphasis on TNBCs, and to investigate AR status during tumor progression, we evaluated a large series of primary BCs and matching metastases and recurrences. AR status was performed on 356 primary BCs, 135 matching metastases, and 12 recurrences using a next-generation Tissue Microarray (ngTMA). A commercially available AR antibody was used to determine AR-status by immunohistochemistry. AR positivity was defined as any nuclear staining in tumor cells ≥1 %. AR expression was correlated with pathological tumor features of the primary tumor. Additionally, the concordance rate of AR expression between the different tumor sites was determined. AR status was positive in: 87 % (307/353) of primary tumors, 86.1 % (105/122) of metastases, and in 66.7 % (8/12) of recurrences. TNBC tested positive in 11.4 %, (4/35) of BCs. A discrepant result was seen in 4.3 % (5/117) of primary BC and matching lymph node (LN) metastases. Three AR negative primary BCs were positive in the matching LN metastasis, representing 17.6 % of all negative BCs with lymph node metastases (3/17). Two AR positive primary BCs were negative in the matching LN metastasis, representing 2.0 % of all AR positive BCs with LN metastases (2/100). No discrepancies were seen between primary BC and distant metastases or recurrence (n = 17). Most primary (87 %) and metastasized (86.1 %) BCs are AR positive including a significant fraction of TNBCs (11.4 %). Further, AR status is highly conserved during tumor progression and a change only occurs in a small fraction (4.1 %). Our study supports the notion that targeting AR could be effective for many BC patients and that re-testing of AR status in formerly negative or mixed type BC's is recommended.

Absolute timing of sulfide and gold mineralization: A comparison of Re-Os molybdenite and Ar-Ar mica methods from the Tintina Gold Belt, Alaska

USGS Publications Warehouse

Selby, D.; Creaser, R.A.; Hart, C.J.R.; Rombach, C.S.; Thompson, J.F.H.; Smith, Moira T.; Bakke, A.A.; Goldfarb, R.J.

2002-01-01

New Re-Os molybdenite dates from two lode gold deposits of the Tintina Gold Belt, Alaska, provide direct timing constraints for sulfide and gold mineralization. At Fort Knox, the Re-Os molybdenite date is identical to the U-Pb zircon age for the host intrusion, supporting an intrusive-related origin for the deposit. However, 40Ar/39Ar dates from hydrothermal and igneous mica are considerably younger. At the Pogo deposit, Re-Os molybdenite dates are also much older than 40Ar/39Ar dates from hydrothermal mica, but dissimilar to the age of local granites. These age relationships indicate that the Re-Os molybdenite method records the timing of sulfide and gold mineralization, whereas much younger 40Ar/39Ar dates are affected by post-ore thermal events, slow cooling, and/or systemic analytical effects. The results of this study complement a growing body of evidence to indicate that the Re-Os chronometer in molybdenite can be an accurate and robust tool for establishing timing relations in ore systems.

Thymic stromal lymphopoietin (TSLP) is associated with allergic rhinitis in children with asthma.

PubMed

Bunyavanich, Supinda; Melen, Erik; Wilk, Jemma B; Granada, Mark; Soto-Quiros, Manuel E; Avila, Lydiana; Lasky-Su, Jessica; Hunninghake, Gary M; Wickman, Magnus; Pershagen, Göran; O'Connor, George T; Weiss, Scott T; Celedón, Juan C

2011-01-18

Allergic rhinitis (AR) affects up to 80% of children with asthma and increases asthma severity. Thymic stromal lymphopoietin (TSLP) is a key mediator of allergic inflammation. The role of the TSLP gene (TSLP) in the pathogenesis of AR has not been studied. To test for associations between variants in TSLP, TSLP-related genes, and AR in children with asthma. We genotyped 15 single nucleotide polymorphisms (SNPs) in TSLP, OX40L, IL7R, and RXRα in three independent cohorts: 592 asthmatic Costa Rican children and their parents, 422 nuclear families of North American children with asthma, and 239 Swedish children with asthma. We tested for associations between these SNPs and AR. As we previously reported sex-specific effects for TSLP, we performed overall and sex-stratified analyses. We additionally performed secondary analyses for gene-by-gene interactions. Across the three cohorts, the T allele of TSLP SNP rs1837253 was undertransmitted in boys with AR and asthma as compared to boys with asthma alone. The SNP was associated with reduced odds for AR (odds ratios ranging from 0.56 to 0.63, with corresponding Fisher's combined P value of 1.2 × 10-4). Our findings were significant after accounting for multiple comparisons. SNPs in OX40L, IL7R, and RXRα were not consistently associated with AR in children with asthma. There were nominally significant interactions between gene pairs. TSLP SNP rs1837253 is associated with reduced odds for AR in boys with asthma. Our findings support a role for TSLP in the pathogenesis of AR in children with asthma.

[Clinical symptoms and immunology inspection characteristics of nasal cavity local allergy].

PubMed

Yin, Z X; Zhu, Y; Zhai, X; Zhang, J L; Liu, G

2017-08-05

Objective: To investigate the clinical symptoms and immunology inspection characteristics of nasal cavity local allergy. Method: Selected 60 patients as observation group, who had only nasal local allergy symptoms, allergen skin prick test and serum allergen specific IgE (SIgE) test were negative, 40 allergic rhinitis (AR) patients and 40 healthy volunteers as control groups. To detect Symptom scores and VAS scores, and eosinophilia counts in venous blood, allergen skin prick test (SPT), serum allergen SIgE test, nasal secretions allergen SIgE test, nasal mucous membrane excitation test in both observation group and AR group, eosinophilia counts in nasal secretion, taked the data for statistical analysis. Result: There was no difference ( P > 0.05) in the symptom scores and VAS scores of observation group and the AR group. The eosinophilia counts in venous blood in the AR group were higher than in the observation group ( P < 0.05). The eosinophilia counts in venous blood in the observation group were higher than in the healthy volunteers group ( P < 0.05). The positive rate of nasal secretions dust mites and pollen allergen was 90% (54/60) in observation group. There was no significant difference ( P > 0.05) in the eosinophilia percentages in nasal secretion in the observation group and the AR group. There was significant difference ( P < 0.05) in the eosinophilia percentages in nasal secretion in the observation group and the healthy volunteers group. There were 6 patients in observation group whose nasal secretions allergen SIgE test and nasal mucous membrane excitation test were both negative, could be diagnosised as non-allergic rhinitis (NAR). According to eosinophilia counts in venous blood and nasal secretions, 4 patients were diagnosised as vasomotor rhinitis and 2 patients were diagnosised as NAR with eosinophilia syndrome. There were 54 patients in observation group whose nasal secretions allergen SIgE test and (or) nasal mucous membrane excitation test were positive, could be diagnosised as local allergic rhinitis. After three years, all of the observation group patients were detected with SPT and serum allergen SIgE test. Five patients diagnosed as local allergic rhinitis before three years were positive. Six patients diagnosed as NAR before three years were negative. Conclusion: For patients with the typical medical history and symptoms of AR, but allergen SPT and serum allergen SIgE test were negative, there was local specific hypersensitivity in nasal mucosa, but the reaction was not accompanied by systemic sensitization. Combined with nasal secretions allergen SIgE test or allergen nasal mucosa proocation tests positive, could be diagnosed as local allergic rhinitis. Copyright© by the Editorial Department of Journal of Clinical Otorhinolaryngology Head and Neck Surgery.

Determinants of Ligand Subtype-Selectivity at α1A-Adrenoceptor Revealed Using Saturation Transfer Difference (STD) NMR.

PubMed

Yong, Kelvin J; Vaid, Tasneem M; Shilling, Patrick J; Wu, Feng-Jie; Williams, Lisa M; Deluigi, Mattia; Plückthun, Andreas; Bathgate, Ross A D; Gooley, Paul R; Scott, Daniel J

2018-04-20

α 1A - and α 1B -adrenoceptors (α 1A -AR and α 1B -AR) are closely related G protein-coupled receptors (GPCRs) that modulate the cardiovascular and nervous systems in response to binding epinephrine and norepinephrine. The GPCR gene superfamily is made up of numerous subfamilies that, like α 1A -AR and α 1B -AR, are activated by the same endogenous agonists but may modulate different physiological processes. A major challenge in GPCR research and drug discovery is determining how compounds interact with receptors at the molecular level, especially to assist in the optimization of drug leads. Nuclear magnetic resonance spectroscopy (NMR) can provide great insight into ligand-binding epitopes, modes, and kinetics. Ideally, ligand-based NMR methods require purified, well-behaved protein samples. The instability of GPCRs upon purification in detergents, however, makes the application of NMR to study ligand binding challenging. Here, stabilized α 1A -AR and α 1B -AR variants were engineered using Cellular High-throughput Encapsulation, Solubilization, and Screening (CHESS), allowing the analysis of ligand binding with Saturation Transfer Difference NMR (STD NMR). STD NMR was used to map the binding epitopes of epinephrine and A-61603 to both receptors, revealing the molecular determinants for the selectivity of A-61603 for α 1A -AR over α 1B -AR. The use of stabilized GPCRs for ligand-observed NMR experiments will lead to a deeper understanding of binding processes and assist structure-based drug design.

A synthetic decursin analog with increased in vivo stability suppresses androgen receptor signaling in vitro and in vivo.

PubMed

Zhang, Yong; Shaik, Ahmad Ali; Xing, Chengguo; Chai, Yubo; Li, Li; Zhang, Jinhui; Zhang, Wei; Kim, Sung-Hoon; Lü, Junxuan; Jiang, Cheng

2012-10-01

Targeting androgen receptor (AR) signaling with agents distinct from current antagonist drugs remains a rational approach to the prevention and treatment of prostate cancer (PCa). Our previous studies have shown that decursin and isomer decursinol angelate (DA), isolated from the Korean medicinal herb Angelica gigas Nakai, interrupt AR signaling and possess anti-PCa activities in vitro. In the LNCaP PCa cell model, these pyranoccoumarin compounds exhibit properties distinct from currently used antagonists (e.g., Casodex). However, both are rapidly de-esterified to decursinol, a partial AR agonist. We report here that a synthetic decursin analog, decursinol phenylthiocarbamate (DPTC), has greater in vivo stability than the parent compounds. DPTC-decursinol conversion was undetectable in mice. Furthermore, in LNCaP cells, DPTC decreased prostate specific antigen (PSA) expression, down-regulated AR abundance and mRNA and inhibited AR nuclear translocation. The effect of DPTC on AR and PSA mRNA and protein abundance was also observed in VCaP cells expressing wild type AR. DPTC inhibited growth of both PCa cell lines through G(1) cell cycle arrest and apoptosis, as did decursin and DA. Furthermore, i.p. administration of DPTC for 3 weeks suppressed the expression of AR target genes probasin and Nkx3.1 in mouse prostate glands. Overall, our data suggest that DPTC represents a prototype lead compound for development of in vivo stable and active novel decursin analogs for the prevention or therapy of PCa.

NFI Transcription Factors Interact with FOXA1 to Regulate Prostate-Specific Gene Expression

PubMed Central

Elliott, Amicia D.; DeGraff, David J.; Anderson, Philip D.; Anumanthan, Govindaraj; Yamashita, Hironobu; Sun, Qian; Friedman, David B.; Hachey, David L.; Yu, Xiuping; Sheehan, Jonathan H.; Ahn, Jung-Mo; Raj, Ganesh V.; Piston, David W.; Gronostajski, Richard M.; Matusik, Robert J.

2014-01-01

Androgen receptor (AR) action throughout prostate development and in maintenance of the prostatic epithelium is partly controlled by interactions between AR and forkhead box (FOX) transcription factors, particularly FOXA1. We sought to identity additional FOXA1 binding partners that may mediate prostate-specific gene expression. Here we identify the nuclear factor I (NFI) family of transcription factors as novel FOXA1 binding proteins. All four family members (NFIA, NFIB, NFIC, and NFIX) can interact with FOXA1, and knockdown studies in androgen-dependent LNCaP cells determined that modulating expression of NFI family members results in changes in AR target gene expression. This effect is probably mediated by binding of NFI family members to AR target gene promoters, because chromatin immunoprecipitation (ChIP) studies found that NFIB bound to the prostate-specific antigen enhancer. Förster resonance energy transfer studies revealed that FOXA1 is capable of bringing AR and NFIX into proximity, indicating that FOXA1 facilitates the AR and NFI interaction by bridging the complex. To determine the extent to which NFI family members regulate AR/FOXA1 target genes, motif analysis of publicly available data for ChIP followed by sequencing was undertaken. This analysis revealed that 34.4% of peaks bound by AR and FOXA1 contain NFI binding sites. Validation of 8 of these peaks by ChIP revealed that NFI family members can bind 6 of these predicted genomic elements, and 4 of the 8 associated genes undergo gene expression changes as a result of individual NFI knockdown. These observations suggest that NFI regulation of FOXA1/AR action is a frequent event, with individual family members playing distinct roles in AR target gene expression. PMID:24801505

Infarct-Induced Steroidogenic Acute Regulatory Protein: A Survival Role in Cardiac Fibroblasts

PubMed Central

Anuka, Eli; Yivgi-Ohana, Natalie; Eimerl, Sarah; Garfinkel, Benjamin; Melamed-Book, Naomi; Chepurkol, Elena; Aravot, Dan; Zinman, Tova; Shainberg, Asher; Hochhauser, Edith

2013-01-01

Steroidogenic acute regulatory protein (StAR) is indispensable for steroid hormone synthesis in the adrenal cortex and the gonadal tissues. This study reveals that StAR is also expressed at high levels in nonsteroidogenic cardiac fibroblasts confined to the left ventricle of mouse heart examined 3 days after permanent ligation of the left anterior descending coronary artery. Unlike StAR, CYP11A1 and 3β-hydroxysteroid dehydrogenase proteins were not observed in the postinfarction heart, suggesting an apparent lack of de novo cardiac steroidogenesis. Work with primary cultures of rat heart cells revealed that StAR is induced in fibroblasts responding to proapoptotic treatments with hydrogen peroxide or the kinase inhibitor staurosporine (STS). Such induction of StAR in culture was noted before spontaneous differentiation of the fibroblasts to myofibroblasts. STS induction of StAR in the cardiac fibroblasts conferred a marked resistance to apoptotic cell death. Consistent with that finding, down-regulation of StAR by RNA interference proportionally increased the number of STS-treated apoptotic cells. StAR down-regulation also resulted in a marked increase of BAX activation in the mitochondria, an event known to associate with the onset of apoptosis. Last, STS treatment of HeLa cells showed that apoptotic demise characterized by mitochondrial fission, cytochrome c release, and nuclear fragmentation is arrested in individual HeLa cells overexpressing StAR. Collectively, our in vivo and ex vivo evidence suggests that postinfarction expression of nonsteroidogenic StAR in cardiac fibroblasts has novel antiapoptotic activity, allowing myofibroblast precursor cells to survive the traumatized event, probably to differentiate and function in tissue repair at the infarction site. PMID:23831818

Green tea polyphenol EGCG blunts androgen receptor function in prostate cancer

PubMed Central

Siddiqui, Imtiaz A.; Asim, Mohammad; Hafeez, Bilal B.; Adhami, Vaqar M.; Tarapore, Rohinton S.; Mukhtar, Hasan

2011-01-01

Androgen deprivation therapy is the major treatment for advanced prostate cancer (PCa). However, it is a temporary remission, and the patients almost inevitably develop hormone refractory prostate cancer (HRPC). HRPC is almost incurable, although most HRPC cells still express androgen receptor (AR) and depend on the AR for growth, making AR a prime drug target. Here, we provide evidence that epigallocatechin-3-gallate (EGCG), the major polyphenol in green tea, is a direct antagonist of androgen action. In silico modeling and FRET-based competition assay showed that EGCG physically interacts with the ligand-binding domain of AR by replacing a high-affinity labeled ligand (IC50 0.4 μM). The functional consequence of this interaction was a decrease in AR-mediated transcriptional activation, which was due to EGCG mediated inhibition of interdomain N-C termini interaction of AR. Treatment with EGCG also repressed the transcriptional activation by a hotspot mutant AR (T877A) expressed ectopically as well as the endogenous AR mutant. As the physiological consequence of AR antagonism, EGCG repressed R1881-induced PCa cell growth. In a xenograft model, EGCG was found to inhibit AR nuclear translocation and protein expression. We also observed a significant down-regulation of androgen-regulated miRNA-21 and up-regulation of a tumor suppressor, miRNA-330, in tumors of mice treated with EGCG. Taken together, we provide evidence that EGCG functionally antagonizes androgen action at multiple levels, resulting in inhibition of PCa growth.—Siddiqui, I. A., Asim, M., Hafeez, B. B., Adhami, V. M., Tarapore, R. S., Mukhtar, H. Green tea polyphenol EGCG blunts androgen receptor function in prostate cancer. PMID:21177307

Regional Climate Change across the Continental U.S. Projected from Downscaling IPCC AR5 Simulations

NASA Astrophysics Data System (ADS)

Otte, T. L.; Nolte, C. G.; Otte, M. J.; Pinder, R. W.; Faluvegi, G.; Shindell, D. T.

2011-12-01

Projecting climate change scenarios to local scales is important for understanding and mitigating the effects of climate change on society and the environment. Many of the general circulation models (GCMs) that are participating in the Intergovernmental Panel on Climate Change (IPCC) Fifth Assessment Report (AR5) do not fully resolve regional-scale processes and therefore cannot capture local changes in temperature and precipitation extremes. We seek to project the GCM's large-scale climate change signal to the local scale using a regional climate model (RCM) by applying dynamical downscaling techniques. The RCM will be used to better understand the local changes of temperature and precipitation extremes that may result from a changing climate. Preliminary results from downscaling NASA/GISS ModelE simulations of the IPCC AR5 Representative Concentration Pathway (RCP) scenario 6.0 will be shown. The Weather Research and Forecasting (WRF) model will be used as the RCM to downscale decadal time slices for ca. 2000 and ca. 2030 and illustrate potential changes in regional climate for the continental U.S. that are projected by ModelE and WRF under RCP6.0.

Atomic weights of the elements 2009 (IUPAC technical report)

USGS Publications Warehouse

Wieser, M.E.; Coplen, T.B.

2011-01-01

The biennial review of atomic-weight determinations and other cognate data has resulted in changes for the standard atomic weights of 11 elements. Many atomic weights are not constants of nature, but depend upon the physical, chemical, and nuclear history of the material. The standard atomic weights of 10 elements having two or more stable isotopes have been changed to reflect this variability of atomic-weight values in natural terrestrial materials. To emphasize the fact that these standard atomic weights are not constants of nature, each atomic-weight value is expressed as an interval. The interval is used together with the symbol [a; b] to denote the set of atomic-weight values, Ar(E), of element E in normal materials for which a ≤ Ar(E) ≤ b. The symbols a and b denote the bounds of the interval [a; b]. The revised atomic weight of hydrogen, Ar(H), is [1.007 84; 1.008 11] from 1.007 94(7); lithium, Ar(Li), is [6.938; 6.997] from 6.941(2); boron, Ar(B), is [10.806; 10.821] from 10.811(7); carbon, Ar(C), is [12.0096; 12.0116] from 12.0107(8); nitrogen, Ar(N), is [14.006 43; 14.007 28] from 14.0067(2); oxygen, Ar(O), is [15.999 03; 15.999 77] from 15.9994(3); silicon, Ar(Si), is [28.084; 28.086] from 28.0855(3); sulfur, Ar(S), is [32.059; 32.076] from 32.065(2); chlorine, Ar(Cl), is [35.446; 35.457] from 35.453(2); and thallium, Ar(Tl), is [204.382; 204.385] from 204.3833(2). This fundamental change in the presentation of the atomic weights represents an important advance in our knowledge of the natural world and underscores the significance and contributions of chemistry to the well-being of humankind in the International Year of Chemistry 2011. The standard atomic weight of germanium, Ar(Ge), was also changed to 72.63(1) from 72.64(1).

Fucci2a: a bicistronic cell cycle reporter that allows Cre mediated tissue specific expression in mice.

PubMed

Mort, Richard Lester; Ford, Matthew Jonathan; Sakaue-Sawano, Asako; Lindstrom, Nils Olof; Casadio, Angela; Douglas, Adam Thomas; Keighren, Margaret Anne; Hohenstein, Peter; Miyawaki, Atsushi; Jackson, Ian James

2014-01-01

Markers of cell cycle stage allow estimation of cell cycle dynamics in cell culture and during embryonic development. The Fucci system incorporates genetically encoded probes that highlight G1 and S/G2/M phases of the cell cycle allowing live imaging. However the available mouse models that incorporate Fucci are beset by problems with transgene inactivation, varying expression level, lack of conditional potential and/or the need to maintain separate transgenes-there is no transgenic mouse model that solves all these problems. To address these shortfalls we re-engineered the Fucci system to create 2 bicistronic Fucci variants incorporating both probes fused using the Thosea asigna virus 2A (T2A) self cleaving peptide. We characterize these variants in stable 3T3 cell lines. One of the variants (termed Fucci2a) faithfully recapitulated the nuclear localization and cell cycle stage specific florescence of the original Fucci system. We go on to develop a conditional mouse allele (R26Fucci2aR) carefully designed for high, inducible, ubiquitous expression allowing investigation of cell cycle status in single cell lineages within the developing embryo. We demonstrate the utility of R26Fucci2aR for live imaging by using high resolution confocal microscopy of ex vivo lung, kidney and neural crest development. Using our 3T3 system we describe and validate a method to estimate cell cycle times from relatively short time-lapse sequences that we then apply to our neural crest data. The Fucci2a system and the R26Fucci2aR mouse model are compelling new tools for the investigation of cell cycle dynamics in cell culture and during mouse embryonic development.

Revitalizing Nuclear Operations in the Joint Environment

DTIC Science & Technology

2014-02-01

height of the Cold War, US schol - ars and joint operational planners were working simultaneously on weapons development and operational art to employ...leadership’s large-target- category withholds thought necessary to maintain stability in a strategic crisis. The inclusion of nuclear effects and...escalation. The inclusion of these points in tomorrow’s doctrine as well as an intellec- tual discussion on the topic will inform Joint Staff planners

In Vitro Mutational Analysis of the β2 Adrenergic Receptor, an In Vivo Surrogate Odorant Receptor

PubMed Central

Pfister, Patrick; Tomoiaga, Delia; Rogers, Matthew E.; Feinstein, Paul

2015-01-01

Many G-protein coupled receptors (GPCRs), such as odorant receptors (ORs), cannot be characterized in heterologous cells because of their difficulty in trafficking to the plasma membrane. In contrast, a surrogate OR, the GPCR mouse β2-adrenergic-receptor (mβ2AR), robustly traffics to the plasma membrane. We set out to characterize mβ2AR mutants in vitro for their eventual use in olfactory axon guidance studies. We performed an extensive mutational analysis of mβ2AR using a Green Fluorescent Protein-tagged mβ2AR (mβ2AR::GFP) to easily assess the extent of its plasma membrane localization. In order to characterize mutants for their ability to successfully transduce ligand-initiated signal cascades, we determined the half maximal effective concentrations (EC50) and maximal response to isoprenaline, a known mβ2AR agonist. Our analysis reveals that removal of amino terminal (Nt) N-glycosylation sites and the carboxy terminal (Ct) palmitoylation site of mβ2AR do not affect its plasma membrane localization. By contrast, when both the Nt and Ct of mβ2AR are replaced with those of M71 OR, plasma membrane trafficking is impaired. We further analyze three mβ2AR mutants (RDY, E268A, and C327R) used in olfactory axon guidance studies and are able to decorrelate their plasma membrane trafficking with their capacity to respond to isoprenaline. A deletion of the Ct prevents proper trafficking and abolishes activity, but plasma membrane trafficking can be selectively rescued by a Tyrosine to Alanine mutation in the highly conserved GPCR motif NPxxY. This new loss-of-function mutant argues for a model in which residues located at the end of transmembrane domain 7 can act as a retention signal when unmasked. Additionally, to our surprise, amongst our set of mutations only Ct mutations appear to lower mβ2AR EC50s revealing their critical role in G-protein coupling. We propose that an interaction between the Nt and Ct is necessary for proper folding and/or transport of GPCRs. PMID:26513247

Fine-scale genetic population structure in a mobile marine mammal: inshore bottlenose dolphins in Moreton Bay, Australia.

PubMed

Ansmann, Ina C; Parra, Guido J; Lanyon, Janet M; Seddon, Jennifer M

2012-09-01

Highly mobile marine species in areas with no obvious geographic barriers are expected to show low levels of genetic differentiation. However, small-scale variation in habitat may lead to resource polymorphisms and drive local differentiation by adaptive divergence. Using nuclear microsatellite genotyping at 20 loci, and mitochondrial control region sequencing, we investigated fine-scale population structuring of inshore bottlenose dolphins (Tursiops aduncus) inhabiting a range of habitats in and around Moreton Bay, Australia. Bayesian structure analysis identified two genetic clusters within Moreton Bay, with evidence of admixture between them (F(ST) = 0.05, P = 0.001). There was only weak isolation by distance but one cluster of dolphins was more likely to be found in shallow southern areas and the other in the deeper waters of the central northern bay. In further analysis removing admixed individuals, southern dolphins appeared genetically restricted with lower levels of variation (AR = 3.252, π = 0.003) and high mean relatedness (r = 0.239) between individuals. In contrast, northern dolphins were more diverse (AR = 4.850, π = 0.009) and were mixing with a group of dolphins outside the bay (microsatellite-based STRUCTURE analysis), which appears to have historically been distinct from the bay dolphins (mtDNA Φ(ST) = 0.272, P < 0.001). This study demonstrates the ability of genetic techniques to expose fine-scale patterns of population structure and explore their origins and mechanisms. A complex variety of inter-related factors including local habitat variation, differential resource use, social behaviour and learning, and anthropogenic disturbances are likely to have played a role in driving fine-scale population structure among bottlenose dolphins in Moreton Bay. © 2012 Blackwell Publishing Ltd.

Rare gases in Samoan xenoliths

NASA Astrophysics Data System (ADS)

Poreda, R. J.; Farley, K. A.

1992-09-01

The rare gas isotopic compositions of residual harzburgite xenoliths from Savai'i (SAV locality) and an unnamed seamount south of the Samoan chain (PPT locality) provide important constraints on the rare gas evolution of the mantle and atmosphere. Despite heterogeneous trace element compositions, the rare gas characteristics of the xenoliths from each of the two localities are strikingly similar. SAV and PPT xenoliths have 3He/ 4He ratios of11.1 ± 0.5 R A and21.6 ± 1 R A, respectively; this range is comparable to the 3He/ 4He ratios in Samoan lavas and clearly demonstrates that they have trapped gases from a relatively undegassed reservoir. The neon results are not consistent with mixing between MORB and a plume source with an atmospheric signature. Rather, the neon isotopes reflect either a variably degassed mantle (with a relative order of degassing of Loihi < PPT < Reunion < SAV < MORB), or mixing between the Loihi source and MORB. The data supports the conclusions of Honda et al. that the 20Ne/ 22Ne ratio in the mantle more closely resembles the solar ratio than the atmospheric one. 40Ar/ 36Ar ratios in the least contaminated samples range from 4,000 to 12,000 with the highest values in the 22 RA PPT xenoliths. There is no evidence for atmospheric 40Ar/ 36Ar ratios in the mantle source of these samples, which indicates that the lower mantle may have 40Ar/ 36Ar ratios in excess of 5,000. Xenon isotopic anomalies in 129Xe and 136Xe are as high as 6%, or about half of the maximum MORB excess and are consistent with the less degassed nature of the Samoan mantle source. These results contradict previous suggestions that the high 3He/ 4He mantle has a near-atmospheric heavy rare gas isotopic composition.

Expression of the cancer-testis antigen BORIS correlates with prostate cancer.

PubMed

Cheema, Zubair; Hari-Gupta, Yukti; Kita, Georgia-Xanthi; Farrar, Dawn; Seddon, Ian; Corr, John; Klenova, Elena

2014-02-01

BORIS, a paralogue of the transcription factor CTCF, is a member of the cancer-testis antigen (CT) family. BORIS is normally present at high levels in the testis; however it is aberrantly expressed in various tumors and cancer cell lines. The main objectives of this study were to investigate BORIS expression together with sub-cellular localization in both prostate cell lines and tumor tissues, and assess correlations between BORIS and clinical/pathological characteristics. We examined BORIS mRNA expression, protein levels and cellular localization in a panel of human prostate tissues, cancer and benign, together with a panel prostate cell lines. We also compared BORIS levels and localization with clinical/pathological characteristics in prostate tumors. BORIS was detected in all inspected prostate cancer cell lines and tumors, but was absent in benign prostatic hyperplasia. Increased levels of BORIS protein positively correlated with Gleason score, T-stage and androgen receptor (AR) protein levels in prostate tumors. The relationship between BORIS and AR was further highlighted in prostate cell lines by the ability of ectopically expressed BORIS to activate the endogenous AR mRNA and protein. BORIS localization in the nucleus plus cytoplasm was also associated with higher BORIS levels and Gleason score. Detection of BORIS in prostate tumors suggests potential applications of BORIS as a biomarker for prostate cancer diagnosis, as an immunotherapy target and, potentially, a prognostic marker of more aggressive prostate cancer. The ability of BORIS to activate the AR gene indicates BORIS involvement in the growth and development of prostate tumors. © 2013 Wiley Periodicals, Inc.

AR on the move; boarding the microtubule expressway to the nucleus

PubMed Central

Thadani-Mulero, Maria; Nanus, David M.; Giannakakou, Paraskevi

2012-01-01

Recent studies have shown that the microtubule-stabilizing drug, paclitaxel, which is commonly used for the treatment of prostate cancer inhibits signaling from the androgen receptor (AR) by inhibiting its nuclear accumulation downstream of microtubule stabilization. This mechanism is independent of paclitaxel-induced mitotic arrest and could provide an alternative mechanism of drug action that can explain its clinical activity. In this review, we highlight the importance of signaling and trafficking pathways that depend on intact and dynamic microtubules and as such they represent downstream targets of microtubule inhibitors. We showcase prostate cancer, which is driven by the activity of the androgen receptor (AR), as recent reports have revealed a connection between the microtubule-dependent trafficking of AR and the clinical efficacy of taxanes. Identification and further elucidation of microtubule-dependent tumor-specific pathways will help us better understand the molecular basis of clinical taxane resistance as well as identify individual patients more likely to respond to treatment. PMID:22987486

Novel Confocal Microscopic and Flow Cytometric Based Assays to Visualize and Detect the (Beta)2-Adrenergic Receptor in Human Lymphocyte and Mononuclear Cell Populations

NASA Technical Reports Server (NTRS)

Salicru, A. N.; Crucian, B. E.; Nelman, M. A.; Sams, C. F.; Actor, J. K.; Marshall, G. D.

2006-01-01

The data show that immunophenotyping of leukocyte populations with (beta)2AR is possible with the commercially available Ab, although the FC assay is limited to the IST as a result of the Ab binding site to the intracellular C-terminus of the 2AR. The FC assay has applications for measuring alterations in total (beta)2AR in human leukocyte populations as changes in fluorescence. In addition, CM confirms that both surface and intracellular compartments stain positively for the (beta)2AR and can be used for qualitative assays that screen for changes in receptor compartmentalization and localization.

Androgen actions in mouse wound healing: Minimal in vivo effects of local antiandrogen delivery.

PubMed

Wang, Yiwei; Simanainen, Ulla; Cheer, Kenny; Suarez, Francia G; Gao, Yan Ru; Li, Zhe; Handelsman, David; Maitz, Peter

2016-05-01

The aims of this work were to define the role of androgens in female wound healing and to develop and characterize a novel wound dressing with antiandrogens. Androgens retard wound healing in males, but their role in female wound healing has not been established. To understand androgen receptor (AR)-mediated androgen actions in male and female wound healing, we utilized the global AR knockout (ARKO) mouse model, with a mutated AR deleting the second zinc finger to disrupt DNA binding and transcriptional activation. AR inactivation enhanced wound healing rate in males by increasing re-epithelialization and collagen deposition even when wound contraction was eliminated. Cell proliferation and migration in ARKO male fibroblasts was significantly increased compared with wild-type (WT) fibroblasts. However, ARKO females showed a similar healing rate compared to WT females. To exploit local antiandrogen effects in wound healing, while minimizing off-target systemic effects, we developed a novel electrospun polycaprolactone (PCL) scaffold wound dressing material for sustained local antiandrogen delivery. Using the antiandrogen hydroxyl flutamide (HF) at 1, 5, and 10 mg/mL in PCL scaffolds, controlled HF delivery over 21 days significantly enhanced in vitro cell proliferation of human dermal fibroblasts and human keratinocytes. HF-PCL scaffolds also promoted in vivo wound healing in mice compared with open wounds but not to PCL scaffolds. © 2016 by the Wound Healing Society.

Atmospheric River Tracking Method Intercomparison Project (ARTMIP): Science Goals and Preliminary Analysis

NASA Astrophysics Data System (ADS)

Shields, C. A.; Rutz, J. J.; Wehner, M. F.; Ralph, F. M.; Leung, L. R.

2017-12-01

The Atmospheric River Tracking Method Intercomparison Project (ARTMIP) is a community effort whose purpose is to quantify uncertainties in atmospheric river (AR) research solely due to different identification and tracking techniques. Atmospheric rivers transport significant amounts of moisture in long, narrow filamentary bands, typically travelling from the subtropics to the mid-latitudes. They are an important source of regional precipitation impacting local hydroclimate, and in extreme cases, cause severe flooding and infrastructure damage in local communities. Our understanding of ARs, from forecast skill to future climate projections, all hinge on how we define ARs. By comparing a diverse set of detection algorithms, the uncertainty in our definition of ARs, (including statistics and climatology), and the implications of those uncertainties, can be analyzed and quantified. ARTMIP is divided into two broad phases that aim to answer science questions impacted by choice of detection algorithm. How robust are AR metrics such as climatology, storm duration, and relationship to extreme precipitation? How are the AR metrics in future climate projections impacted by choice of algorithm? Some algorithms rely on threshold values for water vapor. In a warmer world, the background state, by definition, is moister due to the Clausius-Clapeyron relationship, and could potentially skew results. Can uncertainty bounds be accurately placed on each metric? Tier 1 participants will apply their algorithms to a high resolution common dataset (MERRA2) and provide the greater group AR metrics (frequency, location, duration, etc). Tier 2 research will encompass sensitivity studies regarding resolution, reanalysis choice, and future climate change scenarios. ARTMIP is currently in the Tier 1 Phase and will begin Tier 2 in 2018. Preliminary metrics and analysis from Tier 1 will be presented.

XRD-based 40Ar/39Ar age correction for fine-grained illite, with application to folded carbonates in the Monterrey Salient (northern Mexico)

NASA Astrophysics Data System (ADS)

Fitz-Díaz, Elisa; Hall, Chris M.; van der Pluijm, Ben A.

2016-05-01

Due to their minute size, 40Ar/39Ar analysis of illite faces significant analytical challenges, including mineral characterization and, especially, effects of grain size and crystallography on 39Ar recoil. Quantifying the effects of 39Ar recoil requires the use of sample vacuum encapsulation during irradiation, which permits the measurement of the fraction of recoiled 39Ar as well as the 39Ar and 40Ar∗ retained within illite crystals that are released during step heating. Total-Gas Ages (TGA) are calculated by using both recoiled and retained argon, which is functionally equivalent to K-Ar ages, while Retention Ages (RA) only involve retained Ar in the crystal. Natural applications have shown that TGA fits stratigraphic constraints of geological processes when the average illite crystallite thickness (ICT) is smaller than 10 nm, and that RA matches these constraints for ICTs larger than 50 nm. We propose a new age correction method that takes into account the average ICT and corresponding recoiled 39Ar for a sample, with X-ray Corrected Ages (XCA) lying between Total-Gas and Retention Ages depending on ICT. This correction is particularly useful in samples containing authigenic illite formed in the anchizone, with typical ICT values between 10 and 50 nm. In three samples containing authigenic illite from Cretaceous carbonates in the Monterrey Salient in northern Mexico, there is a range in TGAs among the different size-fractions of 46-49, 36-43 and 40-52 Ma, while RAs range from 54-64, 47-52 and 53-54 Ma, respectively. XCA calculations produce tighter age ranges for these samples of 52.5-56, 45.5-48.5 and 49-52.5 Ma, respectively. In an apparent age vs ICT or %2M 1illite plot, authigenic illite grains show a slope that is in general slightly positive for TGA, slightly negative for RA, but close to zero for XCA, with thinner crystallites showing more dispersion than thicker ones. In order to test if dispersion is due to a different formation history or the result of retention capability, degassing spectra were modeled for site XCA averages and overall XCA average. Modeling shows that local site age average best match the measured spectra, instead of a global average age, indicating that illite growth reflects local deformation, and is not the result of regional metamorphism. Modeling also shows that Ar-degassing spectra are very sensitive to grain size, such that age interpretation based on Ar-plateaus is meaningless for most fine-grained clays.

Cardiac Alpha1-Adrenergic Receptors: Novel Aspects of Expression, Signaling Mechanisms, Physiologic Function, and Clinical Importance

PubMed Central

O’Connell, Timothy D.; Jensen, Brian C.; Baker, Anthony J.

2014-01-01

Adrenergic receptors (AR) are G-protein-coupled receptors (GPCRs) that have a crucial role in cardiac physiology in health and disease. Alpha1-ARs signal through Gαq, and signaling through Gq, for example, by endothelin and angiotensin receptors, is thought to be detrimental to the heart. In contrast, cardiac alpha1-ARs mediate important protective and adaptive functions in the heart, although alpha1-ARs are only a minor fraction of total cardiac ARs. Cardiac alpha1-ARs activate pleiotropic downstream signaling to prevent pathologic remodeling in heart failure. Mechanisms defined in animal and cell models include activation of adaptive hypertrophy, prevention of cardiac myocyte death, augmentation of contractility, and induction of ischemic preconditioning. Surprisingly, at the molecular level, alpha1-ARs localize to and signal at the nucleus in cardiac myocytes, and, unlike most GPCRs, activate “inside-out” signaling to cause cardioprotection. Contrary to past opinion, human cardiac alpha1-AR expression is similar to that in the mouse, where alpha1-AR effects are seen most convincingly in knockout models. Human clinical studies show that alpha1-blockade worsens heart failure in hypertension and does not improve outcomes in heart failure, implying a cardioprotective role for human alpha1-ARs. In summary, these findings identify novel functional and mechanistic aspects of cardiac alpha1-AR function and suggest that activation of cardiac alpha1-AR might be a viable therapeutic strategy in heart failure. PMID:24368739

Probing Subsurface Flows in NOAA Active Region 12192: Comparison with NOAA 10486

NASA Astrophysics Data System (ADS)

Jain, Kiran; Tripathy, S. C.; Hill, F.

2017-11-01

NOAA Active Region (AR) 12192 is the biggest AR observed in solar cycle 24 so far. This was a long-lived AR that survived for four Carrington rotations (CRs) and exhibited several unusual phenomena. We measure the horizontal subsurface flows in this AR in multiple rotations using the ring-diagram technique of local helioseismology and the Global Oscillation Network Group (GONG+) Dopplergrams, and we investigate how different was the plasma flow in AR 12192 from that in AR 10486. Both regions produced several high M- and X-class flares, but they had different coronal mass ejection (CME) productivity. Our analysis suggests that these ARs had unusually large horizontal flow amplitude with distinctly different directions. While meridional flow in AR 12192 was poleward that supports the flux transport to poles, it was equatorward in AR 10486. Furthermore, there was a sudden increase in the magnitude of estimated zonal flow in shallow layers in AR 12192 during the X3.1 flare; however, it reversed direction in AR 10486 with the X17.2 flare. These flow patterns produced strong twists in horizontal velocity with depth in AR 10486 that persisted throughout the disk passage, as opposed to AR 12192, which produced a twist only after the eruption of the X3.1 flare that disappeared soon after. Our study indicates that the sunspot rotation combined with the reorganization of magnetic field in AR 10486 was not sufficient to decrease the flow energy even after several large flares that might have triggered CMEs. Furthermore, in the absence of sunspot rotation in AR 12192, this reorganization of magnetic field contributed significantly to the substantial release of flow energy after the X3.1 flare.

Anti-neuroinflammatory efficacy of the aldose reductase inhibitor FMHM via phospholipase C/protein kinase C-dependent NF-κB and MAPK pathways

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zeng, Ke-Wu; Li, Jun; Dong, Xin

2013-11-15

Aldose reductase (AR) has a key role in several inflammatory diseases: diabetes, cancer and cardiovascular diseases. Therefore, AR inhibition seems to be a useful strategy for anti-inflammation therapy. In the central nervous system (CNS), microglial over-activation is considered to be a central event in neuroinflammation. However, the effects of AR inhibition in CNS inflammation and its underlying mechanism of action remain unknown. In the present study, we found that FMHM (a naturally derived AR inhibitor from the roots of Polygala tricornis Gagnep.) showed potent anti-neuroinflammatory effects in vivo and in vitro by inhibiting microglial activation and expression of inflammatory mediators.more » Mechanistic studies showed that FMHM suppressed the activity of AR-dependent phospholipase C/protein kinase C signaling, which further resulted in downstream inactivation of the IκB kinase/IκB/nuclear factor-kappa B (NF-κB) inflammatory pathway. Therefore, AR inhibition-dependent NF-κB inactivation negatively regulated the transcription and expression of various inflammatory genes. AR inhibition by FMHM exerted neuroprotective effects in lipopolysaccharide-induced neuron–microglia co-cultures. These findings suggested that AR is a potential target for neuroinflammation inhibition and that FMHM could be an effective agent for treating or preventing neuroinflammatory diseases. - Highlights: • FMHM is a natural-derived aldose reductase (AR) inhibitor. • FMHM inhibits various neuroinflammatory mediator productions in vitro and in vivo. • FMHM inhibits neuroinflammation via aldose reductase/PLC/PKC-dependent NF-κB pathway. • FMHM inhibits neuroinflammation via aldose reductase/PLC/PKC-dependent MAPK pathway. • FMHM protects neurons against inflammatory injury in microglia-neuron co-cultures.« less

A novel class of pyranocoumarin anti-androgen receptor signaling compounds.

PubMed

Guo, Junming; Jiang, Cheng; Wang, Zhe; Lee, Hyo-Jeong; Hu, Hongbo; Malewicz, Barbara; Lee, Hyo-Jung; Lee, Jae-Ho; Baek, Nam-In; Jeong, Jin-Hyun; Kim, Dae-Keun; Kang, Kyung-Sun; Kim, Sung-Hoon; Lu, Junxuan

2007-03-01

Androgen and the androgen receptor (AR)-mediated signaling are crucial for prostate cancer development. Novel agents that can inhibit AR signaling in ligand-dependent and ligand-independent manners are desirable for the chemoprevention of prostate carcinogenesis and for the treatment of advanced prostate cancer. We have shown recently that the pyranocoumarin compound decursin from the herb Angelica gigas possesses potent anti-AR activities distinct from the anti-androgen bicalutamide. Here, we compared the anti-AR activities and the cell cycle arrest and apoptotic effects of decursin and two natural analogues in the androgen-dependent LNCaP human prostate cancer cell culture model to identify structure-activity relationships and mechanisms. Decursin and its isomer decursinol angelate decreased prostate-specific antigen expression with IC(50) of approximately 1 mumol/L. Both inhibited the androgen-stimulated AR nuclear translocation and transactivation, decreased AR protein abundance through proteasomal degradation, and induced G(0/1) arrest and morphologic differentiation. They also induced caspase-mediated apoptosis and reactive oxygen species at higher concentrations. Furthermore, they lacked the agonist activity of bicalutamide in the absence of androgen and were more potent than bicalutamide for suppressing androgen-stimulated cell growth. Decursinol, which does not contain a side chain, lacked the reactive oxygen species induction and apoptotic activities and exerted paradoxically an inhibitory and a stimulatory effect on AR signaling and cell growth. In conclusion, decursin and decursinol angelate are members of a novel class of nonsteroidal compounds that exert a long-lasting inhibition of both ligand-dependent and ligand-independent AR signaling. The side chain is critical for sustaining the anti-AR activities and the growth arrest and apoptotic effects.

CX4945 suppresses the growth of castration-resistant prostate cancer cells by reducing AR-V7 expression.

PubMed

Deng, Chuangzhong; Chen, Jieping; Guo, Shengjie; Wang, Yanjun; Zhou, Qianghua; Li, Zaishang; Yang, Xingping; Yu, Xingsu; Zhang, Zhenfeng; Zhou, Fangjian; Han, Hui; Yao, Kai

2017-08-01

The aberrant expression of casein kinase 2 (CK2) has been reported to be involved in the tumorigenesis and progression of prostate cancer. The inhibition of CK2 activity represses androgen-dependent prostate cancer cells by attenuating the androgen receptor (AR) signaling pathway. In this study, we examined the effect of CK2 inhibition in castration-resistant prostate cancer (CRPC) cells, in which AR variants (ARVs) play a predominant role. A newly synthetic CK2 selective inhibitor CX4945 was utilized to study the effect of CK2 inhibition in CRPC cells by CCK8 assay and colony formation assay. Protein and mRNA levels of full-length AR (AR-FL) and AR-V7 were determined by qPCR and western blot, respectively. The nuclear translocation of p50 and p65 was assessed to reflect the activity of the NF-κB pathway. CX4945 reduced the proliferation of CRPC cells in a dose-dependent and time-dependent manner. AR-V7 rather than AR-FL was downregulated by CX4945 in both the mRNA and protein level. Furthermore, CX4945 could restore the sensitivity of CRPC cells to bicalutamide. The analysis of possible mechanisms demonstrated that the inhibition of CK2 diminished the phosphorylation of p65 at ser529 and thus attenuated the activity of the NF-κB pathway. The inhibition of CK2 by CX4945 can repress the viability of CRPC cells and restore their sensitivity to anti-androgen therapy by suppressing AR-V7. This finding presents a potential option for the treatment of prostate cancer, especially CRPC.

Erratum: Epigenetic silencing of miR-34a in human prostate cancer cells and tumor tissue specimens can be reversed by BR-DIM treatment.

PubMed

Kong, D; Heath, E; Chen, W; Cher, M; Powell, I; Heilbrun, L; Li, Y; Ali, S; Sethi, S; Hassan, O; Hwang, C; Gupta, N; Chitale, D; Sakr, Wa; Menon, M; Sarkar, Fh

2013-01-01

Androgen Receptor (AR) signaling is critically important during the development and progression of prostate cancer (PCa). The AR signaling is also important in the development of castrate resistant prostate cancer (CRPC) where AR is functional even after androgen deprivation therapy (ADT); however, little is known regarding the transcriptional and functional regulation of AR in PCa. Moreover, treatment options for primary PCa for preventing the occurrence of CRPC is limited; therefore, novel strategy for direct inactivation of AR is urgently needed. In this study, we found loss of miR-34a, which targets AR, in PCa tissue specimens, especially in patients with higher Gleason grade tumors, consistent with increased expression of AR. Forced over-expression of miR-34a in PCa cell lines led to decreased expression of AR and prostate specific antigen (PSA) as well as the expression of Notch-1, another important target of miR-34a. Most importantly, BR-DIM intervention in PCa patients prior to radical prostatectomy showed reexpression of miR-34a, which was consistent with decreased expression of AR, PSA and Notch-1 in PCa tissue specimens. Moreover, BR-DIM intervention led to nuclear exclusion both in PCa cell lines and in tumor tissues. PCa cells treated with BR-DIM and 5-aza-dC resulted in the demethylation of miR-34a promoter concomitant with inhibition of AR and PSA expression in LNCaP and C4-2B cells. These results suggest, for the first time, epigenetic silencing of miR-34a in PCa, which could be reversed by BR-DIM treatment and, thus BR-DIM could be useful for the inactivation of AR in the treatment of PCa.[This corrects the article on p. 14 in vol. 4.].

Measurement of Isobaric Analogue Resonances of 47Ar with the Active-Target Time Projection Chamber

NASA Astrophysics Data System (ADS)

Bradt, Joshua William

While the nuclear shell model accurately describes the structure of nuclei near stability, the structure of unstable, neutron-rich nuclei is still an area of active research. One region of interest is the set of nuclei near N=28. The shell model suggests that these nuclei should be approximately spherical due to the shell gap predicted by their magic number of neutrons; however, experiments have shown that the nuclei in this region rapidly become deformed as protons are removed from the spherical 48Ca. This makes 46Ar a particularly interesting system as it lies in a transition region between 48Ca and lighter isotones that are known to be deformed. An experiment was performed at the National Superconducting Cyclotron Laboratory (NSCL) to measure resonant proton scattering on 46Ar. The resonances observed in this reaction correspond to unbound levels in the 47K intermediate state nucleus which are isobaric analogues of states in the 47Ar nucleus. By measuring the spectroscopic factors of these states in 47Ar, we gain information about the single-particle structure of this system, which is directly related to the size of the N=28 shell gap. Four resonances were observed: one corresponding to the ground state in 47Ar, one corresponding its first excited 1/2- state, and two corresponding to 1/2+ states in either 47Ar or the intermediate state nucleus. However, only a limited amount of information about these states could be recovered due to the low experimental statistics and limited angular resolution caused by pileup rejection and the inability to accurately reconstruct the beam particle track. In addition to the nuclear physics motivations, this experiment served as the radioactive beam commissioning for the Active-Target Time Projection Chamber (AT-TPC). The AT-TPC is a new gas-filled charged particle detector built at the NSCL to measure low-energy radioactive beams from the ReA3 facility. Since the gas inside the detector serves as both the tracking medium and the scattering target, reactions are measured over a continuous range of energies with near-4π solid angle coverage. This experiment demonstrated that tracks recorded by the AT-TPC can be reconstructed to a good resolution, and it established the feasibility of performing similar experiments with this detector in the future.

Targeted Androgen Pathway Suppression in Localized Prostate Cancer: A Pilot Study

PubMed Central

Mostaghel, Elahe A.; Nelson, Peter S.; Lange, Paul; Lin, Daniel W.; Taplin, Mary Ellen; Balk, Steven; Ellis, William; Kantoff, Philip; Marck, Brett; Tamae, Daniel; Matsumoto, Alvin M.; True, Lawrence D.; Vessella, Robert; Penning, Trevor; Hunter Merrill, Rachel; Gulati, Roman; Montgomery, Bruce

2014-01-01

Purpose Ligand-mediated activation of the androgen receptor (AR) is critical for prostate cancer (PCa) survival and proliferation. The failure to completely ablate tissue androgens may limit suppression of PCa growth. We evaluated combinations of CYP17A and 5-α-reductase inhibitors for reducing prostate androgen levels, AR signaling, and PCa volumes. Patients and Methods Thirty-five men with intermediate/high-risk clinically localized PCa were randomly assigned to goserelin combined with dutasteride (ZD), bicalutamide and dutasteride (ZBD), or bicalutamide, dutasteride, and ketoconazole (ZBDK) for 3 months before prostatectomy. Controls included patients receiving combined androgen blockade with luteinizing hormone-releasing hormone agonist and bicalutamide. The primary outcome measure was tissue dihydrotestosterone (DHT) concentration. Results Prostate DHT levels were substantially lower in all experimental arms (0.02 to 0.04 ng/g v 0.92 ng/g in controls; P < .001). The ZBDK group demonstrated the greatest percentage decline in serum testosterone, androsterone, and dehydroepiandrosterone sulfate (P < .05 for all). Staining for AR and the androgen-regulated genes prostate-specific antigen and TMPRSS2 was strongly suppressed in benign glands and moderately in malignant glands (P < .05 for all). Two patients had pathologic complete response, and nine had ≤ 0.2 cm3 of residual tumor (defined as a near-complete response), with the largest numbers of complete and near-complete responses in the ZBDK group. Conclusion Addition of androgen synthesis inhibitors lowers prostate androgens below that achieved with standard therapy, but significant AR signaling remains. Tissue-based analysis of steroids and AR signaling is critical to informing the search for optimal local and systemic control of high-risk prostate cancer. PMID:24323034

Androgen receptor polyglutamine repeat length affects receptor activity and C2C12 cell development.

PubMed

Sheppard, Ryan L; Spangenburg, Espen E; Chin, Eva R; Roth, Stephen M

2011-10-20

Testosterone (T) has an anabolic effect on skeletal muscle and is believed to exert its local effects via the androgen receptor (AR). The AR harbors a polymorphic stretch of glutamine repeats demonstrated to inversely affect receptor transcriptional activity in prostate and kidney cells. The effects of AR glutamine repeat length on skeletal muscle are unknown. In this study we examined the effect of AR CAG repeat length on AR function in C2C12 cells. AR expression vectors harboring 14, 24, and 33 CAG repeats were used to assess AR transcriptional activity. C2C12 cell proliferation, differentiation, gene expression, myotube formation, and myonuclear fusion index were assessed. Transcriptional activity increased with increasing repeat length and in response to testosterone (AR14 = 3.91 ± 0.26, AR24 = 25.21 ± 1.72, AR33 = 36.08 ± 3.22 relative light units; P < 0.001). Ligand activation was increased for AR33 (2.10 ± 0.04) compared with AR14 (1.54 ± 0.09) and AR24 (1.57 ± 0.05, P < 0.001). AR mRNA expression was elevated in each stably transfected line. AR33 cell proliferation (20,512.3 ± 1,024.0) was decreased vs. AR14 (27,604.17 ± 1,425.3; P < 0.001) after 72 h. Decreased CK activity in AR14 cells (54.9 ± 2.9 units/μg protein) in comparison to AR33 (70.8 ± 8.1) (P < 0.05) was noted. The myonuclear fusion index was lower for AR14 (15.21 ± 3.24%) and AR33 (9.97 ± 3.14%) in comparison to WT (35.07 ± 5.60%, P < 0.001). AR14 and AR33 cells also displayed atypical myotube morphology. RT-PCR revealed genotype differences in myostatin and myogenin expression. We conclude that AR polyglutamine repeat length is directly associated with transcriptional activity and alters the growth and development of C2C12 cells. This polymorphism may contribute to the heritability of muscle mass in humans.

Immunostaining of the androgen receptor and sequence analysis of its DNA-binding domain in canine prostate cancer.

PubMed

Lai, Chen-Li; van den Ham, René; Mol, Jan; Teske, Erik

2009-09-01

Prostate cancer in the dog (cPC) has many features in common with hormone refractory human prostate cancer. As cPC is seen more often in castrated dogs, the contribution of the androgen receptor (AR) to the development of prostate cancer remains questionable. The aim of the present study was to evaluate the presence of the AR by immunohistochemistry in cPC. AR staining was observed in most tumors from intact and castrated dogs, but the proportion of positive cells and the staining intensity were much lower than in the prostate of healthy, non-castrated dogs. Most of the positive staining was seen in the cytoplasm rather than in the nuclei of the tumor cells. The predominant cytoplasmic localization was not related to mutations in exon 3 of the DNA-binding domain of the AR, as shown by sequence analysis of microdissected AR positive tumor cells. Other mechanisms that lead to an impaired androgen-AR signaling or a basal/stem cell like origin may explain the low cytoplasmic AR staining in cPC.

Reductions in the Cardiac Transient Outward K+ Current Ito Caused by Chronic β-Adrenergic Receptor Stimulation Are Partly Rescued by Inhibition of Nuclear Factor κB.

PubMed

Panama, Brian K; Korogyi, Adam S; Aschar-Sobbi, Roozbeh; Oh, Yena; Gray, Charles B B; Gang, Hongying; Brown, Joan Heller; Kirshenbaum, Lorrie A; Backx, Peter H

2016-02-19

The fast transient outward potassium current (Ito,f) plays a critical role in the electrical and contractile properties of the myocardium. Ito,f channels are formed by the co-assembly of the pore-forming α-subunits, Kv4.2 and Kv4.3, together with the accessory β-subunit KChIP2. Reductions of Ito,f are common in the diseased heart, which is also associated with enhanced stimulation of β-adrenergic receptors (β-ARs). We used cultured neonatal rat ventricular myocytes to examine how chronic β-AR stimulation decreases Ito,f. To determine which downstream pathways mediate these Ito,f changes, adenoviral infections were used to inhibit CaMKIIδc, CaMKIIδb, calcineurin, or nuclear factor κB (NF-κB). We observed that chronic β-AR stimulation with isoproterenol (ISO) for 48 h reduced Ito,f along with mRNA expression of all three of its subunits (Kv4.2, Kv4.3, and KChIP2). Inhibiting either CaMKIIδc nor CaMKIIδb did not prevent the ISO-mediated Ito,f reductions, even though CaMKIIδc and CaMKIIδb clearly regulated Ito,f and the mRNA expression of its subunits. Likewise, calcineurin inhibition did not prevent the Ito,f reductions induced by β-AR stimulation despite strongly modulating Ito,f and subunit mRNA expression. In contrast, NF-κB inhibition partly rescued the ISO-mediated Ito,f reductions in association with restoration of KChIP2 mRNA expression. Consistent with these observations, KChIP2 promoter activity was reduced by p65 as well as β-AR stimulation. In conclusion, NF-κB, and not CaMKIIδ or calcineurin, partly mediates the Ito,f reductions induced by chronic β-AR stimulation. Both mRNA and KChIP2 promoter data suggest that the ISO-induced Ito,f reductions are, in part, mediated through reduced KChIP2 transcription caused by NF-κB activation. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Fast decoder for local quantum codes using Groebner basis

NASA Astrophysics Data System (ADS)

Haah, Jeongwan

2013-03-01

Based on arXiv:1204.1063. A local translation-invariant quantum code has a description in terms of Laurent polynomials. As an application of this observation, we present a fast decoding algorithm for translation-invariant local quantum codes in any spatial dimensions using the straightforward division algorithm for multivariate polynomials. The running time is O (n log n) on average, or O (n2 log n) on worst cases, where n is the number of physical qubits. The algorithm improves a subroutine of the renormalization-group decoder by Bravyi and Haah (arXiv:1112.3252) in the translation-invariant case. This work is supported in part by the Insitute for Quantum Information and Matter, an NSF Physics Frontier Center, and the Korea Foundation for Advanced Studies.

Mesenchymal stem cell therapy for acute radiation syndrome: innovative medical approaches in military medicine.

PubMed

Eaton, Erik B; Varney, Timothy R

2015-01-01

After a radiological or nuclear event, acute radiation syndrome (ARS) will present complex medical challenges that could involve the treatment of hundreds to thousands of patients. Current medical doctrine is based on limited clinical data and remains inadequate. Efforts to develop medical innovations that address ARS complications are unlikely to be generated by industry because of market uncertainties specific to this type of injury. A prospective strategy could be the integration of cellular therapy to meet the medical demands of ARS. The most clinically advanced cellular therapy to date is the administration of mesenchymal stem cells (MSCs). Results of currently published investigations describing MSC safety and efficacy in a variety of injury and disease models demonstrate the unique qualities of this reparative cell population in adapting to the specific requirements of the damaged tissue in which the cells integrate. This report puts forward a rationale for the further evaluation of MSC therapy to address the current unmet medical needs of ARS. We propose that the exploration of this novel therapy for the treatment of the multivariate complications of ARS could be of invaluable benefit to military medicine.

A Somatically Acquired Enhancer of the Androgen Receptor Is a Noncoding Driver in Advanced Prostate Cancer.

PubMed

Takeda, David Y; Spisák, Sándor; Seo, Ji-Heui; Bell, Connor; O'Connor, Edward; Korthauer, Keegan; Ribli, Dezső; Csabai, István; Solymosi, Norbert; Szállási, Zoltán; Stillman, David R; Cejas, Paloma; Qiu, Xintao; Long, Henry W; Tisza, Viktória; Nuzzo, Pier Vitale; Rohanizadegan, Mersedeh; Pomerantz, Mark M; Hahn, William C; Freedman, Matthew L

2018-06-09

Increased androgen receptor (AR) activity drives therapeutic resistance in advanced prostate cancer. The most common resistance mechanism is amplification of this locus presumably targeting the AR gene. Here, we identify and characterize a somatically acquired AR enhancer located 650 kb centromeric to the AR. Systematic perturbation of this enhancer using genome editing decreased proliferation by suppressing AR levels. Insertion of an additional copy of this region sufficed to increase proliferation under low androgen conditions and to decrease sensitivity to enzalutamide. Epigenetic data generated in localized prostate tumors and benign specimens support the notion that this region is a developmental enhancer. Collectively, these observations underscore the importance of epigenomic profiling in primary specimens and the value of deploying genome editing to functionally characterize noncoding elements. More broadly, this work identifies a therapeutic vulnerability for targeting the AR and emphasizes the importance of regulatory elements as highly recurrent oncogenic drivers. Copyright © 2018 Elsevier Inc. All rights reserved.

The anti-hyperplasia, anti-oxidative and anti-inflammatory properties of Qing Ye Dan and swertiamarin in testosterone-induced benign prostatic hyperplasia in rats.

PubMed

Wu, Xinying; Gu, Ye; Li, Lun

2017-01-04

Qing Ye Dan (QYD) is the whole plant of Swertia mileensis and used in Chinese folk medicine for the treatment of prostatitis, benign prostatic hyperplasia (BPH) and so on. This study was to investigate the effects of QYD and its main component swertiamarin on BPH induced by testosterone in rats. The prostatic expressions of vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), basic fibroblast growth factor (βFGF) and proliferating cell nuclear antigen (PCNA) were detected by immunohistochemistry assay. Prostatic levels of oxidative stress and inflammatory-related factors were also analyzed. Additionally, the prostatic expressions of androgen receptor (AR), estrogen receptor (ER)-α, ER-β, hypoxia-inducible factor (HIF)-1α, B-cell CLL/lymphoma (Bcl)-2 and Bcl-2-associated X protein (Bax) were measured by western blot. The epithelial-mesenchymal transition (EMT) associated factors were evaluated by quantitative RT-PCR. It showed that QYD and swertiamarin ameliorated the testosterone-induced prostatic hyperplasia and collagen deposition, attenuated the over-expressions of HIF-1α, VEGF, EGF, βFGF, PCNA, AR and ER-α, reduced the ratio of Bcl-2/Bax, enhanced the expression of ER-β, inhibited the oxidative stress and local inflammation, as well as relieved prostatic EMT. It suggested that QYD and swertiamarin had prostatic protective potential against BPH. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Conserved Binding Mode of Human [beta subscript 2] Adrenergic Receptor Inverse Agonists and Antagonist Revealed by X-ray Crystallography

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wacker, Daniel; Fenalti, Gustavo; Brown, Monica A.

2010-11-15

G protein-coupled receptors (GPCRs) represent a large fraction of current pharmaceutical targets, and of the GPCRs, the {beta}{sub 2} adrenergic receptor ({beta}{sub 2}AR) is one of the most extensively studied. Previously, the X-ray crystal structure of {beta}{sub 2}AR has been determined in complex with two partial inverse agonists, but the global impact of additional ligands on the structure or local impacts on the binding site are not well-understood. To assess the extent of such ligand-induced conformational differences, we determined the crystal structures of a previously described engineered {beta}{sub 2}AR construct in complex with two inverse agonists: ICI 118,551 (2.8 {angstrom}),more » a recently described compound (2.8 {angstrom}) (Kolb et al, 2009), and the antagonist alprenolol (3.1 {angstrom}). The structures show the same overall fold observed for the previous {beta}{sub 2}AR structures and demonstrate that the ligand binding site can accommodate compounds of different chemical and pharmacological properties with only minor local structural rearrangements. All three compounds contain a hydroxy-amine motif that establishes a conserved hydrogen bond network with the receptor and chemically diverse aromatic moieties that form distinct interactions with {beta}{sub 2}AR. Furthermore, receptor ligand cross-docking experiments revealed that a single {beta}{sub 2}AR complex can be suitable for docking of a range of antagonists and inverse agonists but also indicate that additional ligand-receptor structures may be useful to further improve performance for in-silico docking or lead-optimization in drug design.« less

Effects of androgens on cardiovascular remodeling.

PubMed

Ikeda, Yasumasa; Aihara, Ken-ichi; Yoshida, Sumiko; Akaike, Masashi; Matsumoto, Toshio

2012-07-01

Androgens, the male sex hormones, exert various biological effects on many target organs through the transcriptional effects of the nuclear androgen receptor (AR). ARs are expressed not only in classical target organs, such as the brain, genital organs, bone, and skeletal muscles, but also in the cardiovascular system. Because the female sex hormones estrogens are well-known to protect against cardiovascular disease, sex has been considered to have a significant clinical impact on cardiovascular mortality. However, the influence of androgens on the cardiovascular system has not been fully elucidated. To clarify this issue, we analyzed the effects of administration of angiotensin II and doxorubicin, an anticancer agent, in a loading model in male wild-type and AR-deficient mice. In this review, we focus on the actions of androgens as potential targets for the prevention of cardiovascular diseases in males.

Apparent loss-of-function mutant GPCRs revealed as constitutively desensitized receptors.

PubMed

Wilbanks, Alyson M; Laporte, Stéphane A; Bohn, Laura M; Barak, Larry S; Caron, Marc G

2002-10-08

The DRY motif is a triplet amino acid sequence (aspartic acid, arginine, and tyrosine) that is highly conserved in G protein-coupled receptors (GPCRs). Recently, we have shown that a molecular determinant for nephrogenic diabetes insipidus, the vasopressin receptor with a substitution at the DRY motif arginine (V2R R137H), is a constitutively desensitized receptor that is unable to couple to G proteins due to its constitutive association with beta-arrestin [Barak, L. S. (2001) Proc. Natl. Acad. Sci. U.S.A. 98, 93-98]. Additionally, the mutant receptors are localized in endocytic vesicles, identical to wild-type receptors stimulated with agonist. In this study, we asked whether the constitutively desensitized phenotype observed in the V2R R137H represents a general paradigm that may be extended to other GPCRs. We show that arginine substitutions in the DRY motifs of the alpha(1B) adrenergic receptor (alpha(1B)-AR) and angiotensin II type 1A receptor (AT(1A)R) result in receptors that are uncoupled from G proteins, associated with beta-arrestins, and found localized in endocytic vesicles rather than at the plasma membrane in the absence of agonists. The localization of the alpha(1B)-ARs and AT(1A)Rs with arginine substitutions can be restored to the plasma membrane by either using selective antagonists or preventing the endocytosis of the beta-arrestin-receptor complexes. These results indicate that the arginine residue of the DRY motif is essential for preserving the localization of the inactive receptor complex. Furthermore, constitutive desensitization may underlie some loss-of-function receptor phenotypes and represent an unappreciated mechanism of hormonal resistance.

Characterization of the wintertime particulate (PM1) pollution at an urban background site of Nicosia, Cyprus

NASA Astrophysics Data System (ADS)

Pikridas, Michael; Sciare, Jean; Vrekoussis, Mihalis; Oikonomou, Konstantina; Merabet, Hamza; Mihalopoulos, Nikos; Yassaa, Nouredine; Savvides, Chrysanthos

2016-04-01

As part of MISTRALS-ChArMEx (Chemistry-Aerosol Mediterranean Experiment, http://charmex.lsce.ipsl.fr/), and MISTRALS-ENVI-Med "CyAr" (Cyprus Aerosols and gas precursors) programs, a 1-month intensive field campaign has been performed in December 2014 at an urban background site of Nicosia (Cyprus) - a typical European city of the Eastern Mediterranean - with the objective to document the major (local versus imported) sources responsible for wintertime particulate (PM1) pollution. Several near real-time analyzers were deployed for that purpose (TEOM 1400, OPC Grimm 1.108, Q-ACSM, Aethalometer AE31) allowing to investigate in near-real time the major chemical components of submicron aerosols (Black Carbon, Organics, Sulphate, Nitrate, Ammonium). Quality control of Q-ACSM and Aethalometer datasets was performed through closure studies (using co-located TEOM / OPC Grimm). Comparisons were also performed with other on-line / off-line measurements performed by the local Air quality network (DLI) at other locations in Nicosia with the objective to check the consistency and representativeness of our observations. Very high levels of Black Carbon and OA were systematically observed every night (with maximum concentrations around 22:00 local time) pointing to local combustion sources most probably related to domestic heating. Source apportionment of organic aerosols (OA) was performed using the SourceFinder software (SoFi, http://www.psi.ch/acsm-stations/me-2) allowing the distinction between various primary/secondary OA sources and helped us to better characterize the combustion sources being responsible for the observed elevated nighttime PM1 levels. Acknowledgements: This campaign has been funded by MISTRALS (ChArMEx et ENVI-Med CyAr programs), CNRS-INSU, CEA, CyI, DLI, CDER and ECPL.

A Multi-Receptor and Multi-Species Assay for Potential Endocrine Disruptor Targets (SLAS meeting)

EPA Science Inventory

Screening methods for detecting potential endocrine disrupting chemicals rely chiefly on transactivation assays targeting nuclear receptors such as the estrogen (ER) and androgen receptors (AR). These assays are predominately human-based; yet environmental exposure can affect div...

Androgenic/estrogenic balance in the male rat cerebral circulation: metabolic enzymes and sex steroid receptors

PubMed Central

Gonzales, Rayna J; Ansar, Saema; Duckles, Sue P; Krause, Diana N

2008-01-01

Tissues from males can be regulated by a balance of androgenic and estrogenic effects because of local metabolism of testosterone and expression of relevant steroid hormone receptors. As a critical first step to understanding sex hormone influences in the cerebral circulation of males, we investigated the presence of enzymes that metabolize testosterone to active products and their respective receptors. We found that cerebral blood vessels from male rats express 5α-reductase type 2 and aromatase, enzymes responsible for conversion of testosterone into dihydrotestosterone (DHT) and 17β-estradiol, respectively. Protein levels of these enzymes, however, were not modulated by long-term in vivo hormone treatment. We also showed the presence of receptors for both androgens (AR) and estrogens (ER) from male cerebral vessels. Western blot analysis showed bands corresponding to the full-length AR (110 kDa) and ERα (66 kDa). Long-term in vivo treatment of orchiectomized rats with testosterone or DHT, but not estrogen, increased AR levels in cerebral vessels. In contrast, ERα protein levels were increased after in vivo treatment with estrogen but not testosterone. Fluorescent immunostaining revealed ERα, AR, and 5α-reductase type 2 in both the endothelial and smooth muscle layers of cerebral arteries, whereas aromatase staining was solely localized to the endothelium. Thus, cerebral vessels from males are target tissues for both androgens and estrogen. Furthermore, local metabolism of testosterone might balance opposing androgenic and estrogenic influences on cerebrovascular as well as brain function in males. PMID:17406656

Atmospheric Rivers in VR-CESM: Historical Comparison and Future Projections

NASA Astrophysics Data System (ADS)

McClenny, E. E.; Ullrich, P. A.

2016-12-01

Atmospheric rivers (ARs) are responsible for most of the horizontal vapor transport from the tropics, and bring upwards of half the annual precipitation to midlatitude west coasts. The difference between a drought year and a wet year can come down to 1-2 ARs. Such few events transform an otherwise arid region into one which supports remarkable biodiversity, productive agriculture, and booming human populations. It follows that such a sensitive hydroclimate feature would demand priority in evaluating end-of-century climate runs, and indeed, the AR subfield has grown significantly over the last decade. However, results tend to vary wildly from study to study, raising questions about how to best approach ARs in models. The disparity may result from any number of issues, including the ability for a model to properly resolve a precipitating AR, to the formulation and application of an AR detection algorithm. ARs pose a unique problem in global climate models (GCMs) computationally and physically, because the GCM horizontal grid must be fine enough to resolve coastal mountain range topography and force orographic precipitation. Thus far, most end-of-century projections on ARs have been performed on models whose grids are too coarse to resolve mountain ranges, causing authors to draw conclusions on AR intensity from water vapor content or transport alone. The use of localized grid refinement in the Variable Resolution version of NCAR's Community Earth System Model (VR-CESM) has succeeded in resolving AR landfall. This study applies an integrated water vapor AR detection algorithm to historical and future projections from VR-CESM, with historical ARs validated against NASA's Modern Era Retrospective-Analysis for Research and Applications. Results on end-of-century precipitating AR frequency, intensity, and landfall location will be discussed.

Diminished androgen and estrogen receptors and aromatase levels in hypogonadal diabetic men: reversal with testosterone.

PubMed

Ghanim, Husam; Dhindsa, Sandeep; Abuaysheh, Sanaa; Batra, Manav; Kuhadiya, Nitesh D; Makdissi, Antoine; Chaudhuri, Ajay; Dandona, Paresh

2018-03-01

One-third of males with type 2 diabetes (T2DM) have hypogonadism, characterized by low total and free testosterone concentrations. We hypothesized that this condition is associated with a compensatory increase in the expression of androgen receptors (AR) and that testosterone replacement reverses these changes. We also measured estrogen receptor and aromatase expression. This is a randomized double-blind placebo-controlled trial. Thirty-two hypogonadal and 32 eugonadal men with T2DM were recruited. Hypogonadal men were randomized to receive intramuscular testosterone or saline every 2 weeks for 22 weeks. We measured AR, ERα and aromatase expression in peripheral blood mononuclear cells (MNC), adipose tissue and skeletal muscle in hypogonadal and eugonadal males with T2DM at baseline and after 22 weeks of treatment in those with hypogonadism. The mRNA expression of AR, ERα (ESR1) and aromatase in adipose tissue from hypogonadal men was significantly lower as compared to eugonadal men, and it increased significantly to levels comparable to those in eugonadal patients with T2DM following testosterone treatment. AR mRNA expression was also significantly lower in MNC from hypogonadal patients compared to eugonadal T2DM patients. Testosterone administration in hypogonadal patients also restored AR mRNA and nuclear extract protein levels from MNC to that in eugonadal patients. In the skeletal muscle, AR mRNA and protein expression are lower in men with hypogonadism. Testosterone treatment restored AR expression levels to that comparable to levels in eugonadal men. We conclude that, contrary to our hypothesis, the expression of AR, ERα and aromatase is significantly diminished in hypogonadal men as compared to eugonadal men with type 2 diabetes. Following testosterone replacement, there is a reversal of these deficits. © 2018 European Society of Endocrinology.

The prohibitin-repressive interaction with E2F1 is rapidly inhibited by androgen signalling in prostate cancer cells

PubMed Central

Koushyar, S; Economides, G; Zaat, S; Jiang, W; Bevan, C L; Dart, D A

2017-01-01

Prohibitin (PHB) is a tumour suppressor molecule with pleiotropic activities across several cellular compartments including mitochondria, cell membrane and the nucleus. PHB and the steroid-activated androgen receptor (AR) have an interplay where AR downregulates PHB, and PHB represses AR. Additionally, their cellular locations and chromatin interactions are in dynamic opposition. We investigated the mechanisms of cell cycle inhibition by PHB and how this is modulated by AR in prostate cancer. Using a prostate cancer cell line overexpressing PHB, we analysed the gene expression changes associated with PHB-mediated cell cycle arrest. Over 1000 gene expression changes were found to be significant and gene ontology analysis confirmed PHB-mediated repression of genes essential for DNA replication and synthesis, for example, MCMs and TK1, via an E2F1 regulated pathway—agreeing with its G1/S cell cycle arrest activity. PHB is known to inhibit E2F1-mediated transcription, and the PHB:E2F1 interaction was seen in LNCaP nuclear extracts, which was then reduced by androgen treatment. Upon two-dimensional western blot analysis, the PHB protein itself showed androgen-mediated charge differentiation (only in AR-positive cells), indicating a potential dephosphorylation event. Kinexus phosphoprotein array analysis indicated that Src kinase was the main interacting intracellular signalling hub in androgen-treated LNCaP cells, and that Src inhibition could reduce this AR-mediated charge differentiation. PHB charge change may be associated with rapid dissociation from chromatin and E2F1, allowing the cell cycle to proceed. The AR and androgens may deactivate the repressive functions of PHB upon E2F1 leading to cell cycle progression, and indicates a role for AR in DNA replication licensing. PMID:28504694

Synergistic activation of the androgen receptor by bombesin and low-dose androgen.

PubMed

Dai, Jie; Shen, Ruoqian; Sumitomo, Makoto; Stahl, Rosalyn; Navarro, Daniel; Gershengorn, Marvin C; Nanus, David M

2002-07-01

Neuropeptide growth factors such as bombesinare implicated in progression to androgen-independent prostate cancer (PC). We examined the impact of bombesin on androgen receptor (AR)-mediated gene expression. The AR together with the AR-responsive probasin ARR(3)tk-luc or PSA-pPUE-ELB-luc promoter was cotransfected into Swiss 3T3 and PC-3 cells, both of which express high-affinity bombesin receptors; the cells were incubated with bombesin (0-50 nM) and dihydrotestosterone (DHT; 0-10 nM), and luciferase activities were measured. DHT increased transcription approximately 40-fold at doses of 1 and 10 nM but had no effect at 10 pM. Bombesin alone, or with 1 or 10 nM DHT, did not further increase transcription. However, 5 nM bombesin and 10 pM DHT, doses that by themselves had no effect, resulted in a approximately 20 fold increase in transcription (P < 0.005). This synergistic effect was blocked by bombesin receptor antagonists and recombinant neutral endopeptidase, which hydrolyzes bombesin. Bombesin and DHT together also increased binding of nuclear extracts from PC-3 cells transfected with AR to a consensus androgen response element in mobility shift assays and increased the level of secreted prostate-specific antigen in LNCaP cell supernatant compared with DHT or bombesin alone. Immunoprecipitation of AR from (32)P-labeled LNCaP cells revealed that 5 nM bombesin + 10 pM DHT induced AR phosphorylation comparable with 1 nM DHT, whereas bombesin or 10 pM DHT alone did not. These data indicate that bombesin can synergize with low (castrate) levels of DHT to induce AR-mediated transcription and suggest that neuropeptides promote AR-mediated signaling in androgen-independent prostate cancer.

Vulvar field resection: novel approach to the surgical treatment of vulvar cancer based on ontogenetic anatomy.

PubMed

Höckel, Michael; Schmidt, Katja; Bornmann, Karoline; Horn, Lars-Christian; Dornhöfer, Nadja

2010-10-01

Current local treatment of vulvar cancer is wide tumor excision and radical vulvectomy based on functional anatomy established from the adult and on the view of radial progressive tumor permeation. Standard surgery is associated with a considerable local failure rate and severe disturbance of the patients' body image. Vulvar field resection (VFR) is based on ontogenetic anatomy and on the concept of local tumor spread within permissive compartments. VFR combined with anatomical reconstruction (AR) is proposed as a new surgical approach to the treatment of vulvar cancer. A prospective trial was launched to test the compartment theory for vulvar cancer and to assess safety and effectiveness of the new therapy. In 54 consecutive patients 46 tumors were locally confined to the tissue compartment differentiated from the vulvar anlage. The 8 tumors having transgressed into adjacent tissue compartments of different embryonic origins exhibited signs of advanced malignant progression. 38 patients with vulvar cancer, stages T1-3 were treated with VFR and AR. The perioperative complication rate was low. At 19 (3-50) months follow-up no patient failed locally. 33 patients estimated their body image as undisturbed. Vulvar cancer permeates within ontogenetic tissue compartments and surgical treatment with VFR and AR appears to be safe and effective. Patients should benefit from the new approach as local tumor control is high and the preserved tissue can be successfully used for restoration of vulvar form and function. Confirmatory trials with more patients and longer follow-up are suggested. Copyright © 2010 Elsevier Inc. All rights reserved.

Inhibition of Hippocampal β-Adrenergic Receptors Impairs Retrieval But Not Reconsolidation of Cocaine-Associated Memory and Prevents Subsequent Reinstatement

PubMed Central

Otis, James M; Fitzgerald, Michael K; Mueller, Devin

2014-01-01

Retrieval of drug-associated memories is critical for maintaining addictive behaviors, as presentation of drug-associated cues can elicit drug seeking and relapse. Recently, we and others have demonstrated that β-adrenergic receptor (β-AR) activation is necessary for retrieval using both rat and human memory models. Importantly, blocking retrieval with β-AR antagonists persistently impairs retrieval and provides protection against subsequent reinstatement. However, the neural locus at which β-ARs are required for maintaining retrieval and subsequent reinstatement is unclear. Here, we investigated the necessity of dorsal hippocampus (dHipp) β-ARs for drug-associated memory retrieval. Using a cocaine conditioned place preference (CPP) model, we demonstrate that local dHipp β-AR blockade before a CPP test prevents CPP expression shortly and long after treatment, indicating that dHipp β-AR blockade induces a memory retrieval disruption. Furthermore, this retrieval disruption provides long-lasting protection against cocaine-induced reinstatement. The effects of β-AR blockade were dependent on memory reactivation and were not attributable to reconsolidation disruption as blockade of β-ARs immediately after a CPP test had little effect on subsequent CPP expression. Thus, cocaine-associated memory retrieval is mediated by β-AR activity within the dHipp, and disruption of this activity could prevent cue-induced drug seeking and relapse long after treatment. PMID:23907403

Inhibition of hippocampal β-adrenergic receptors impairs retrieval but not reconsolidation of cocaine-associated memory and prevents subsequent reinstatement.

PubMed

Otis, James M; Fitzgerald, Michael K; Mueller, Devin

2014-01-01

Retrieval of drug-associated memories is critical for maintaining addictive behaviors, as presentation of drug-associated cues can elicit drug seeking and relapse. Recently, we and others have demonstrated that β-adrenergic receptor (β-AR) activation is necessary for retrieval using both rat and human memory models. Importantly, blocking retrieval with β-AR antagonists persistently impairs retrieval and provides protection against subsequent reinstatement. However, the neural locus at which β-ARs are required for maintaining retrieval and subsequent reinstatement is unclear. Here, we investigated the necessity of dorsal hippocampus (dHipp) β-ARs for drug-associated memory retrieval. Using a cocaine conditioned place preference (CPP) model, we demonstrate that local dHipp β-AR blockade before a CPP test prevents CPP expression shortly and long after treatment, indicating that dHipp β-AR blockade induces a memory retrieval disruption. Furthermore, this retrieval disruption provides long-lasting protection against cocaine-induced reinstatement. The effects of β-AR blockade were dependent on memory reactivation and were not attributable to reconsolidation disruption as blockade of β-ARs immediately after a CPP test had little effect on subsequent CPP expression. Thus, cocaine-associated memory retrieval is mediated by β-AR activity within the dHipp, and disruption of this activity could prevent cue-induced drug seeking and relapse long after treatment.

Synoptic evolution of Atmospheric River landfalls in Northern California and the pre-conditioning of their characteristics by the climate state

NASA Astrophysics Data System (ADS)

Gershunov, A.; Guirguis, K.; Shulgina, T.; Clemesha, R.; Ralph, M.

2017-12-01

Atmospheric Rivers (ARs) contribute the lion's share of water resources for California, but can also cause flooding and draw heavily on emergency resources of state and local governments. Comprehensive probabilistic tools relating landfalling ARs to pre-existing weather/climate conditions could be useful for subseasonal forecasting, emergency preparedness and water resource management. We examine ARs targeting the Northern California coast using long-term observations of synoptic-scale circulation, high-resolution precipitation, and a seven-decade-long catalog of AR landfalls to quantify distinct orientations of landfalling ARs. Using a probabilistic approach to relate these historic events to precursor weather patterns, we identify synoptic circulation patterns that precede AR landfalls at various lead times in the range of 0-30 days. Examination of the evolution of these precursor patterns reveals subtle but important differences in the atmospheric states that lead to AR landfalls versus those that don't. Synoptic precursors can also differentiate between orientations of ARs at landfall, which produce rather different precipitation patterns over the region's complex topography. Moreover, low-frequency climate forcing appears to modulate the likelihood of AR landfalls, as well as their preferred orientations. These results provide a link between seasonal and subseasonal timescales and suggest a new approach toward extended-range prediction of land-falling atmospheric rivers and their related precipitation.

Atmospheric River Importance to Extratropical Climate and Hydrology

NASA Astrophysics Data System (ADS)

Nash, D.; Waliser, D. E.; Guan, B.; Ye, H.; Ralph, F. M.

2017-12-01

Atmospheric Rivers (ARs) are narrow, long, water vapor rich corridors of the atmosphere that are responsible for over 90% of the poleward moisture transport across mid-latitudes and into high latitudes. This suggests a crucial role for ARs in helping establish the extra-tropical atmospheric water budget and hydroclimate variability. However, the contribution of ARs to the extra-tropical atmospheric water budget has yet to be quantified, including impacts on water vapor transport and storage, and precipitation. This study characterizes the roles of AR related atmospheric transport on combined and individual atmospheric water budget variables over extratropical regions of both hemispheres based on MERRA2 reanalysis products during 1997-2014. Results show that poleward water vapor transport related to ARs is strongly related to changes in water vapor storage and especially precipitation in higher latitudes in both hemispheres, with the relationship dependent on averaging period. For example, for the annual cycle climatology, both AR transport and local evaporation support the variation in precipitation. However, on monthly time scales, the water budget at higher latitudes tends to be dominated by the balance between AR transport and precipitation. On pentad and daily time scales, AR transport is related to both precipitation and water vapor storage changes. These results indicate the important role of the episodic, extreme moisture transports associated with ARs in helping establish the high latitude water and energy cycles, and associated hydroclimate.

Comparative investigation of pure and mixed rare gas atoms on coronene molecules.

PubMed

Rodríguez-Cantano, Rocío; Bartolomei, Massimiliano; Hernández, Marta I; Campos-Martínez, José; González-Lezana, Tomás; Villarreal, Pablo; Pérez de Tudela, Ricardo; Pirani, Fernando; Hernández-Rojas, Javier; Bretón, José

2017-01-21

Clusters formed by the combination of rare gas (RG) atoms of He, Ne, Ar, and Kr on coronene have been investigated by means of a basin-hopping algorithm and path integral Monte Carlo calculations at T = 2 K. Energies and geometries have been obtained and the role played by the specific RG-RG and RG-coronene interactions on the final results is analysed in detail. Signatures of diffuse behavior of the He atoms on the surface of the coronene are in contrast with the localization of the heavier species, Ar and Kr. The observed coexistence of various geometries for Ne suggests the motion of the RG atoms on the multi-well potential energy surface landscape offered by the coronene. Therefore, the investigation of different clusters enables a comparative analysis of localized versus non-localized features. Mixed Ar-He-coronene clusters have also been considered and the competition of the RG atoms to occupy the docking sites on the molecule is discussed. All the obtained information is crucial to assess the behavior of coronene, a prototypical polycyclic aromatic hydrocarbon clustering with RG atoms at a temperature close to that of interstellar medium, which arises from the critical balance of the interactions involved.

Vinclozolin Exposure in Utero Induces Postpubertal Prostatitis and Reduces Sperm Production via a Reversible Hormone-Regulated Mechanism

PubMed Central

Cowin, Prue A.; Gold, Elspeth; Aleksova, Jasna; O'Bryan, Moira K.; Foster, Paul M. D.; Scott, Hamish S.; Risbridger, Gail P.

2010-01-01

Vinclozolin is an endocrine-disrupting chemical (EDC) that binds with high affinity to the androgen receptor (AR) and blocks the action of gonadal hormones on male reproductive organs. An alternative mechanism of action of Vinclozolin involves transgenerational effects on the male reproductive tract. We previously reported in utero Vinclozolin exposure-induced prostatitis (prostate inflammation) in postpubertal rats concurrent with down-regulation of AR and increased nuclear factor-κB activation. We postulated the male reproductive abnormalities induced by in utero Vinclozolin exposure could be reversed by testosterone supplementation, in contrast to the permanent modifications involving DNA methyltransferases (Dnmts) described by others. To test this hypothesis, we administered high-dose testosterone at puberty to Vinclozolin-treated rats and determined the effect on anogenital distance (AGD); testicular germ cell apoptosis, concentration of elongated spermatids, and the onset of prostatitis. Concurrently we examined Dnmt1, −3A, −3B, and −3L mRNA expression. Consistent with previous reports, in utero exposure to Vinclozolin significantly reduced AGD, increased testicular germ cell apoptosis 3-fold, reduced elongated spermatid number by 40%, and induced postpubertal prostatitis in 100% of exposed males. Administration of high-dose testosterone (25 mg/kg) at puberty normalized AGD, reduced germ cell apoptosis, and restored elongated spermatid number. Testosterone restored AR and nuclear factor-κB expression in the prostate and abolished Vinclozolin-induced prostatitis. Altered Dnmt expression was evident with in utero Vinclozolin exposure and was not normalized after testosterone treatment. These data demonstrate in utero Vinclozolin-induced male reproductive tract abnormalities are AR mediated and reversible and involve a mechanism independent of Dnmt expression. PMID:20056826

Vinclozolin exposure in utero induces postpubertal prostatitis and reduces sperm production via a reversible hormone-regulated mechanism.

PubMed

Cowin, Prue A; Gold, Elspeth; Aleksova, Jasna; O'Bryan, Moira K; Foster, Paul M D; Scott, Hamish S; Risbridger, Gail P

2010-02-01

Vinclozolin is an endocrine-disrupting chemical (EDC) that binds with high affinity to the androgen receptor (AR) and blocks the action of gonadal hormones on male reproductive organs. An alternative mechanism of action of Vinclozolin involves transgenerational effects on the male reproductive tract. We previously reported in utero Vinclozolin exposure-induced prostatitis (prostate inflammation) in postpubertal rats concurrent with down-regulation of AR and increased nuclear factor-kappaB activation. We postulated the male reproductive abnormalities induced by in utero Vinclozolin exposure could be reversed by testosterone supplementation, in contrast to the permanent modifications involving DNA methyltransferases (Dnmts) described by others. To test this hypothesis, we administered high-dose testosterone at puberty to Vinclozolin-treated rats and determined the effect on anogenital distance (AGD); testicular germ cell apoptosis, concentration of elongated spermatids, and the onset of prostatitis. Concurrently we examined Dnmt1, -3A, -3B, and -3L mRNA expression. Consistent with previous reports, in utero exposure to Vinclozolin significantly reduced AGD, increased testicular germ cell apoptosis 3-fold, reduced elongated spermatid number by 40%, and induced postpubertal prostatitis in 100% of exposed males. Administration of high-dose testosterone (25 mg/kg) at puberty normalized AGD, reduced germ cell apoptosis, and restored elongated spermatid number. Testosterone restored AR and nuclear factor-kappaB expression in the prostate and abolished Vinclozolin-induced prostatitis. Altered Dnmt expression was evident with in utero Vinclozolin exposure and was not normalized after testosterone treatment. These data demonstrate in utero Vinclozolin-induced male reproductive tract abnormalities are AR mediated and reversible and involve a mechanism independent of Dnmt expression.

In Vitro Biologic Activities of the Antimicrobials Triclocarban, Its Analogs, and Triclosan in Bioassay Screens: Receptor-Based Bioassay Screens

PubMed Central

Ahn, Ki Chang; Zhao, Bin; Chen, Jiangang; Cherednichenko, Gennady; Sanmarti, Enio; Denison, Michael S.; Lasley, Bill; Pessah, Isaac N.; Kültz, Dietmar; Chang, Daniel P.Y.; Gee, Shirley J.; Hammock, Bruce D.

2008-01-01

Background Concerns have been raised about the biological and toxicologic effects of the antimicrobials triclocarban (TCC) and triclosan (TCS) in personal care products. Few studies have evaluated their biological activities in mammalian cells to assess their potential for adverse effects. Objectives In this study, we assessed the activity of TCC, its analogs, and TCS in in vitro nuclear-receptor–responsive and calcium signaling bioassays. Materials and methods We determined the biological activities of the compounds in in vitro, cell-based, and nuclear-receptor–responsive bioassays for receptors for aryl hydrocarbon (AhR), estrogen (ER), androgen (AR), and ryanodine (RyR1). Results Some carbanilide compounds, including TCC (1–10 μM), enhanced estradiol (E2)-dependent or testosterone-dependent activation of ER- and AR-responsive gene expression up to 2.5-fold but exhibited little or no agonistic activity alone. Some carbanilides and TCS exhibited weak agonistic and/or antagonistic activity in the AhR-responsive bioassay. TCS exhibited antagonistic activity in both ER- and AR-responsive bioassays. TCS (0.1–10 μM) significantly enhanced the binding of [3H]ryanodine to RyR1 and caused elevation of resting cytosolic [Ca2+] in primary skeletal myotubes, but carbanilides had no effect. Conclusions Carbanilides, including TCC, enhanced hormone-dependent induction of ER- and AR-dependent gene expression but had little agonist activity, suggesting a new mechanism of action of endocrine-disrupting compounds. TCS, structurally similar to noncoplanar ortho-substituted poly-chlorinated biphenyls, exhibited weak AhR activity but interacted with RyR1 and stimulated Ca2+ mobilization. These observations have potential implications for human and animal health. Further investigations are needed into the biological and toxicologic effects of TCC, its analogs, and TCS. PMID:18795164

Bisphenol A disrupts the temporal pattern of histofunctional changes in the female reproductive tract of Caiman latirostris.

PubMed

Galoppo, Germán H; Canesini, Guillermina; Tavalieri, Yamil E; Stoker, Cora; Kass, Laura; Luque, Enrique H; Muñoz-de-Toro, Mónica

2017-12-01

Recently, we have described the ontogeny of histofunctional differentiation changes in the oviduct of Caiman latirostris. The expression of estrogen receptor alpha and progesterone receptor shows that the caiman oviduct could be a target of the action of xenoestrogens such as the widely environmentally present Bisphenol A (BPA), early in life. The aims of this study were: to complement oviduct characterization by establishing the ontogenetic changes in androgen receptor (AR) expression and assessing the effects of early postnatal exposure to 17-β-estradiol (E2) or BPA on the histofunctional features of the oviduct. AR was expressed in all the stages studied. The spatial pattern of AR immunostaining changed from neonatal to juvenile caimans. In the luminal epithelium, changes were at the subcellular level, from cytoplasmic to nuclear. In the subepithelium, although both cytoplasmic and nuclear AR expression was observed, changes were mainly at tissue level, from the subepithelial compartment to the outer muscular layer. The oviduct was highly sensitive to E2 and BPA at the early postnatal developmental stage. E2- and BPA-exposed caimans showed increased luminal epithelial height and higher proliferative activity. Changes in histomorphological features (measured by a scoring system), steroid hormone receptors, collagen remodeling and muscle-associated proteins suggest a precocious oviduct histofunctional differentiation in E2- and BPA-exposed caimans. The modification of the temporal pattern of oviductal biomarkers suggests that organizational changes could impair C. latirostris reproductive health later in life. The alterations in the caiman female reproductive tract exposed to BPA highlight the importance of preserving aquatic environments from plastic pollution. Copyright © 2017 Elsevier Inc. All rights reserved.

The urinary metabolites of DINCH® have an impact on the activities of the human nuclear receptors ERα, ERβ, AR, PPARα and PPARγ.

PubMed

Engel, Anika; Buhrke, Thorsten; Kasper, Stefanie; Behr, Anne-Cathrin; Braeuning, Albert; Jessel, Sönke; Seidel, Albrecht; Völkel, Wolfgang; Lampen, Alfonso

2018-05-01

DINCH ® (di-isononyl cyclohexane-1,2-dicarboxylate) is a non-phthalate plasticizer that has been developed to replace phthalate plasticizers such as DEHP (di-2-ethylhexyl phthalate) or DINP (di-isononyl phthalate). DINCH ® is metabolized to its corresponding monoester and subsequently to oxidized monoester derivatives. These are conjugated to glucuronic acid and subject to urinary excretion. In contrast to DINCH ® , there are almost no toxicological data available regarding its primary and secondary metabolites. The present study aimed at the characterization of potential endocrine properties of DINCH ® and five DINCH ® metabolites by using reporter gene assays to monitor the activity of the human nuclear receptors ERα, ERβ, AR, PPARα and PPARγ in vitro. DINCH ® itself did not have any effect on the activity of these receptors whereas DINCH ® metabolites were shown to activate all these receptors. In the case of AR, DINCH ® metabolites predominantly enhanced dihydrotestosterone-stimulated AR activity. In the H295R steroidogenesis assay, neither DINCH ® nor any of its metabolites affected estradiol or testosterone synthesis. In conclusion, primary and secondary DINCH ® metabolites exert different effects at the molecular level compared to DINCH ® itself. All these in vitro effects of DINCH ® metabolites, however, were only observed at high concentrations such as 10 μM or above which is about three orders of magnitude above reported DINCH ® metabolite concentrations in human urine. Thus, the in vitro data do not support the notion that DINCH ® or any of the investigated metabolites may exert considerable endocrine effects in vivo at relevant human exposure levels. Copyright © 2018 Elsevier B.V. All rights reserved.

Seasonal morphological variations and age-related changes of the seminal vesicle of viscacha (Lagostomus maximus maximus): an ultrastructural and immunohistochemical study.

PubMed

Chaves, Eduardo M; Aguilera-Merlo, Claudia; Cruceño, Albana; Fogal, Teresa; Piezzi, Ramón; Scardapane, Luis; Dominguez, Susana

2012-05-01

The viscacha is a seasonal rodent that exhibit an annual reproductive cycle with periods of maximum reproductive activity and gonadal regression. We studied seasonal variations in the morphology and cellular population of the seminal vesicles (SVs) during both periods and in impuber animals. Seminal vesicles were studied by light and electronic microscopy. Measurements of epithelial height, nuclear diameter, luminal diameter, and muscular layer were performed. Also, we studied the distribution of androgen receptors (AR) in this gland during the reproductive cycle and in impuber animal. During gonadal regression, principal and clear cells showed signs of reduced functional activity. These were characterized by an epithelium of smaller height, irregular nuclei, and cytoplasm with few organelles, dilated cisterns, and glycogen granules. In impuber animals, the principal cells showed large nuclei with chromatin lax and cytoplasm with small mitochondria, poorly developed Golgi apparatus, and granules of glycogen. On the other hand, the cells exhibited seasonal variations in the distribution and percentage of immunolabeled cells to AR throughout the annual reproductive cycle. During the gonadal regression period, glandular mucosa exhibited numerous epithelial cells with intense nuclear staining. However, fibromuscular stromal cells were weakly positive for AR in contrast to what was observed during the activity period. Considering that testosterone values are lower in adult animals during the period of gonadal regression and in impuber animals, our immunohistochemical results show a significant correlation with the percentage of AR-immunopositive cells. In conclusion, these results demonstrate that the structure of the SVs changes in the activity period of viscacha, probably because of elevated levels of testosterone leading to an increase in the secretory activity of epithelial cells. Copyright © 2012 Wiley Periodicals, Inc.

A high-precision 40Ar/39Ar age for the Nördlinger Ries impact crater, Germany, and implications for the accurate dating of terrestrial impact events

NASA Astrophysics Data System (ADS)

Schmieder, Martin; Kennedy, Trudi; Jourdan, Fred; Buchner, Elmar; Reimold, Wolf Uwe

2018-01-01

40Ar/39Ar dating of specimens of moldavite, the formation of which is linked to the Ries impact in southern Germany, with a latest-generation ARGUS VI multi-collector mass spectrometer yielded three fully concordant plateau ages with a weighted mean age of 14.808 ± 0.021 Ma (± 0.038 Ma including all external uncertainties; 2σ; MSWD = 0.40, P = 0.67). This new best-estimate age for the Nördlinger Ries is in general agreement with previous 40Ar/39Ar results for moldavites, but constitutes a significantly improved precision with respect to the formation age of the distal Ries-produced tektites. Separates of impact glass from proximal Ries ejecta (suevite glass from three different surface outcrops) and partially melted feldspar particles from impact melt rock of the SUBO 18 Enkingen drill core failed to produce meaningful ages. These glasses show evidence for excess 40Ar introduction, which may have been incurred during interaction with hydrothermal fluids. Only partially reset 40Ar/39Ar ages could be determined for the feldspathic melt separates from the Enkingen core. The new 40Ar/39Ar results for the Ries impact structure constrain the duration of crater cooling, during the prevailing hydrothermal activity, to locally at least ∼60 kyr. With respect to the dating of terrestrial impact events, this paper briefly discusses a number of potential issues and effects that may be the cause for seemingly precise, but on a kyr-scale inaccurate, impact ages.

Variations on morphology and elemental composition of mineral dust particles from local, regional, and long-range transport meteorological scenarios

NASA Astrophysics Data System (ADS)

Coz, Esther; Gómez-Moreno, Francisco J.; Casuccio, Gary S.; ArtíñAno, BegoñA.

2010-06-01

Mineral dust is the second major source of PM10 in Madrid, reaching up to 80% of the PM10 mass during certain long-range dust transport events. Three different types of scenarios have been found to be associated with the high particle concentration episodes in the city: local anthropogenic, regional recirculation, and African dust transport processes. The present study focuses on the characterization of the individual mineral dust particles related to some chemical and morphological features during these three types of episodes, with special attention to local and regional episodes. To achieve this purpose, four different samples were selectively collected during the 2004-2005 period campaigns, one corresponding to each type of scenario and other sample from an Atlantic ventilated one. Meteorological situation, dust source identification, impact on ambient concentrations, size range distribution, and particle individual analysis have been characterized for each of them. Elemental composition and morphology of more than 30,000 mineral particles were analyzed by computer-controlled scanning electron microscopy. Particles were grouped into clusters based on their elemental composition, and the aspect ratio (AR) of each cluster or category was compared for each type of episode. The AR was related to the mineralogical crystal structure of each chemical cluster. The dates chosen for microscopy analysis were in good agreement in size distribution and chemical composition with the average of the dates in the entire campaign and with those from previous campaigns. Major differences between local/regional and long-range transported mineral dust were found in the relative abundance between carbonates and silicates, with much higher abundance of calcium carbonates in the first ones. These differences between silicate and carbonate contents were consistent with the results found in previous campaigns and were directly related to the composition of the parent topsoil by studying the Ca/Si ratios of similar episodes recorded all over the Iberian Peninsula. Differences in morphology were also found for these scenarios. The predominance of calcium carbonate under regional and local influence is scientifically relevant since this mineral is known to react with both SO2 and HNO3 in the atmosphere. Larger average AR values were found for dust particles from long-range transport, and smaller average AR values were found for particles from local and regional resuspended dust. The increasing average AR value has been linked to the silicate cluster presence, whereas a reduction has been observed within the carbonate cluster.

Functional Characterization of Paralogous Gonadotropin-Releasing Hormone-Type and Corazonin-Type Neuropeptides in an Echinoderm

PubMed Central

Tian, Shi; Egertová, Michaela; Elphick, Maurice R.

2017-01-01

Homologs of the vertebrate neuropeptide gonadotropin-releasing hormone (GnRH) have been identified in invertebrates, including the insect neuropeptide corazonin (CRZ). Recently, we reported the discovery of GnRH-type and CRZ-type signaling systems in an echinoderm, the starfish Asterias rubens, demonstrating that the evolutionary origin of paralogous GnRH-type and CRZ-type neuropeptides can be traced back to the common ancestor of protostomes and deuterostomes. Here, we have investigated the physiological roles of the GnRH-type (ArGnRH) and the CRZ-type (ArCRZ) neuropeptides in A. rubens, using mRNA in situ hybridization, immunohistochemistry and in vitro pharmacology. ArGnRH precursor (ArGnRHP)-expressing cells and ArGnRH-immunoreactive cells and/or processes are present in the radial nerve cords, circumoral nerve ring, digestive system (e.g., cardiac stomach and pyloric stomach), body wall-associated muscle (apical muscle), and appendages (tube feet, terminal tentacle). The general distribution of ArCRZ precursor (ArCRZP)-expressing cells is similar to that of ArGnRHP, but with specific local differences. For example, cells expressing ArGnRHP are present in both the ectoneural and hyponeural regions of the radial nerve cords and circumoral nerve ring, whereas cells expressing ArCRZP were only observed in the ectoneural region. In vitro pharmacological experiments revealed that both ArGnRH and ArCRZ cause contraction of cardiac stomach, apical muscle, and tube foot preparations. However, ArGnRH was more potent/effective than ArCRZ as a contractant of the cardiac stomach, whereas ArCRZ was more potent/effective than ArGnRH as a contractant of the apical muscle. These findings demonstrate that both ArGnRH and ArCRZ are myoexcitatory neuropeptides in starfish, but differences in their expression patterns and pharmacological activities are indicative of distinct physiological roles. This is the first study to investigate the physiological roles of both GnRH-type and CRZ-type neuropeptides in a deuterostome, providing new insights into the evolution and comparative physiology of these paralogous neuropeptide signaling systems in the Bilateria. PMID:29033898

B-H Bond Activation by an Amidinate-Stabilized Amidosilylene: Non-Innocent Amidinate Ligand.

PubMed

Khoo, Sabrina; Shan, Yu-Liang; Yang, Ming-Chung; Li, Yongxin; Su, Ming-Der; So, Cheuk-Wai

2018-05-21

The activation of B-H and B-Cl bonds in boranes by base-stabilized low-valent silicon compounds is described. The reaction of the amidinato amidosilylene-borane adduct [L{Ar(Me 3 Si)N}SiBH 3 ] [1; L = PhC(N tBu) 2 , and Ar = 2,6- iPr 2 C 6 H 3 ] with MeOTf in toluene at room temperature formed [L{Ar(Me 3 Si)N}SiBH 2 OTf] (2). [LSiN(SiMe 3 )Ar] in compound 2 then underwent a B-H bond activation with BH 2 OTf in refluxing toluene to afford the B-H bond activation product [LB(H)Si(H)(OTf){N(SiMe 3 )Ar}] (3). On the other hand, when compound 2 was reacted with 4-dimethylaminopyridine in refluxing toluene, another B-H bond activation product [(μ-κ1:κ1-L)B(H)(DMAP)Si(H){N(Ar)SiMe 3 }]OTf (4) was afforded. Mechanistic studies show that "(μ-κ1:κ1-L)B(H)(OTf)Si(H){N(Ar)SiMe 3 }" (2A) is the key intermediate in the reactions mentioned above. The formation of 2A is further evidenced by the activation of the B-Cl bond in PhBCl 2 by the amidinato silicon(I) dimer [LSi:] 2 to form the B-Cl bond activation product [(μ-κ1:κ1-L)B(Cl)(Ph)Si(Cl)] 2 (6). Compounds 2-4 and 6 were characterized by nuclear magnetic resonance spectroscopy and X-ray crystallography.

Year-2017 nuclear quadrupole moments

NASA Astrophysics Data System (ADS)

Pyykkö, Pekka

2018-05-01

A 'year-2017' set of nuclear quadrupole moments, Q, is presented. Compared to the previous, 'year-2008' set, a major revision of the value, or an improvement of the accuracy is reported for 21H, 37, 3918Ar, 39, 40, 4119K, 6730Zn, 48Cd, 49In, 50Sn (Mössbauer state), 51Sb, 87Fr and 90Th. Slight improvements or valuable reconfirmations exist for 4Be, 6C, 16S, 17Cl, 33As, 35Br, 53I, 54Xe, 56Ba, 57La and 72Hf.

Attaining Stability: A Case for Accepting a Nuclearized Iran

DTIC Science & Technology

2009-02-11

St ra te gy Re se ar ch Pr oj ec t ATTAINING STABILITY: A CASE FOR ACCEPTING A NUCLEARIZED IRAN BY BRIGADIER NAUSHAD KAYANI Pakistan Army...DISTRIBUTION STATEMENT A : Approved for Public Release. Distribution is Unlimited. Only a work of the United States Government is not subject to copyright. Based...upon the nature of a particular student-author’s employment, a paper may not be a work of the United States Government and may, in fact, be protected

Prokaryotic arsenate reductase enhances arsenate resistance in Mammalian cells.

PubMed

Wu, Dan; Tao, Xuanyu; Wu, Gaofeng; Li, Xiangkai; Liu, Pu

2014-01-01

Arsenic is a well-known heavy metal toxicant in the environment. Bioremediation of heavy metals has been proposed as a low-cost and eco-friendly method. This article described some of recent patents on transgenic plants with enhanced heavy metal resistance. Further, to test whether genetic modification of mammalian cells could render higher arsenic resistance, a prokaryotic arsenic reductase gene arsC was transfected into human liver cancer cell HepG2. In the stably transfected cells, the expression level of arsC gene was determined by quantitative real-time PCR. Results showed that arsC was expressed in HepG2 cells and the expression was upregulated by 3 folds upon arsenate induction. To further test whether arsC has function in HepG2 cells, the viability of HepG2-pCI-ArsC cells exposed to arsenite or arsenate was compared to that of HepG2-pCI cells without arsC gene. The results indicated that arsC increased the viability of HepG2 cells by 25% in arsenate, but not in arsenite. And the test of reducing ability of stably transfected cells revealed that the concentration of accumulated trivalent arsenic increased by 25% in HepG2-pCI-ArsC cells. To determine the intracellular localization of ArsC, a fusion vector with fluorescent marker pEGFP-N1-ArsC was constructed and transfected into.HepG2. Laser confocal microscopy showed that EGFP-ArsC fusion protein was distributed throughout the cells. Taken together, these results demonstrated that prokaryotic arsenic resistant gene arsC integrated successfully into HepG2 genome and enhanced arsenate resistance of HepG2, which brought new insights of arsenic detoxification in mammalian cells.

Prevalence of pollen-induced allergic rhinitis with high pollen exposure in grasslands of northern China.

PubMed

Wang, X-Y; Ma, T-T; Wang, X-Y; Zhuang, Y; Wang, X-D; Ning, H-Y; Shi, H-Y; Yu, R-L; Yan, D; Huang, H-D; Bai, Y-F; Shan, G-L; Zhang, B; Song, Q-K; Zhang, Y-F; Zhang, T-J; Jia, D-Z; Liu, X-L; Kang, Z-X; Yan, W-J; Yang, B-T; Bao, X-Z; Sun, S-H; Zhang, F-F; Yu, W-H; Bai, C-L; Wei, T; Yang, T; Ma, T-Q; Wu, X-B; Liu, J-G; Du, H; Zhang, L; Yan, Y; Wang, D-Y

2018-06-01

The aim of this study was to investigate the prevalence of epidemiologic and physician-diagnosed pollen-induced AR (PiAR) in the grasslands of northern China and to study the impact of the intensity and time of pollen exposure on PiAR prevalence. A multistage, clustered and proportionately stratified random sampling with a field interviewer-administered survey study was performed together with skin prick tests (SPT) and measurements of the daily pollen count. A total of 6043 subjects completed the study, with a proportion of 32.4% epidemiologic AR and 18.5% PiAR. The prevalence was higher in males than females (19.6% vs 17.4%, P = .024), but no difference between the two major residential and ethnic groups (Han and Mongolian) was observed. Subjects from urban areas showed higher prevalence of PiAR than rural areas (23.1% vs 14.0%, P < .001). Most PiAR patients were sensitized to two or more pollens (79.4%) with artemisia, chenopodium, and humulus scandens being the most common pollen types, which were similarly found as the top three sensitizing pollen allergens by SPT. There were significant regional differences in the prevalence of epidemiologic AR (from 18.6% to 52.9%) and PiAR (from 10.5% to 31.4%) among the six areas investigated. PiAR symptoms were positively associated with pollen counts, temperature, and precipitation (P < .05), but negatively with wind speed and pressure P < .05). Pollen-induced AR (PiAR) prevalence in the investigated region is extremely high due to high seasonal pollen exposure, which was influenced by local environmental and climate conditions. © 2018 The Authors. Allergy Published by John Wiley and Sons Ltd.

Androgen receptor expression in the human vagina under different physiological and treatment conditions.

PubMed

Baldassarre, M; Perrone, A M; Giannone, F A; Armillotta, F; Battaglia, C; Costantino, A; Venturoli, S; Meriggiola, M C

2013-01-01

Recent data report an important role of testosterone (T) in modulating female sexual responses, but little is known about the expression and distribution of androgen receptor (AR) in the human vagina. Therefore, the aims of our study were to evaluate the expression of AR in the human vagina in premenopausal (PrM) and menopausal (M) women and in T-treated women. Vaginal biopsies were obtained from PrM and postmenopausal women and from women with gender identity disorder (female to male (FtM)) receiving exogenous T. AR gene and protein expression levels in vaginal tissues were determined by real-time PCR and western blot analysis, respectively, whereas the localization of AR in vaginal mucosa and stroma was performed by immunohistochemistry. ARs were detected by immunostaining both in the mucosa and stroma. In vaginal mucosa, AR density score decreases with age but does not change with T administration. In stromal tissue, AR density score does not change with age but significantly increases with T administration (P<0.01). AR protein expression was significantly increased in FtM subjects (P<0.001). The expression of AR messenger RNA (mRNA) evaluated by Real-time PCR showed a significantly higher mRNA expression in FtM versus M patients (P<0.01) and in PrM versus M subjects (P<0.05). In conclusion, we found AR protein and mRNA expression both in the epithelium and stroma of the human vagina in all groups of women. A negative correlation exists between age and AR expression in the vaginal mucosa. T administration increases AR expression in both the mucosa and stroma.

Rapid auxin-induced nitric oxide accumulation and subsequent tyrosine nitration of proteins during adventitious root formation in sunflower hypocotyls

PubMed Central

Yadav, Sunita; David, Anisha; Baluška, František; Bhatla, Satish C.

2013-01-01

Using NO specific probe (MNIP-Cu), rapid nitric oxide (NO) accumulation as a response to auxin (IAA) treatment has been observed in the protoplasts from the hypocotyls of sunflower seedlings (Helianthus annuus L.). Incubation of protoplasts in presence of NPA (auxin efflux blocker) and PTIO (NO scavenger) leads to significant reduction in NO accumulation, indicating that NO signals represent an early signaling event during auxin-induced response. A surge in NO production has also been demonstrated in whole hypocotyl explants showing adventitious root (AR) development. Evidence of tyrosine nitration of cytosolic proteins as a consequence of NO accumulation has been provided by western blot analysis and immunolocalization in the sections of AR producing hypocotyl segments. Most abundant anti-nitrotyrosine labeling is evident in proteins ranging from 25–80 kDa. Tyrosine nitration of a particular protein (25 kDa) is completely absent in presence of NPA (which suppresses AR formation). Similar lack of tyrosine nitration of this protein is also evident in other conditions which do not allow AR differentiation. Immunofluorescent localization experiments have revealed that non-inductive treatments (such as PTIO) for AR develpoment from hypocotyl segments coincide with symplastic and apoplastic localization of tyrosine nitrated proteins in the xylem elements, in contrast with negligible (and mainly apoplastic) nitration of proteins in the interfascicular cells and phloem elements. Application of NPA does not affect tyrosine nitration of proteins even in the presence of an external source of NO (SNP). Tyrosine nitrated proteins are abundant around the nuclei in the actively dividing cells of the root primordium. Thus, NO-modulated rapid response to IAA treatment through differential distribution of tyrosine nitrated proteins is evident as an inherent aspect of the AR development. PMID:23299324

Inhibiting glycogen synthase kinase-3 mitigates the hematopoietic acute radiation syndrome in mice.

PubMed

Lee, Chang-Lung; Lento, William E; Castle, Katherine D; Chao, Nelson J; Kirsch, David G

2014-05-01

Exposure to a nuclear accident or radiological attack can cause death from acute radiation syndrome (ARS), which results from radiation injury to vital organs such as the hematopoietic system. However, the U.S. Food and Drug Administration (FDA) has not approved any medical countermeasures for this specific purpose. With growing concern over nuclear terrorism, there is an urgent need to develop small molecule deliverables that mitigate mortality from ARS. One emerging modulator of hematopoietic stem/progenitor cell (HSPC) activity is glycogen synthase kinase-3 (GSK-3). The inhibition of GSK-3 has been shown to augment hematopoietic repopulation in mouse models of bone marrow transplantation. In this study, we performed an in vitro screen using irradiated bone marrow mononuclear cells (BM-MNCs) to test the effects of four GSK-3 inhibitors: CHIR99021; 6-Bromoindirubin-3'-oxime (BIO); SB415286; and SB216763. This screen showed that SB216763 significantly increased the frequency of c-Kit(+) Lin(-) Sca1(+) (KLS) cells and hematopoietic colony-forming cells in irradiated BM-MNCs. Importantly, administration of a single dose of SB216763 to C57BL/6J mice by subcutaneous injection 24 h after total-body irradiation significantly improved hematopoietic recovery and mitigated hematopoietic ARS. Collectively, our results demonstrate that the GSK-3 inhibitor SB216763 is an effective medical countermeasure against acute radiation injury of the hematopoietic system.

A fence line noble gas monitoring system for nuclear power plants.

PubMed

Grasty, R L; Hovgaard, J; LaMarre, J R

2001-01-01

A noble gas monitoring system has been installed at Ontario Power Generation's Pickering Nuclear Generating Station (PNGS) near Toronto, Canada. This monitoring system allows a direct measure of air kerma from external radiation instead of calculating this based on plant emission data and meteorological models. This has resulted in a reduction in the reported effective dose from external radiation by a factor of at least ten. The system consists of nine self-contained units, each with a 7.6 cm x 7.6 cm (3 inch x 3 inch) NaI(TI) detector that is calibrated for air kerma. The 512-channel gamma ray spectral information is downloaded daily from each unit to a central computer where the data are stored and processed. A spectral stripping procedure is used to remove natural background variations from the spectral windows used to monitor xenon-133 (133Xe), xenon-135 (135Xe), argon-41 (41Ar), and skyshine radiation from the use of radiography sources. Typical monthly minimum detection limits in air kerma are 0.3 nGy for 133Xe, 0.7 nGy for 35Xe, 3 nGy for 41Ar and 2 nGy for skyshine radiation. Based on 9 months of continuous operation, the annualised air kerma due to 133Xe, 135Xe and 41Ar and skyshine radiation were 7 nGy, 8 nGy, 26 nGy and 107 nGy respectively.

Clematichinenoside protects blood brain barrier against ischemic stroke superimposed on systemic inflammatory challenges through up-regulating A20.

PubMed

Han, Dan; Fang, Weirong; Zhang, Rui; Wei, Jie; Kodithuwakku, Nandani Darshika; Sha, Lan; Ma, Wenhuan; Liu, Lifang; Li, Fengwen; Li, Yunman

2016-01-01

Suppression of excessive inflammation can ameliorate blood brain barrier (BBB) injury, which shows therapeutic potential for clinical treatment of brain injury induced by stroke superimposed on systemic inflammatory diseases. In this study, we investigated whether and how clematichinenoside (AR), an anti-inflammatory triterpene saponin, protects brain injury from stroke superimposed on systemic inflammation. Lipopolysaccharide (LPS) was intraperitoneally injected immediately after middle cerebral artery occlusion (MCAO) in rats. Rat microvessel endothelial cells (rBMECs) were exposed to hypoxia/reoxygenation (H/R) coexisting with LPS. The results revealed that AR suppressed the excessive inflammation, restored BBB dysfunction, alleviated brain edema, decreased neutrophil infiltration, lessened neurological dysfunction, and decreased infarct rate. Further study demonstrated that the expression of nucleus nuclear factor kappa B (NF-κB), inducible nitric oxide synthase (iNOS), intercellular adhesion molecule-1 (ICAM-1), tumor necrosis factor-α (TNF-α) and interlukin-1β (IL-1β) were suppressed by AR via zinc finger protein A20. Besides, AR increased in vitro BBB integrity through A20. In conclusion, AR alleviated cerebral inflammatory injury through A20-NF-κB signal pathway, offering an alternative medication for stroke associated with systemic inflammatory diseases. Copyright © 2015 Elsevier Inc. All rights reserved.

A streamlined Python framework for AT-TPC data analysis

NASA Astrophysics Data System (ADS)

Taylor, J. Z.; Bradt, J.; Bazin, D.; Kuchera, M. P.

2017-09-01

User-friendly data analysis software has been developed for the Active-Target Time Projection Chamber (AT-TPC) experiment at the National Superconducting Cyclotron Laboratory at Michigan State University. The AT-TPC, commissioned in 2014, is a gas-filled detector that acts as both the detector and target for high-efficiency detection of low-intensity, exotic nuclear reactions. The pytpc framework is a Python package for analyzing AT-TPC data. The package was developed for the analysis of 46Ar(p, p) data. The existing software was used to analyze data produced by the 40Ar(p, p) experiment that ran in August, 2015. Usage of the package was documented in an analysis manual both to improve analysis steps and aid in the work of future AT-TPC users. Software features and analysis methods in the pytpc framework will be presented along with the 40Ar results.

Structural Stereochemistry of Androstene Hormones Determines Interactions with Human Androgen, Estrogen, and Glucocorticoid Receptors

PubMed Central

Shaak, Thomas L.; Wijesinghe, Dayanjan S.; Chalfant, Charles E.; Diegelmann, Robert F.; Ward, Kevin R.; Loria, Roger M.

2013-01-01

DHEA, 17α-AED, 17β-AED, and 17β-AET exhibit strong biological activity that has been attributed to androgenic, estrogenic, or antiglucocorticoid activity in vivo and in vitro. This study compared DHEA, 17α-AED, 17β-AED, and 17β-AET for their ability to activate the human AR, ER, and GR and determine the relative androgenicity, estrogenicity, and glucocorticoid activity. The results show that, at the receptor level, these androstene hormones are weak AR and even weaker ER activators. Direct androstene hormone activation of the human AR, ERα, and ERβ may not be essential for their biological function. Similarly, these hormones indirectly activated the human GR, only in the presence of high dexamethasone concentrations. These results underscore the major difference between androstene hormone interactions with these nuclear receptors and their biological effects. PMID:24729874

Transition energy measurements in hydrogenlike and heliumlike ions strongly supporting bound-state QED calculations

NASA Astrophysics Data System (ADS)

Kubiček, K.; Mokler, P. H.; Mäckel, V.; Ullrich, J.; López-Urrutia, J. R. Crespo

2014-09-01

For the hydrogenlike Ar17+ ion, the 1s Lamb shift was absolutely determined with a 1.4% accuracy based on Lyman-α wavelength measurements that have negligible uncertainties from nuclear size effects. The result agrees with state-of-the-art quantum electrodynamics (QED) calculations, and demonstrates the suitability of Lyman-α transitions in highly charged ions as x-ray energy standards, accurate at the five parts-per-million level. For the heliumlike Ar16+ ion the transition energy for the 1s2p1P1→1s21S0 line was also absolutely determined on an even higher level of accuracy. Additionally, we present relative measurements of transitions in S15+,S14+, and Fe24+ ions. The data for the heliumlike S14+,Ar16+, and Fe24+ ions stringently confirm advanced bound-state QED predictions including screened QED terms that had recently been contested.

Optimizing detection of noble gas emission at a former UNE site: sample strategy, collection, and analysis

NASA Astrophysics Data System (ADS)

Kirkham, R.; Olsen, K.; Hayes, J. C.; Emer, D. F.

2013-12-01

Underground nuclear tests may be first detected by seismic or air samplers operated by the CTBTO (Comprehensive Nuclear-Test-Ban Treaty Organization). After initial detection of a suspicious event, member nations may call for an On-Site Inspection (OSI) that in part, will sample for localized releases of radioactive noble gases and particles. Although much of the commercially available equipment and methods used for surface and subsurface environmental sampling of gases can be used for an OSI scenario, on-site sampling conditions, required sampling volumes and establishment of background concentrations of noble gases require development of specialized methodologies. To facilitate development of sampling equipment and methodologies that address OSI sampling volume and detection objectives, and to collect information required for model development, a field test site was created at a former underground nuclear explosion site located in welded volcanic tuff. A mixture of SF-6, Xe127 and Ar37 was metered into 4400 m3 of air as it was injected into the top region of the UNE cavity. These tracers were expected to move towards the surface primarily in response to barometric pumping or through delayed cavity pressurization (accelerated transport to minimize source decay time). Sampling approaches compared during the field exercise included sampling at the soil surface, inside surface fractures, and at soil vapor extraction points at depths down to 2 m. Effectiveness of various sampling approaches and the results of tracer gas measurements will be presented.

Opposite long-term synaptic effects of 17β-estradiol and 5α-dihydrotestosterone and localization of their receptors in the medial vestibular nucleus of rats.

PubMed

Grassi, Silvarosa; Scarduzio, Mariangela; Panichi, Roberto; Dall'Aglio, Cecilia; Boiti, Cristiano; Pettorossi, Vito E

2013-08-01

In brainstem slices of male rats, we examined in single neurons of the medial vestibular nucleus (MVN) the effect of exogenous administration of estrogenic (17β-estradiol, E2) and androgenic (5α-dihydrotestosterone, DHT) steroids on the synaptic response to vestibular afferent stimulation. By whole cell patch clamp recordings we showed that E2 induced synaptic long-term potentiation (LTP) that was cancelled by the subsequent administration of DHT. Conversely, DHT induced synaptic long-term depression (LTD) that was partially reversed by E2. The electrophysiological findings were supported by immunohistochemical analysis showing the presence of estrogen (ER: α and β) and androgen receptors (AR) in the MVN neurons. We found that a large number of neurons were immunoreactive for ERα, ERβ, and AR and most of them co-localized ERβ and AR. We also showed the presence of P450-aromatase (ARO) in the MVN neurons, clearly proving that E2 can be locally synthesized in the MVN. On the whole, these results demonstrate a role of estrogenic and androgenic signals in modulating vestibular synaptic plasticity and suggest that the enhancement or depression of vestibular synaptic response may depend on the local conversion of T into E2 or DHT. Copyright © 2013 Elsevier Inc. All rights reserved.

Androgen Triggers the Pro-Migratory CXCL12/CXCR4 Axis in AR-Positive Breast Cancer Cell Lines: Underlying Mechanism and Possible Implications for the Use of Aromatase Inhibitors in Breast Cancer.

PubMed

Azariadis, Kalliopi; Kiagiadaki, Fotini; Pelekanou, Vasiliki; Bempi, Vasiliki; Alexakis, Kostas; Kampa, Marilena; Tsapis, Andreas; Castanas, Elias; Notas, George

2017-01-01

Reports regarding the role of androgen in breast cancer (BC) are conflicting. Some studies suggest that androgen could lead to undesirable responses in the presence of certain BC tumor characteristics. We have shown that androgen induces C-X-C motif chemokine 12 (CXCL12) in BC cell lines. Our aim was to identify the mechanisms regulating the phenotypic effects of androgen-induced CXCL12 on Androgen Receptor (AR) positive BC cell lines. We analyzed the expression of CXCL12 and its receptors with qPCR and ELISA and the role of Nuclear Receptor Coactivator 1 (NCOA1) in this effect. AR effects on the CXCL12 promoter was studied via Chromatin-immunoprecipitation. We also analyzed publically available data from The Cancer Genome Atlas to verify AR-CXCL12 interactions and to identify the effect or Aromatase Inhibitors (AI) therapy on CXCL12 expression and disease progression in AR positive cases. CXCL12 induction occurs only in AR-positive BC cell lines, possibly via an Androgen Response Element, upstream of the CXCL12 promoter. The steroid receptor co-regulator NCOA1 is critical for this effect. Androgen only induced the motility of p53-mutant BC cells T47D cells via upregulation of CXCR4 expression while they had no effect on wild-type p53 MCF-7 cells. Loss of CXCR4 expression and depletion of CXCL12 abolished the effect of androgen in T47D cells while inhibition of p53 expression in MCF-7 cells made them responsive to androgen and increased their motility in the presence to androgen. Patients with estrogen receptor positive (ER+)/AR+ BC treated with AIs were at increased risk of disease progression compared to ER+/AR+ non-AI treated and ER+/AR- AI treated cases. AIs may lead to unfavorable responses in some ER/AR positive BC cases, especially in patients with AR+, p53 mutant tumors. © 2017 The Author(s). Published by S. Karger AG, Basel.

Anode power deposition in a MPD thruster with a magnetically annulled Hall parameter anode

NASA Technical Reports Server (NTRS)

Gallimore, Alec D.; Kelly, Arnold J.; Jahn, Robert G.

1992-01-01

Results from previous studies indicate that the anode fall increases monotonically with the electron Hall parameter. In an attempt to reduce the anode fall by decreasing the local electron Hall parameter, a proof-of-concept test was performed in which an array of 36 permanent magnets were imbedded within the anode of a high power quasi-steady MPD thruster to decrease the local azimuthal component of the induced magnetic field. The modified thruster was operated at power levels between 150 kW and 4 MW with Ar and He propellants. Terminal voltage, triple probe, floating probe, and magnetic probe measurements were made to characterize the performance of the thruster with new anode. Incorporation of the modified anode resulted in a reduction of the anode fall by up to 15 V with Ar and 20 V with He, which corresponded to decreased anode power fractions of 40 and 45 percent with Ar and He, respectively.

Report of the Secretary of Defense Task Force on DoD Nuclear Weapons Management. Phase 1. The Air Force’s Nuclear Mission

DTIC Science & Technology

2008-09-01

under- resourced. • Missile transfer vans /warhead transfer vans require upgrades. • ICBM weapon system test sets under-funded; the coding system...Air Force’s Nuclear Mission D-1 Appendix D. Current B-52 Basing Status Barksdale AFB, LA 64 B-52Hs Minot AFB, ND 27 B-52Hs Edwards AFB, CA 3...Barksdale – 64 B-52s 2 BW (ACC) 15 TF; 24 CC; 7 BAI 53 WG (ACC) 2 Test Coded 917 WG (AFRC) 8 CC; 1 BAI 7 Unfunded AR Edwards - 3 B-52s 412 TW 2 Test

The NSET Subcommittee | Nano

Science.gov Websites

Charles Ying Nuclear Regulatory Commission (NRC) Brian Thomas* U.S. Department of Agriculture (USDA ) Agriculture Research Service (ARS) James Lindsay Forest Service (FS) World L.S. Nieh National Institute of Food and Agriculture (NIFA) Hongda Chen U.S. International Trade Commission (USITC) Elizabeth R

Branched Chain RNA In Situ Hybridization for Androgen Receptor Splice Variant AR-V7 as a Prognostic Biomarker for Metastatic Castration-Sensitive Prostate Cancer.

PubMed

Saylor, Philip J; Lee, Richard J; Arora, Kshitij S; Deshpande, Vikram; Hu, Rong; Olivier, Kara; Meneely, Erika; Rivera, Miguel N; Ting, David T; Wu, Chin-Lee; Miyamoto, David T

2017-01-15

The androgen receptor (AR) mRNA splice variant AR-V7 has emerged as a predictive biomarker for response to AR-targeted therapies. There are currently no commercially available assays to detect AR splice variants. The branched chain RNA in situ hybridization (ISH) platform enables the highly sensitive detection of RNA transcripts in formalin-fixed, paraffin-embedded (FFPE) tissues. We designed a branched chain RNA ISH probe to target the unique cryptic exon CE3 of AR-V7 using multiple tiling probes. This automated ISH assay was applied to tumor tissue from two distinct clinical cohorts that we hypothesized would differ in AR-V7 status. We detected AR-V7 in all tumor samples from men with metastatic castration-resistant prostate cancer with tissue obtained after disease progression despite at least one subsequent line of hormonal therapy (abiraterone, enzalutamide, or bicalutamide; n = 12). We detected AR-V7 in just one tumor from men who had undergone prostatectomy for localized adenocarcinoma (n = 30; Gleason 4 + 5 = 9 in the AR-V7-positive sample). Given the apparent distinction between the above groups by AR-V7 signal, we analyzed pretreatment AR-V7 status as a predictive and prognostic biomarker in men with treatment-naïve metastatic disease. Patients with metastases but without detectable AR-V7 RNA at baseline had significantly longer overall survival (log-rank P = 0.044) and a trend toward superior progression-free survival (log-rank P = 0.055). Within an institutional cohort, the RNA ISH assay identified AR-V7 within FFPE tissue and may have prognostic value in metastatic castration-sensitive prostate cancer. These preliminary findings warrant further study in larger cohorts. Clin Cancer Res; 23(2); 363-9. ©2016 AACR. ©2016 American Association for Cancer Research.

Filgrastim for the treatment of hematopoietic acute radiation syndrome.

PubMed

Farese, A M; MacVittie, T J

2015-09-01

The U.S. Food and Drug Administration (FDA) recently approved Neupogen(®) (filgrastim) for the treatment of patients with radiation-induced myelosuppression following a radiological/nuclear incident. It is the first medical countermeasure currently approved by the FDA for this indication under the criteria of the FDA "animal rule". This article summarizes the consequences of high-dose radiation exposure, a description of the hematopoietic acute radiation syndrome (H-ARS), the use of hematopoietic growth factors in radiation accident victims and current available treatments for H-ARS with an emphasis on the use of Neupogen in this scenario. Copyright 2015 Prous Science, S.A.U. or its licensors. All rights reserved.

Chromatin-associated RNA sequencing (ChAR-seq) maps genome-wide RNA-to-DNA contacts

PubMed Central

Jukam, David; Teran, Nicole A; Risca, Viviana I; Smith, Owen K; Johnson, Whitney L; Skotheim, Jan M; Greenleaf, William James

2018-01-01

RNA is a critical component of chromatin in eukaryotes, both as a product of transcription, and as an essential constituent of ribonucleoprotein complexes that regulate both local and global chromatin states. Here, we present a proximity ligation and sequencing method called Chromatin-Associated RNA sequencing (ChAR-seq) that maps all RNA-to-DNA contacts across the genome. Using Drosophila cells, we show that ChAR-seq provides unbiased, de novo identification of targets of chromatin-bound RNAs including nascent transcripts, chromosome-specific dosage compensation ncRNAs, and genome-wide trans-associated RNAs involved in co-transcriptional RNA processing. PMID:29648534

Inhibition of nitrogen-fixing activity of the cyanobiont affects the localization of glutamine synthetase in hair cells of Azolla.

PubMed

Uheda, Eiji; Maejima, Kazuhiro

2009-10-15

In the Azolla-Anabaena association, the host plant Azolla efficiently incorporates and assimilates ammonium ions that are released from the nitrogen-fixing cyanobiont, probably via glutamine synthetase (GS; EC 6.3.1.2) in hair cells, which are specialized cells protruding into the leaf cavity. In order to clarify the regulatory mechanism underlying ammonium assimilation in the Azolla-Anabaena association, Azolla plants were grown under an argon environment (Ar), in which the nitrogen-fixing activity of the cyanobiont was inhibited specifically and completely. The localization of GS in hair cells was determined by immunoelectron microscopy and quantitative analysis of immunogold labeling. Azolla plants grew healthily under Ar when nitrogen sources, such as NO(3)(-) and NH(4)(+), were provided in the growth medium. Both the number of cyanobacterial cells per leaf and the heterocyst frequency of the plants under Ar were similar to those of plants in a nitrogen environment (N(2)). In hair cells of plants grown under Ar, regardless of the type of nitrogen source provided, only weak labeling of GS was observed in the cytoplasm and in chloroplasts. In contrast, in hair cells of plants grown under N(2), abundant labeling of GS was observed in both sites. These findings indicate that specific inhibition of the nitrogen-fixing activity of the cyanobiont affects the localization of GS isoenzymes. Ammonium fixed and released by the cyanobiont could stimulate GS synthesis in hair cells. Simultaneously, the abundant GS, probably GS1, in these cells, could assimilate ammonium rapidly.

Arousal effect of caffeine depends on adenosine A2A receptors in the shell of the nucleus accumbens

PubMed Central

Lazarus, Michael; Shen, Hai-Ying; Cherasse, Yoan; Qu, Wei-Min; Huang, Zhi-Li; Bass, Caroline E.; Winsky-Sommerer, Raphaelle; Semba, Kazue; Fredholm, Bertil B.; Boison, Detlev; Hayaishi, Osamu; Urade, Yoshihiro; Chen, Jiang-Fan

2011-01-01

Caffeine, the most widely used psychoactive compound, is an adenosine receptor antagonist. It promotes wakefulness by blocking adenosine A2A receptors (A2ARs) in the brain, but the specific neurons on which caffeine acts to produce arousal have not been identified. Using selective gene deletion strategies based on the Cre/loxP technology in mice and focal RNA interference to silence the expression of A2ARs in rats by local infection with adeno-associated virus carrying short-hairpin RNA, we report that the A2ARs in the shell region of the nucleus accumbens (NAc) are responsible for the effect of caffeine on wakefulness. Caffeine-induced arousal was not affected in rats when A2ARs were focally removed from the NAc core or other A2AR-positive areas of the basal ganglia. Our observations suggest that caffeine promotes arousal by activating pathways that traditionally have been associated with motivational and motor responses in the brain. PMID:21734299

Localized etching of an insulator film coated on a copper wire using an atmospheric-pressure microplasma jet.

PubMed

Yoshiki, Hiroyuki

2007-04-01

Atmospheric-pressure microplasma jets (APmicroPJs) of Ar and ArO(2) gases were generated from the tip of a stainless steel surgical needle having outer and inner diameters of 0.4 and 0.2 mm, respectively, with a rf excitation of 13.56 MHz. The steel needle functions both as a powered electrode and a gas nozzle. The operating power is 1.2-6 W and the corresponding peak-to-peak voltage Vp.p. is about 1.5 kV. The APmicroPJ was applied to the localized etching of a polyamide-imide insulator film (thickness of 10 microm) of a copper winding wire of 90 microm diameter. The insulator film around the copper wire was completely removed by the irradiated plasma from a certain direction without fusing the wire. The removal time under the Ar APmicroPJ irradiation was only 3 s at a rf power of 4 W. Fluorescence microscopy and scanning electron microscope images reveal that good selectivity of the insulator film to the copper wire was achieved. In the case of ArO(2) APmicroPJ irradiation with an O(2) concentration of 10% or more, the removed copper surface was converted to copper monoxide CuO.

Model-Based Referenceless Quality Metric of 3D Synthesized Images Using Local Image Description.

PubMed

Gu, Ke; Jakhetiya, Vinit; Qiao, Jun-Fei; Li, Xiaoli; Lin, Weisi; Thalmann, Daniel

2017-07-28

New challenges have been brought out along with the emerging of 3D-related technologies such as virtual reality (VR), augmented reality (AR), and mixed reality (MR). Free viewpoint video (FVV), due to its applications in remote surveillance, remote education, etc, based on the flexible selection of direction and viewpoint, has been perceived as the development direction of next-generation video technologies and has drawn a wide range of researchers' attention. Since FVV images are synthesized via a depth image-based rendering (DIBR) procedure in the "blind" environment (without reference images), a reliable real-time blind quality evaluation and monitoring system is urgently required. But existing assessment metrics do not render human judgments faithfully mainly because geometric distortions are generated by DIBR. To this end, this paper proposes a novel referenceless quality metric of DIBR-synthesized images using the autoregression (AR)-based local image description. It was found that, after the AR prediction, the reconstructed error between a DIBR-synthesized image and its AR-predicted image can accurately capture the geometry distortion. The visual saliency is then leveraged to modify the proposed blind quality metric to a sizable margin. Experiments validate the superiority of our no-reference quality method as compared with prevailing full-, reduced- and no-reference models.

Early Pleistocene 40Ar/39Ar ages for Bapang Formation hominins, Central Jawa, Indonesia

PubMed Central

Larick, Roy; Ciochon, Russell L.; Zaim, Yahdi; Sudijono; Suminto; Rizal, Yan; Aziz, Fachroel; Reagan, Mark; Heizler, Matthew

2001-01-01

The Sangiran dome is the primary stratigraphic window for the Plio-Pleistocene deposits of the Solo basin of Central Jawa. The dome has yielded nearly 80 Homo erectus fossils, around 50 of which have known findspots. With a hornblende 40Ar/39Ar plateau age of 1.66 ± 0.04 mega-annum (Ma) reportedly associated with two fossils [Swisher, C.C., III, Curtis, G. H., Jacob, T., Getty, A. G., Suprijo, A. & Widiasmoro (1994) Science 263, 1118–1121), the dome offers evidence that early Homo dispersed to East Asia during the earliest Pleistocene. Unfortunately, the hornblende pumice was sampled at Jokotingkir Hill, a central locality with complex lithostratigraphic deformation and dubious specimen provenance. To address the antiquity of Sangiran H. erectus more systematically, we investigate the sedimentary framework and hornblende 40Ar/39Ar age for volcanic deposits in the southeast quadrant of the dome. In this sector, Bapang (Kabuh) sediments have their largest exposure, least deformation, and most complete tephrostratigraphy. At five locations, we identify a sequence of sedimentary cycles in which H. erectus fossils are associated with epiclastic pumice. From sampled pumice, eight hornblende separates produced 40Ar/39Ar plateau ages ranging from 1.51 ± 0.08 Ma at the Bapang/Sangiran Formation contact, to 1.02 ± 0.06 Ma, at a point above the hominin-bearing sequence. The chronological sequence of 40Ar/39Ar ages follows stratigraphic order across the southeast quadrant. An intermediate level yielding four nearly complete crania has an age of about 1.25 Ma. PMID:11309488

Early Pleistocene 40Ar/39Ar ages for Bapang Formation hominins, Central Jawa, Indonesia.

PubMed

Larick, R; Ciochon, R L; Zaim, Y; Sudijono; Suminto; Rizal, Y; Aziz, F; Reagan, M; Heizler, M

2001-04-24

The Sangiran dome is the primary stratigraphic window for the Plio-Pleistocene deposits of the Solo basin of Central Jawa. The dome has yielded nearly 80 Homo erectus fossils, around 50 of which have known findspots. With a hornblende (40)Ar/(39)Ar plateau age of 1.66 +/- 0.04 mega-annum (Ma) reportedly associated with two fossils [Swisher, C.C., III, Curtis, G. H., Jacob, T., Getty, A. G., Suprijo, A. & Widiasmoro (1994) Science 263, 1118-1121), the dome offers evidence that early Homo dispersed to East Asia during the earliest Pleistocene. Unfortunately, the hornblende pumice was sampled at Jokotingkir Hill, a central locality with complex lithostratigraphic deformation and dubious specimen provenance. To address the antiquity of Sangiran H. erectus more systematically, we investigate the sedimentary framework and hornblende (40)Ar/(39)Ar age for volcanic deposits in the southeast quadrant of the dome. In this sector, Bapang (Kabuh) sediments have their largest exposure, least deformation, and most complete tephrostratigraphy. At five locations, we identify a sequence of sedimentary cycles in which H. erectus fossils are associated with epiclastic pumice. From sampled pumice, eight hornblende separates produced (40)Ar/(39)Ar plateau ages ranging from 1.51 +/- 0.08 Ma at the Bapang/Sangiran Formation contact, to 1.02 +/- 0.06 Ma, at a point above the hominin-bearing sequence. The chronological sequence of (40)Ar/(39)Ar ages follows stratigraphic order across the southeast quadrant. An intermediate level yielding four nearly complete crania has an age of about 1.25 Ma.

Neuroprotection by caffeine in the MPTP model of Parkinson’s disease and its dependence on adenosine A2A receptors

PubMed Central

Xu, Kui; Di Luca, Daniel Garbin; Orrú, Marco; Xu, Yuehang; Chen, Jiang-Fan; Schwarzschild, Michael A.

2016-01-01

Considerable epidemiological and laboratory data have suggested that caffeine, a nonselective adenosine receptor antagonist, may protect against the underlying neurodegeneration of Parkinson’s disease (PD). Although both caffeine and more specific antagonists of the A2A subtype of adenosine receptor (A2AR) have been found to confer protection in animal models of PD, the dependence of caffeine’s neuroprotective effects on the A2AR is not known. To definitively determine its A2AR dependence, the effect of caffeine on MPTP neurotoxicity was compared in wild-type (WT) and A2AR gene global knockout (A2A KO) mice, as well as in CNS cell type-specific (conditional) A2AR knockout (cKO) mice that lack the receptor either in postnatal forebrain neurons or in astrocytes. In WT and in heterozygous A2AR KO mice caffeine pretreatment (25 mg/kg ip) significantly attenuated MPTP-induced depletion of striatal dopamine. By contrast in homozygous A2AR global KO mice caffeine had no effect on MPTP toxicity. In forebrain neuron A2AR cKO mice, caffeine lost its locomotor stimulant effect, whereas its neuroprotective effect was mostly preserved. In astrocytic A2AR cKO mice, both caffeine’s locomotor stimulant and protective properties were undiminished. Taken together, these results indicate that neuroprotection by caffeine in the MPTP model of PD relies on the A2AR, although the specific cellular localization of these receptors remains to be determined. PMID:26905951

Nuclear and chloroplast microsatellite markers to assess genetic diversity and evolution in hazelnut species, hybrids and cultivars

USDA-ARS?s Scientific Manuscript database

The U.S. Department of Agriculture (USDA), Agricultural Research Service (ARS), National Clonal Germplasm Repository (NCGR) in Corvallis, Oregon, preserves more than 800 accessions of hazelnut (Corylus) including C. avellana cultivars and representatives of 10 other recognized shrub and tree species...

Collaborative Research: Calibration for IMS Stations in Eastern Asia

DTIC Science & Technology

2007-07-01

Atomnaya Energia , Vol.87, Issue 3, 1989 (in Russian). 142 BondAr, I. Combining 1-D models for regional calibration, in Proceedings of a Workshop on IMS...Zelentsov and V.N. Mikhailov, Characteristics of 96 underground nuclear explosions at the Semipalatinsk Test Site, Atomaya Energia , (in Russian), Vol. 67

The Role of Nuclear Receptor Coactivators in Recurrent Prostate Cancer

DTIC Science & Technology

2006-02-01

hyp- oplasia congenita and hypogonadotropic hypogonadism (34). From an evolutionary perspective, the AR AF2 region of the ligand binding domain is more...linked adrenal hypoplasia congenita and hypogo- nadotropic hypogonadism . Nature 372:672–676. 35. Muscatelli, F., A. P. Walker, E. De Plaen, A. N

Effect of radiotherapy after breast-conserving surgery in older patients with early breast cancer and breast ductal carcinoma in situ: a meta-analysis

PubMed Central

Chen, Wen-jun; Zhang, Xi; Wu, Cong-cong; Zhang, Chao-ying; Sun, Shuang-shuang; Wu, Jian

2017-01-01

Background There are no consistent agreements on whether radiotherapy after breast-conserving surgery (BCS) could provide local control and survival benefit for older patients with early breast cancer or breast ductal carcinoma in situ (DCIS). The present study aimed to evaluate the efficacy of radiotherapy after BCS in older patients with early breast cancer or DCIS. Results Radiotherapy could reduce the risk of local relapse in older patients with early breast cancer. The 5-year AR of local relapse was 2.2% and 6.2% for radiotherapy and non-radiotherapy group, respectively, with low 5-year ARD of 4.0% and high NNT of 25. The 10-year AR of local relapse was 5.3% and 10.5% for radiotherapy and non-radiotherapy group, respectively, with the 10-year ARD of 5.2% and NNT of 20. However, radiotherapy could not improve survival benefits, including overall survival, cancer-specific survival, breast-cancer-specific survival, and distant relapse. Moreover, radiotherapy could reduce the risk of ipsilateral breast events in older patients with DCIS. Materials and Methods PubMed and Embase database were searched for relevant studies. Hazard ratios (HRs), risk ratios (RRs), absolute risk (AR), absolute risk difference (ARD), and number needed to treat (NNT) were used as effect measures to evaluate the efficacy of radiotherapy in older patients. Conclusions Our study indicates that radiotherapy could slightly reduce the risk of local relapse in older patients with favorable early breast cancer. However, radiotherapy cannot translate into significant survival benefits. PMID:28415667

The Suppressor of AAC2 Lethality SAL1 Modulates Sensitivity of Heterologously Expressed Artemia ADP/ATP Carrier to Bongkrekate in Yeast

PubMed Central

Wysocka-Kapcinska, Monika; Torocsik, Beata; Turiak, Lilla; Tsaprailis, George; David, Cynthia L.; Hunt, Andrea M.; Vekey, Karoly; Adam-Vizi, Vera; Kucharczyk, Roza; Chinopoulos, Christos

2013-01-01

The ADP/ATP carrier protein (AAC) expressed in Artemia franciscana is refractory to bongkrekate. We generated two strains of Saccharomyces cerevisiae where AAC1 and AAC3 were inactivated and the AAC2 isoform was replaced with Artemia AAC containing a hemagglutinin tag (ArAAC-HA). In one of the strains the suppressor of ΔAAC2 lethality, SAL1, was also inactivated but a plasmid coding for yeast AAC2 was included, because the ArAACΔsal1Δ strain was lethal. In both strains ArAAC-HA was expressed and correctly localized to the mitochondria. Peptide sequencing of ArAAC expressed in Artemia and that expressed in the modified yeasts revealed identical amino acid sequences. The isolated mitochondria from both modified strains developed 85% of the membrane potential attained by mitochondria of control strains, and addition of ADP yielded bongkrekate-sensitive depolarizations implying acquired sensitivity of ArAAC-mediated adenine nucleotide exchange to this poison, independent from SAL1. However, growth of ArAAC-expressing yeasts in glycerol-containing media was arrested by bongkrekate only in the presence of SAL1. We conclude that the mitochondrial environment of yeasts relying on respiratory growth conferred sensitivity of ArAAC to bongkrekate in a SAL1-dependent manner. PMID:24073201

Downregulation of androgen receptors by NaAsO2 via inhibition of AKT-NF-κB and HSP90 in castration resistant prostate cancer.

PubMed

Kim, Yunlim; Park, Sang Eun; Moon, Jeong-Weon; Kim, Bong-Min; Kim, Ha-Gyeong; Jeong, In Gab; Yoo, Sangjun; Ahn, Jae Beom; You, Dalsan; Pak, Jhang Ho; Kim, Sujong; Hwang, Jung Jin; Kim, Choung-Soo

2017-07-01

Androgen and androgen receptor (AR) play essential roles in the development and maintenance of prostate cancer. The recently identified AR splice variants (AR-Vs) have been considered as a plausible mechanism for the primary resistance against androgen deprivation therapy (ADT) in castration-resistant prostate cancer (CRPC). Sodium meta-arsenite (NaAsO 2 ; KML001; Kominox), a trivalent arsenical, is an orally bioavailable and water soluble, which is currently in phase I/II clinical trials for the treatment of prostate cancer. It has a potent anti-cancer effect on prostate cancer cells and xenografts. The aim of this study was to examine the effect of NaAsO 2 on AR signaling in LNCaP and 22Rv1 CRPC cells. We used hormone-sensitive LNCaP cells, hormone-insensitive 22Rv1 cells, and CRPC patient-derived primary cells. We analyzed anti-cancer effect of NaAsO 2 using real-time quantitative reverse transcription-PCR, Western blotting, immunofluorescence staining and CellTiter Glo® luminescent assay. Statistical evaluation of the results was performed by one-way ANOVA. NaAsO 2 significantly reduced the translocation of AR and AR-Vs to the nucleus as well as their level in LNCaP and 22Rv1 cells. Besides, the level of the prostate-specific antigen (PSA), downstream target gene of AR, was also decreased. This compound was also an effective modulator of AKT-dependent NF-κB activation which regulates AR. NaAsO 2 significantly inhibited phosphorylation of AKT and expression and nuclear translocation of NF-κB. We then investigated the effect of NaAsO 2 on AR stabilization. NaAsO 2 promoted HSP90 acetylation by down-regulating HDAC6, which reduces the stability of AR in prostate cancer cells. Here, we show that NaAsO 2 disrupts AR signaling at multiple levels by affecting AR expression, stability, and degradation in primary tumor cell cultures from prostate cancer patients as well as CRPC cell lines. These results suggest that NaAsO 2 could be a novel therapeutics for prostate cancer. © 2017 Wiley Periodicals, Inc.

Antibiotic Resistance in Animal and Environmental Samples Associated with Small-Scale Poultry Farming in Northwestern Ecuador.

PubMed

Braykov, Nikolay P; Eisenberg, Joseph N S; Grossman, Marissa; Zhang, Lixin; Vasco, Karla; Cevallos, William; Muñoz, Diana; Acevedo, Andrés; Moser, Kara A; Marrs, Carl F; Foxman, Betsy; Trostle, James; Trueba, Gabriel; Levy, Karen

2016-01-01

The effects of animal agriculture on the spread of antibiotic resistance (AR) are cross-cutting and thus require a multidisciplinary perspective. Here we use ecological, epidemiological, and ethnographic methods to examine populations of Escherichia coli circulating in the production poultry farming environment versus the domestic environment in rural Ecuador, where small-scale poultry production employing nontherapeutic antibiotics is increasingly common. We sampled 262 "production birds" (commercially raised broiler chickens and laying hens) and 455 "household birds" (raised for domestic use) and household and coop environmental samples from 17 villages between 2010 and 2013. We analyzed data on zones of inhibition from Kirby-Bauer tests, rather than established clinical breakpoints for AR, to distinguish between populations of organisms. We saw significantly higher levels of AR in bacteria from production versus household birds; resistance to either amoxicillin-clavulanate, cephalothin, cefotaxime, and gentamicin was found in 52.8% of production bird isolates and 16% of household ones. A strain jointly resistant to the 4 drugs was exclusive to a subset of isolates from production birds (7.6%) and coop surfaces (6.5%) and was associated with a particular purchase site. The prevalence of AR in production birds declined with bird age (P < 0.01 for all antibiotics tested except tetracycline, sulfisoxazole, and trimethoprim-sulfamethoxazole). Farming status did not impact AR in domestic environments at the household or village level. Our results suggest that AR associated with small-scale poultry farming is present in the immediate production environment and likely originates from sources outside the study area. These outside sources might be a better place to target control efforts than local management practices. IMPORTANCE In developing countries, small-scale poultry farming employing antibiotics as growth promoters is being advanced as an inexpensive source of protein and income. Here, we present the results of a large ecoepidemiological study examining patterns of antibiotic resistance (AR) in E. coli isolates from small-scale poultry production environments versus domestic environments in rural Ecuador, where such backyard poultry operations have become established over the past decade. Our previous research in the region suggests that introduction of AR bacteria through travel and commerce may be an important source of AR in villages of this region. This report extends the prior analysis by examining small-scale production chicken farming as a potential source of resistant strains. Our results suggest that AR strains associated with poultry production likely originate from sources outside the study area and that these outside sources might be a better place to target control efforts than local management practices.

Perturbation expansion theory corrected from basis set superposition error. I. Locally projected excited orbitals and single excitations.

PubMed

Nagata, Takeshi; Iwata, Suehiro

2004-02-22

The locally projected self-consistent field molecular orbital method for molecular interaction (LP SCF MI) is reformulated for multifragment systems. For the perturbation expansion, two types of the local excited orbitals are defined; one is fully local in the basis set on a fragment, and the other has to be partially delocalized to the basis sets on the other fragments. The perturbation expansion calculations only within single excitations (LP SE MP2) are tested for water dimer, hydrogen fluoride dimer, and colinear symmetric ArM+ Ar (M = Na and K). The calculated binding energies of LP SE MP2 are all close to the corresponding counterpoise corrected SCF binding energy. By adding the single excitations, the deficiency in LP SCF MI is thus removed. The results suggest that the exclusion of the charge-transfer effects in LP SCF MI might indeed be the cause of the underestimation for the binding energy. (c) 2004 American Institute of Physics.

Synergistic Activation of Steroidogenic Acute Regulatory Protein Expression and Steroid Biosynthesis by Retinoids: Involvement of cAMP/PKA Signaling

PubMed Central

Manna, Pulak R.; Slominski, Andrzej T.; King, Steven R.; Stetson, Cloyce L.

2014-01-01

Both retinoic acid receptors (RARs) and retinoid X receptors (RXRs) mediate the action of retinoids that play important roles in reproductive development and function, as well as steroidogenesis. Regulation of steroid biosynthesis is principally mediated by the steroidogenic acute regulatory protein (StAR); however, the modes of action of retinoids in the regulation of steroidogenesis remain obscure. In this study we demonstrate that all-trans retinoic acid (atRA) enhances StAR expression, but not its phosphorylation (P-StAR), and progesterone production in MA-10 mouse Leydig cells. Activation of the protein kinase A (PKA) cascade, by dibutyrl-cAMP or type I/II PKA analogs, markedly increased retinoid-responsive StAR, P-StAR, and steroid levels. Targeted silencing of endogenous RARα and RXRα, with small interfering RNAs, resulted in decreases in 9-cis RA-stimulated StAR and progesterone levels. Truncation of and mutational alterations in the 5′-flanking region of the StAR gene demonstrated the importance of the −254/−1-bp region in retinoid responsiveness. An oligonucleotide probe encompassing an RXR/liver X receptor recognition motif, located within the −254/−1-bp region, specifically bound MA-10 nuclear proteins and in vitro transcribed/translated RXRα and RARα in EMSAs. Transcription of the StAR gene in response to atRA and dibutyrl-cAMP was influenced by several factors, its up-regulation being dependent on phosphorylation of cAMP response-element binding protein (CREB). Chromatin immunoprecipitation studies revealed the association of phosphorylation of CREB, CREB binding protein, RXRα, and RARα to the StAR promoter. Further studies elucidated that hormone-sensitive lipase plays an important role in atRA-mediated regulation of the steroidogenic response that involves liver X receptor signaling. These findings delineate the molecular events by which retinoids influence cAMP/PKA signaling and provide additional and novel insight into the regulation of StAR expression and steroidogenesis in mouse Leydig cells. PMID:24265455

Selective regulation of nuclear orphan receptors 4A by adenosine receptor subtypes in human mast cells

PubMed Central

Zhang, Li; Paine, Catherine

2010-01-01

Nuclear orphan receptors 4A (NR4A) are early responsive genes that belong to the superfamily of hormone receptors and comprise NR4A1, NR4A2 and NR4A3. They have been associated to transcriptional activation of multiple genes involved in inflammation, apoptosis and cell cycle control. Here, we establish a link between NR4As and adenosine, a paradoxical inflammatory molecule that can contribute to persistence of inflammation or mediate inflammatory shutdown. Transcriptomics screening of the human mast cell-line HMC-1 revealed a sharp induction of transcriptionally active NR4A2 and NR4A3 by the adenosine analogue NECA. The concomitant treatment of NECA and the adenosine receptor A2A (A2AAR) selective antagonist SCH-58261 exaggerated this effect, suggesting that upregulation of these factors in mast cells is mediated by other AR subtypes (A2B and A3) and that A2AAR activation counteracts NR4A2 and NR4A3 induction. In agreement with this, A2AAR-silencing amplified NR4A induction by NECA. Interestingly, a similar A2AAR modulatory effect was observed on ERK1/2 phosphorylation because A2AAR blockage exacerbated NECA-mediated phosphorylation of ERK1/2. In addition, PKC or MEK1/2 inhibition prevented ERK1/2 phosphorylation and antagonized AR-mediated induction of NR4A2 and NR4A3, suggesting the involvement of these kinases in AR to NR4A signaling. Finally, we observed that selective A2AAR activation with CGS-21680 blocked PMA-induced ERK1/2 phosphorylation and modulated the overexpression of functional nuclear orphan receptors 4A. Taken together, these results establish a novel PKC/ERK/nuclear orphan receptors 4A axis for adenosinergic signaling in mast cells, which can be modulated by A2AAR activation, not only in the context of adenosine but of other mast cell activating stimuli as well. PMID:21234122

Ar-39-Ar-40 Evidence for Early Impact Events on the LL Parent Body

NASA Technical Reports Server (NTRS)

Dixon, E. T.; Bogard, D. D.; Garrison, D. H.; Rubin, A. E.

2006-01-01

We determined Ar-39-Ar-40 ages of eight LL chondrites, and one igneous inclusion from an LL chondrite, with the object of understanding the thermal history of the LL-chondrite parent body. The meteorites in this study have a range of petrographic types from LL3.3 to LL6, and shock stages from S1 to S4. These meteorites reveal a range of K-Ar ages from 23.66 to 24.50 Ga, and peak ages from 23.74 to 24.55 Ga. Significantly, three of the eight chondrites (LL4, 5, 6) have K-Ar ages of -4.27 Ga. One of these (MIL99301) preserves an Ar-39-Ar-40 age of 4.23 +/- 0.03 Ga from low-temperature extractions, and an older age of 4.52 +/- 0.08 Ga from the highest temperature extractions. In addition, an igneous-textured impact melt DOM85505,22 has a peak Ar-39-Ar-40 age of >= 4.27 Ga. We interpret these results as evidence for impact events that occurred at about 4.27 Ga on the LL parent body that produced local impact melts, reset the Ar-39-Ar-40 ages of some meteorites, and exhumed (or interred) others, resulting in a range of cooling ages. The somewhat younger peak age of 3.74 Ga from GR095658 (LL3.3) suggests an additional impact event close to timing of impact-reset ages of some other ordinary chondrites between 3.6-3.8 Ga. The results from MIL99301 suggest that some apparently unshocked (Sl) chondrites may have substantially reset Ar-39-Ar-40 ages. A previous petrographic investigation of MIL99301 suggested that reheating to temperatures less than or equal to type 4 petrographic conditions (600C) caused fractures in olivine to anneal, resulting in a low apparent shock stage of S1 (unshocked). The Ar-39-Ar-40 age spectrum of MIL99301 is consistent with this interpretation. Older ages from high-T extractions may date an earlier impact event at 4.52 +/- 0.08 Ga, whereas younger ages from lower-T extractions date a later impact event at 4.23 Ar-39-Ar-40 0.03 Ga that may have caused annealing of feldspar and olivine

Evidence for shock heating and constraints on Martian surface temperatures revealed by 40Ar/ 39Ar thermochronometry of Martian meteorites

NASA Astrophysics Data System (ADS)

Cassata, William S.; Shuster, David L.; Renne, Paul R.; Weiss, Benjamin P.

2010-12-01

The thermal histories of Martian meteorite are important for the interpretation of petrologic, geochemical, geochronological, and paleomagnetic constraints that they provide on the evolution of Mars. In this paper, we quantify 40Ar/ 39Ar ages and Ar diffusion kinetics of Martian meteorites Allan Hills (ALH) 84001, Nakhla, and Miller Range (MIL) 03346. We constrain the thermal history of each meteorite and discuss the resulting implications for their petrology, paleomagnetism, and geochronology. Maskelynite in ALH 84001 yields a 40Ar/ 39Ar isochron age of 4163 ± 35 Ma, which is indistinguishable from recent Pb-Pb ( Bouvier et al., 2009a) and Lu-Hf ages ( Lapen et al., 2010). The high precision of this result arises from clear resolution of a reproducible trapped 40Ar/ 36Ar component in maskelynite in ALH 84001 ( 40Ar/ 36Ar = 632 ± 90). The maskelynite 40Ar/ 39Ar age predates the Late Heavy Bombardment and likely represents the time at which the original natural remanent magnetization (NRM) component observed in ALH 84001 was acquired. Nakhla and MIL 03346 yield 40Ar/ 39Ar isochron ages of 1332 ± 24 and 1339 ± 8 Ma, respectively, which we interpret to date crystallization. Multi-phase, multi-domain diffusion models constrained by the observed Ar diffusion kinetics and 40Ar/ 39Ar age spectra suggest that localized regions within both ALH 84001 and Nakhla were intensely heated for brief durations during shock events at 1158 ± 110 and 913 ± 9 Ma, respectively. These ages may date the marginal melting of pyroxene in each rock, mobilization of carbonates and maskelynite in ALH 84001, and NRM overprints observed in ALH 84001. The inferred peak temperatures of the shock heating events (>1400 °C) are sufficient to mobilize Ar, Sr, and Pb in constituent minerals, which may explain some of the dispersion observed in 40Ar/ 39Ar, Rb-Sr, and U-Th-Pb data toward ages younger than ˜4.1 Ga. The data also place conservative upper bounds on the long-duration residence temperatures of the ALH 84001 and Nakhla protolith to be 22-∞+8 °C and 81-∞+9 °C over the last ˜4.16 Ga and ˜1.35 Ga, respectively. MIL 03346 has apparently not experienced significant shock-heating since it crystallized, consistent with the fact that various chronometers yield concordant ages.

Immunohistochemical panel to characterize canine prostate carcinomas according to aberrant p63 expression.

PubMed

Fonseca-Alves, Carlos Eduardo; Kobayashi, Priscila Emiko; Rivera Calderón, Luis Gabriel; Felisbino, Sérgio Luis; Rinaldi, Jaqueline de Carvalho; Drigo, Sandra Aparecida; Rogatto, Silvia Regina; Laufer-Amorim, Renée

2018-01-01

An unusual variant of prostate adenocarcinoma (PC) expressing nuclear p63 in secretory cells instead of the typical basal expression has been reported in men. Nevertheless, the biological behavior and clinical significance of this phenomenon is unknown. In dogs, this unusual PC subtype has not been described. In this study, p63 immunoexpression was investigated in 90 canine PCs and 20 normal prostate tissues (NT). The p63 expression pattern in luminal or basal cells was confirmed in a selected group of 26 PCs and 20 NT by immunohistochemistry and/or Western blotting assays. Eleven canine PC samples aberrantly expressing p63 (p63+) in secretory cells were compared with 15 p63 negative (p63-) cases in the context of several molecular markers (high molecular weight cytokeratin-HMWC, CK8/18, CK5, AR, PSA, chromogranin, NKX3.1, PTEN, AKT and C-MYC). P63+ samples were positive for CK5, HMWC and CK8/18 and negative for PSA, NKX3.1, PTEN and chromogranin. Five p63+ PCs were negative for AR, and the remaining six samples had low AR expression. In contrast, p63- PC showed AR and PSA positive expression in all 15 samples. Only five p63- PCs were positive for CK5. Both p63+ and p63- PC samples showed higher cytoplasmic AKT expression and nuclear C-MYC staining in comparison with normal tissues. Metastatic (N = 12) and non-metastatic (N = 14) PCs showed similar immunoexpression for all markers tested. In contrast to human PC, canine PC aberrantly expressing p63 showed higher expression levels of HMWC and CK5 and lower levels of NKX3.1. Canine p63+ PC is a very rare PC group showing a distinct phenotype compared to typical canine PC, including AR and PSA negative expression. Although in a limited number of cases, p63 expression was not associated with metastasis in canine PC, and cytoplasmic p63 expression was observed in animals with shorter survival time, similar to human PC cases.

Analysis of specific RNA in cultured cells through quantitative integration of q-PCR and N-SIM single cell FISH images: Application to hormonal stimulation of StAR transcription.

PubMed

Lee, Jinwoo; Foong, Yee Hoon; Musaitif, Ibrahim; Tong, Tiegang; Jefcoate, Colin

2016-07-05

The steroidogenic acute regulatory protein (StAR) has been proposed to serve as the switch that can turn on/off steroidogenesis. We investigated the events that facilitate dynamic StAR transcription in response to cAMP stimulation in MA-10 Leydig cells, focusing on splicing anomalies at StAR gene loci. We used 3' reverse primers in a single reaction to respectively quantify StAR primary (p-RNA), spliced (sp-RNA/mRNA), and extended 3' untranslated region (UTR) transcripts, which were quantitatively imaged by high-resolution fluorescence in situ hybridization (FISH). This approach delivers spatio-temporal resolution of initiation and splicing at single StAR loci, and transfers individual mRNA molecules to cytoplasmic sites. Gene expression was biphasic, initially showing slow splicing, transitioning to concerted splicing. The alternative 3.5-kb mRNAs were distinguished through the use of extended 3'UTR probes, which exhibited distinctive mitochondrial distribution. Combining quantitative PCR and FISH enables imaging of localization of RNA expression and analysis of RNA processing rates. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Non-neural androgen receptors affect sexual differentiation of brain and behaviour.

PubMed

Monks, D A; Swift-Gallant, A

2018-02-01

Although gonadal testosterone is the principal endocrine factor that promotes masculine traits in mammals, the development of a male phenotype requires local production of both androgenic and oestrogenic signals within target tissues. Much of our knowledge concerning androgenic components of testosterone signalling in sexual differentiation comes from studies of androgen receptor (Ar) loss of function mutants. Here, we review these studies of loss of Ar function and of AR overexpression either globally or selectively in the nervous system of mice. Global and neural mutations affect socio-sexual behaviour and the neuroanatomy of these mice in a sexually differentiated manner. Some masculine traits are affected by both global and neural mutation, indicative of neural mediation, whereas other masculine traits are affected only by global mutation, indicative of an obligatory non-neural androgen target. These results support a model in which multiple sites of androgen action coordinate to produce masculine phenotypes. Furthermore, AR overexpression does not always have a phenotype opposite to that of loss of Ar function mutants, indicative of a nonlinear relationship between androgen dose and masculine phenotype in some cases. Potential mechanisms of Ar gene function in non-neural targets in producing masculine phenotypes are discussed. © 2017 British Society for Neuroendocrinology.

The neuronal Ca(2+) -binding protein 2 (NECAB2) interacts with the adenosine A(2A) receptor and modulates the cell surface expression and function of the receptor.

PubMed

Canela, Laia; Luján, Rafael; Lluís, Carme; Burgueño, Javier; Mallol, Josefa; Canela, Enric I; Franco, Rafael; Ciruela, Francisco

2007-09-01

Heptaspanning membrane also known as G protein-coupled receptors (GPCR) do interact with a variety of intracellular proteins whose function is regulate receptor traffic and/or signaling. Using a yeast two-hybrid screen, NECAB2, a neuronal calcium binding protein, was identified as a binding partner for the adenosine A(2A) receptor (A(2A)R) interacting with its C-terminal domain. Co-localization, co-immunoprecipitation and pull-down experiments showed a close and specific interaction between A(2A)R and NECAB2 in both transfected HEK-293 cells and also in rat striatum. Immunoelectron microscopy detection of NECAB2 and A(2A)R in the rat striatopallidal structures indicated that both proteins are co-distributed in the same glutamatergic nerve terminals. The interaction of NECAB2 with A(2A)R modulated the cell surface expression, the ligand-dependent internalization and the receptor-mediated activation of the MAPK pathway. Overall, these results show that A(2A)R interacts with NECAB2 in striatal neurones co-expressing the two proteins and that the interaction is relevant for A(2A)R function.

Characterization of the wintertime particulate (PM1) pollution at an urban background site of Nicosia, Cyprus

NASA Astrophysics Data System (ADS)

Sciare, Jean; Kleanthous, Savvas; Pikridas, Michael; Vrekoussis, Mihalis; Oikonomou, Konstantina; Merabet, Hamza; Mihalopoulos, Nikos; Yassaa, Noureddine

2015-04-01

A 1-month intensive campaign was performed during December 2014 at Nicosia, Cyprus, a city of 240,000 inhabitants, representative of E. Mediterranean medium sized cities. This is the first of a series of intensive campaigns, part of the MISTRALS-ENVI-Med "CyAr" project (Cyprus Aerosols and gas precursors) and MISTRALS-ChArMEx program (Chemistry-Aerosol Mediterranean Experiment, http://charmex.lsce.ipsl.fr/), and , with the objective to distinguish between local and transported sources responsible for wintertime particulate pollution. The mass and composition of the major chemical constituents of submicron aerosols (PM1) was monitored at an urban background station located at the city's suburbs with a suite of real-time analyzers (TEOM 1400, OPC Grimm 1.108, Q-ACSM, Aethalometer AE31). Quality control of Q-ACSM and Aethalometer datasets was performed through closure studies (using co-located TEOM / OPC Grimm). The consistency of the dataset was further validated using the integrated (off-line) and real-time measurements performed by the local air quality network at other locations in the same city. Very high levels of Black Carbon and organics were systematically observed every night, typically maximizing at 22:00 local time, pointing to local combustion sources most probably related to domestic heating. Similar pattern has been observed in other cities in the Eastern Mediterranean (Pikridas et al., 2013) and partly has been attributed to the economic crisis (Vrekoussis et al., 2013). Source apportionment of organic aerosols (OA) was performed using the SourceFinder software (SoFi, http://www.psi.ch/acsm-stations/me-2) allowing the distinction between various primary/secondary OA sources that allowed us to better characterize the combustion sources responsible for the observed elevated nighttime PM1 levels. Acknowledgements: This campaign has been funded by MISTRALS (ENVI-Med CyAr & ChArMEx), CNRS-INSU, CEA, CyI, DLI, CDER and ECPL.

The effect of SEM imaging on the Ar/Ar system in feldspars

NASA Astrophysics Data System (ADS)

Flude, S.; Sherlock, S.; Lee, M.; Kelley, S. P.

2010-12-01

Complex microtextures form in K-feldspar crystals as they cool and are affected by deuteric alteration. This complex structure is the cause of variable closure temperatures for Ar-Ar, a phenomenon which has been utilized in multi domain diffusion (MDD) modelling to recover thermal histories [1]. However, there has been substantial controversy regarding the precise interaction between feldspar microtextures and Ar-diffusion [2,3]. A number of studies have addressed this issue using coupled SEM imaging and Ar/Ar UV laser ablation microprobe (UV-LAMP) analysis on the same sample, to enable direct comparison of microtextures with Ar/Ar age data [4]. Here we have tested the idea that SEM work may affect Ar/Ar ages, leading to inaccurate results in subsequent Ar/Ar analyses. Three splits of alkali feldspar from the Dartmoor Granite in SW England were selected for Ar/Ar UV-LAMP analysis. Split 1 (“control”) was prepared as a polished thick section for Ar/Ar analysis. Split 2 (“SEM”) was prepared as a polished thick section, was chemically-mechanically polished with colloidal silica and underwent SEM imaging (uncoated) and focussed ion beam (FIB) milling (gold coated); electron beam damage in the SEM was maximised by leaving the sample at high magnification for eight minutes. Split 3 (“Etch”) is a cleavage fragment that was etched with HF vapour and underwent low to moderate magnification SEM imaging. The control split gave a range of laser-spot ages consistent with the expected cooling age of the granite and high yields of radiogenic 40Ar* (>90%). The area of the “SEM” split that experienced significant electron beam damage gave younger than expected ages and 40Ar* yields as low as 57%. These are interpreted as a combination of implantation of atmospheric Ar and local redistribution of K within the sample. The area of “SEM” that underwent FIB milling gave ages and 40Ar* yields comparable to the control split, suggesting that the Au-coat minimises FIB damage and that colloidal-polishing and low-magnification SEM imaging do not affect the Ar/Ar system. The “Etch” split gave younger than expected ages and 40Ar* yields as low as 58%, suggesting that HF etching also disrupts the Ar/Ar system. These results suggest that SEM techniques involving intense electron bombardment of an uncoated sample, such as charge contrast imaging and electron backscatter diffraction (EBSD), may disrupt the Ar/Ar system in the sample, leading to spurious results. Etching samples with HF, as is often done for routine Ar/Ar preparation of volcanic phenocrysts, introduces atmospheric Ar and may result in differential loss or gain of K and Ar isotopes, leading to spurious results. References [1] Lovera and Richter, 1989, J. Geophys. Res. 94, 17917-17935. [2] Parsons. et al., 1999, Cont. Min. Pet. 136, 92-110. [3] Mark et al., 2008, Geochim. Cosmochim. Acta, 72 2695-2710. [4] Reddy et al., 2001, Cont. Min. Pet., 141 186-200.

A COMPARATIVE ANALYSIS BETWEEN FRANCE AND JAPAN ON LOCAL GOVERNMENTS' INVOLVEMENT IN NUCLEAR SAFETY GOVERNANCE

NASA Astrophysics Data System (ADS)

Sugawara, Shin-Etsu; Shiroyama, Hideaki

This paper shows a comparative analysis between France and Japan on the way of the local governments' involvement in nuclear safety governance through some interviews. In France, a law came into force that requires related local governments to establish "Commision Locale d'Information" (CLI), which means the local governments officially involve in nuclear regulatory activity. Meanwhile, in Japan, related local governments substantially involve in the operation of nuclear facilities through the "safety agreements" in spite of the lack of legal authority. As a result of comparative analysis, we can point out some institutional input from French cases as follows: to clarify the local governments' roles in the nuclear regulation system, to establish the official channels of communication among nuclear utilities, national regulatory authorities and local governments, and to stipulate explicitly the transparency as a purpose of safety regulation.

Nuclear Data Sheets for A=37

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cameron J.; Nica N.; Cameron,J.

2012-02-01

Nuclear spectroscopic information for experimentally investigated nuclides of mass 37 (Na, Mg, Al, Si, P, S, Cl, Ar, K, Ca) has been evaluated. The principal sources of the 'adopted levels' presented for nuclides close to the stability line are Endt's evaluations (1990En08, 1978En02). The data sets for reactions and decays, including all available gamma-ray data, are based mostly on the original literature. There are no data available for the excited states in {sup 37}Na, {sup 37}Mg, {sup 37}Al; and for {sup 37}Si, only one excited state is known.

Experimental study of the performance of a very small repetitive plasma focus device in different working conditions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Goudarzi, S., E-mail: sgoudarzi@aeoi.org.ir; Babaee, H.; Esmaeli, A.

SORENA-1 is a very small repetitive Mather-type plasma focus device (20 J) that can operate at frequencies up to 1 Hz. This device has been designed and constructed in the Plasma and Nuclear Fusion Research School of the Nuclear Science and Technology Research Institute of Iran. In this article, the structure of SORENA-1 is described and results of experiments with Ar, Ne, and D{sub 2} working gases at several discharge voltages and initial pressures are presented and analyzed.

A Medical Center Network for Optimized Lung Cancer Biospecimen Banking

DTIC Science & Technology

2014-10-01

Y N 0.519 60 70 5 2 2 1.620 2 0.250 2 Yes - Current Smoker AF Jet fuel , Second-hand smoke Jet fuel , Second-hand smoke S0018 Squamous Cell...Second-hand smoke Second-hand smoke S0028 Squamous Cell Carcinoma Stage IIIB N N No - Quit Smoking 150 AF Jet fuel , Nuclear weapons, Second-hand... Jet fuel , Nuclear weapons, Second-hand S0029 Squamous Cell Carcinoma Stage IIA Y N 0.06 100 40 0 1 3 .571 1 8 .043 1 No - Quit Smoking AR Second

Experimental study of the performance of a very small repetitive plasma focus device in different working conditions

NASA Astrophysics Data System (ADS)

Goudarzi, S.; Babaee, H.; Esmaeli, A.; Nasiri, A.

2017-01-01

SORENA-1 is a very small repetitive Mather-type plasma focus device (20 J) that can operate at frequencies up to 1 Hz. This device has been designed and constructed in the Plasma and Nuclear Fusion Research School of the Nuclear Science and Technology Research Institute of Iran. In this article, the structure of SORENA-1 is described and results of experiments with Ar, Ne, and D2 working gases at several discharge voltages and initial pressures are presented and analyzed.

Backbendings of superdeformed bands in 36;40Ar

NASA Astrophysics Data System (ADS)

Xiang, Xu-Hui; He, Xiao-Tao

2018-05-01

Experimentally observed superdeformed (SD) rotational bands in 36Ar and 40Ar are studied by the cranked shell model (CSM) with the pairing correlations treated by a particle-number-conserving (PNC) method. This is the first time that PNC-CSM calculations have been performed on the light nuclear mass region around A=40. The experimental kinematic moments of inertia J (1) versus rotational frequency are reproduced well. The backbending of the SD band at frequency around ℏω=1.5 MeV in 36Ar is attributed to the sharp rise of the simultaneous alignments of the neutron and proton 1d 5/2[202]5/2 pairs and 1f 7/2[321]3/2 pairs, which is a consequence of the band crossing between the 1d 5/2[202]5/2 and 1f 7/2[321]3/2 configuration states. The gentle upbending at low frequency of the SD band in 40Ar is mainly affected by the alignments of the neutron 1f 7/2[321]3/2 pairs and proton 1d 5/2[202]5/2 pairs. The PNC-CSM calculations show that besides the diagonal parts, the off-diagonal parts of the alignments play an important role in the rotational behavior of the SD bands. Supported by National Natural Science Foundation of China (11775112 and 11275098) and the Priority Academic Program Development of Jiangsu Higher Education Institutions

Resveratrol, 4' Acetoxy Resveratrol, R-equol, Racemic Equol or S-equol as Cosmeceuticals to Improve Dermal Health.

PubMed

Lephart, Edwin D

2017-06-03

Phytochemicals are botanical compounds used in dermatology applications as cosmeceuticals to improve skin health. Resveratrol and equol are two of the best-known polyphenolic or phytoestrogens having similar chemical structures and some overlapping biological functions to 17β-estradiol. Human skin gene expression was reviewed for 28 different biomarkers when resveratrol, 4' acetoxy resveratrol (4AR), R -equol, racemic equol or S -equol were tested. Sirtuin 1 activator (SIRT 1) was stimulated by resveratrol and 4AR only. Resveratrol, R -equol and racemic equol were effective on the aging biomarkers proliferating cell nuclear factor (PCNA), nerve growth factor (NGF), 5α-reductase and the calcium binding proteins S100 A8 and A9. Racemic equol and 4AR displayed among the highest levels for the collagens, elastin and tissue inhibitor of the matrix metalloproteinase 1 (TIMP 1). S -equol displayed the lowest level of effectiveness compared to the other compounds. The 4AR analog was more effective compared to resveratrol by 1.6-fold. R -equol and racemic equol were almost equal in potency displaying greater inhibition vs. resveratrol or its 4' analog for the matrix metalloproteinases (MMPs), but among the inflammatory biomarkers, resveratrol, 4AR, R -equol and racemic equol displayed high inhibition. Thus, these cosmeceuticals display promise to improve dermal health; however, further study is warranted to understand how phytochemicals protect/enhance the skin.

Two-parameter partially correlated ground-state electron density of some light spherical atoms from Hartree-Fock theory with nonintegral nuclear charge

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cordero, Nicolas A.; March, Norman H.; Alonso, Julio A.

2007-05-15

Partially correlated ground-state electron densities for some spherical light atoms are calculated, into which nonrelativistic ionization potentials represent essential input data. The nuclear cusp condition of Kato is satisfied precisely. The basic theoretical starting point, however, is Hartree-Fock (HF) theory for the N electrons under consideration but with nonintegral nuclear charge Z{sup '} slightly different from the atomic number Z (=N). This HF density is scaled with a parameter {lambda}, near to unity, to preserve normalization. Finally, some tests are performed on the densities for the atoms Ne and Ar, as well as for Be and Mg.

Phonon-mediated nuclear spin relaxation in H2O

NASA Astrophysics Data System (ADS)

Yamakawa, Koichiro; Azami, Shinya; Arakawa, Ichiro

2017-03-01

A theoretical model of the phonon-mediated nuclear spin relaxation in H2O trapped by cryomatrices has been established for the first time. In order to test the validity of this model, we measured infrared spectra of H2O trapped in solid Ar, which showed absorption peaks due to rovibrational transitions of ortho- and para-H2O in the spectral region of the bending vibration. We monitored the time evolution of the spectra and analyzed the rotational relaxation associated with the nuclear spin flip to obtain the relaxation rates of H2O at temperatures of 5-15 K. Temperature dependence of the rate is discussed in terms of the devised model.

Concentrations of the adrenocorticotropic hormone, corticosterone and sex steroid hormones and the expression of the androgen receptor in the pituitary and adrenal glands of male turkeys (Meleagris gallopavo) during growth and development.

PubMed

Kiezun, J; Kaminska, B; Jankowski, J; Dusza, L

2015-01-01

Androgens take part in the regulation of puberty and promote growth and development. They play their biological role by binding to a specific androgen receptor (AR). The aim of this study was to evaluate the expression of AR mRNA and protein in the pituitary and adrenal glands, to localize AR protein in luteinizing hormone (LH)-producing pituitary and adrenocortical cells, to determine plasma concentrations of adrenocorticotropic hormone (ACTH) and corticosterone and the concentrations of corticosterone, testosterone (T), androstenedione (A4) and oestradiol (E2) in the adrenal glands of male turkeys at the age of 4, 8, 12, 16, 20, 24 and 28weeks. The concentrations of hormones and the expression of AR varied during development. The expression of AR mRNA and protein in pituitary increased during the growth. The increase of AR mRNA levels in pituitary occurred earlier than increase of AR protein. The percentage of pituitary cells expressing ARs in the population of LH-secreting cells increased in week 20. It suggests that AR expression in LH-producing pituitary cells is determined by the phase of development. The drop in adrenal AR mRNA and protein expression was accompanied by an increase in the concentrations of adrenal androgens. Those results could point to the presence of a compensatory mechanism that enables turkeys to avoid the potentially detrimental effects of high androgen concentrations. Our results will expand our knowledge of the role of steroids in the development of the reproductive system of turkeys from the first month of age until maturity. Copyright © 2015 Elsevier Inc. All rights reserved.

Effect of ED-71, a New Active Vitamin D Analog, on Bone Formation in an Orthopedically Expanded Suture in Rats. A Histomorphometric Study

PubMed Central

Uysal, Tancan; Amasyali, Mihri; Enhos, Sukru; Sonmez, Mehmet Fatih; Sagdic, Deniz

2009-01-01

Objectives The aim of this experimental study was to evaluate the effects of ED-71, a new active vitamin D analog, on bone regeneration in response to expansion of the mid-palatal suture, in rats, histomorphometrically. Methods Sixteen male 50–60 days old Wistar rats were separated into two equal groups (control and experimental). Both groups were subjected to expansion, and 30 grams of force was applied to the maxillary incisors with a helical-spring. Experimental group was treated with single-dose ED-71 (0.8 μg/kg body weight) in the mid-palatal suture locally and eight control animals received vehicle solution. Bone regeneration in the mid-palatal suture was evaluated by bone histomorphometric method and mineralized area (Md.Ar), fibrosis area (Fb.Ar), mineralized area/fibrosis area (Md.Ar/Fb.Ar), bone area (B.Ar) and osteoblast number (N.Ob) parameters were evaluated. Mann Whitney-U test was used for statistical evaluation at P<.05 level. Results Statistical analysis showed significant differences between groups for all investigated histomorphometric parameters. Md.Ar (P<.001), Md.Ar/Fb.Ar (P<.001), B.Ar (P<.01) and N.Ob (P<.001) parameters were significantly increased and Fb.Ar (P<.001) measurement was significantly decreased in experimental group. ED-71 group with a mean of 24.55±6.47 showed statistically higher N.Ob than the control group (mean N.Ob: 12.82±5.81). Conclusions ED-71 has positive effects on early phase of bone regeneration in the mid-palatal suture in response to expansion and may be beneficial in routine maxillary expansion procedures. PMID:19756189

Ar-Ar Dating of Martian Meteorite, Dhofar 378: An Early Shock Event?

NASA Technical Reports Server (NTRS)

Park, J.; Bogard, D. D.

2006-01-01

Martian meteorite, Dhofar 378 (Dho378) is a basaltic shergottite from Oman, weighing 15 g, and possessing a black fusion crust. Chemical similarities between Dho378 and the Los Angeles 001 shergottite suggests that they might have derived from the same Mars locale. The plagioclase in other shergottites has been converted to maskelenite by shock, but Dho378 apparently experienced even more intense shock heating, estimated at 55-75 GPa. Dho378 feldspar (approximately 43 modal %) melted, partially flowed and vesiculated, and then partially recrystallized. Areas of feldspathic glass are appreciably enriched in K, whereas individual plagioclases show a range in the Or/An ratio of approximately 0.18-0.017. Radiometric dating of martian shergottites indicate variable formation times of 160-475 Myr, whereas cosmic ray exposure (CRE) ages of shergottites indicate most were ejected from Mars within the past few Myr. Most determined Ar-39-Ar-40 ages of shergottites appear older than other radiometric ages because of the presence of large amounts of martian atmosphere or interior Ar-40. Among all types of meteorites and returned lunar rocks, the impact event that initiated the CRE age very rarely reset the Ar-Ar age. This is because a minimum time and temperature is required to facilitate Ar diffusion loss. It is generally assumed that the shock-texture characteristics in martian meteorites were produced by the impact events that ejected the rocks from Mars, although the time of these shock events (as opposed to CRE ages) are not directly dated. Here we report Ar-39-Ar-40 dating of Dho378 plagioclase. We suggest that the determined age dates the intense shock heating event this meteorite experienced, but that it was not the impact that initiated the CRE age.

ADRA2A is involved in neuro-endocrine regulation of bone resorption

PubMed Central

Mlakar, Vid; Jurkovic Mlakar, Simona; Zupan, Janja; Komadina, Radko; Prezelj, Janez; Marc, Janja

2015-01-01

Adrenergic stimulation is important for osteoclast differentiation and bone resorption. Previous research shows that this happens through β2-adrenergic receptor (AR), but there are conflicting evidence on presence and role of α2A-AR in bone. The aim of this study was to investigate the presence of α2A-AR and its involvement in neuro-endocrine signalling of bone remodelling in humans. Real-time polymerase chain reaction (PCR) and immunohistochemistry were used to investigate α2A-AR receptor presence and localization in bone cells. Functionality of rs553668 and rs1800544 single nucleotide polymorphism SNPs located in α2A-AR gene was analysed by qPCR expression on bone samples and luciferase reporter assay in human osteosarcoma HOS cells. Using real-time PCR, genetic association study between rs553668 A>G and rs1800544 C>G SNPs and major bone markers was performed on 661 Slovenian patients with osteoporosis. α2A-AR is expressed in osteoblasts and lining cells but not in osteocytes. SNP rs553668 has a significant influence on α2A-AR mRNA level in human bone samples through the stability of mRNA. α2A-AR gene locus associates with important bone remodelling markers (BMD, CTX, Cathepsin K and pOC). The results of this study are providing comprehensive new evidence that α2A-AR is involved in neuro-endocrine signalling of bone turnover and development of osteoporosis. As shown by our results the neurological signalling is mediated through osteoblasts and result in bone resorption. Genetic study showed association of SNPs in α2A-AR gene locus with bone remodelling markers, identifying the individuals with higher risk of development of osteoporosis. PMID:25818344

Neuroprotection by caffeine in the MPTP model of parkinson's disease and its dependence on adenosine A2A receptors.

PubMed

Xu, K; Di Luca, D G; Orrú, M; Xu, Y; Chen, J-F; Schwarzschild, M A

2016-05-13

Considerable epidemiological and laboratory data have suggested that caffeine, a nonselective adenosine receptor antagonist, may protect against the underlying neurodegeneration of parkinson's disease (PD). Although both caffeine and more specific antagonists of the A2A subtype of adenosine receptor (A2AR) have been found to confer protection in animal models of PD, the dependence of caffeine's neuroprotective effects on the A2AR is not known. To definitively determine its A2AR dependence, the effect of caffeine on 1-methyl-4-phenyl-1,2,3,6 tetra-hydropyridine (MPTP) neurotoxicity was compared in wild-type (WT) and A2AR gene global knockout (A2A KO) mice, as well as in central nervous system (CNS) cell type-specific (conditional) A2AR knockout (cKO) mice that lack the receptor either in postnatal forebrain neurons or in astrocytes. In WT and in heterozygous A2AR KO mice caffeine pretreatment (25mg/kgip) significantly attenuated MPTP-induced depletion of striatal dopamine. By contrast in homozygous A2AR global KO mice caffeine had no effect on MPTP toxicity. In forebrain neuron A2AR cKO mice, caffeine lost its locomotor stimulant effect, whereas its neuroprotective effect was mostly preserved. In astrocytic A2AR cKO mice, both caffeine's locomotor stimulant and protective properties were undiminished. Taken together, these results indicate that neuroprotection by caffeine in the MPTP model of PD relies on the A2AR, although the specific cellular localization of these receptors remains to be determined. Copyright © 2016 IBRO. All rights reserved.

The complement factor 5a receptor 1 has a pathogenic role in chronic inflammation and renal fibrosis in a murine model of chronic pyelonephritis.

PubMed

Choudhry, Naheed; Li, Ke; Zhang, Ting; Wu, Kun-Yi; Song, Yun; Farrar, Conrad A; Wang, Na; Liu, Cheng-Fei; Peng, Qi; Wu, Weiju; Sacks, Steven H; Zhou, Wuding

2016-09-01

Complement factor 5a (C5a) interaction with its receptor (C5aR1) contributes to the pathogenesis of inflammatory diseases, including acute kidney injury. However, its role in chronic inflammation, particularly in pathogen-associated disorders, is largely unknown. Here we tested whether the development of chronic inflammation and renal fibrosis is dependent on C5aR1 in a murine model of chronic pyelonephritis. C5aR1-deficient (C5aR1-/-) mice showed a significant reduction in bacterial load, tubule injury and tubulointerstitial fibrosis in the kidneys following infection, compared with C5aR1-sufficient mice. This was associated with reduced renal leukocyte infiltration specifically for the population of Ly6Chi proinflammatory monocytes/macrophages and reduced intrarenal gene expression of key proinflammatory and profibrogenic factors in C5aR1-/- mice following infection. Antagonizing C5aR1 decreased renal bacterial load, tissue inflammation and tubulointerstitial fibrosis. Ex vivo and in vitro studies showed that under infection conditions, C5a/C5aR1 interaction upregulated the production of proinflammatory and profibrogenic factors by renal tubular epithelial cells and monocytes/macrophages, whereas the phagocytic function of monocytes/macrophages was down-regulated. Thus, C5aR1-dependent bacterial colonization of the tubular epithelium, C5a/C5aR1-mediated upregulation of local inflammatory responses to uropathogenic E. coli and impairment of phagocytic function of phagocytes contribute to persistent bacterial colonization of the kidney, chronic renal inflammation and subsequent tubulointerstitial fibrosis. Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

AT1 and AT2 Receptors in the Prelimbic Cortex Modulate the Cardiovascular Response Evoked by Acute Exposure to Restraint Stress in Rats.

PubMed

Brasil, Taíz F S; Fassini, Aline; Corrêa, Fernando M

2018-01-01

The prelimbic cortex (PL) is an important structure in the neural pathway integrating stress responses. Brain angiotensin is involved in cardiovascular control and modulation of stress responses. Blockade of angiotensin receptors has been reported to reduce stress responses. Acute restraint stress (ARS) is a stress model, which evokes sustained blood pressure increase, tachycardia, and reduction in tail temperature. We therefore hypothesized that PL locally generated angiotensin and angiotensin receptors modulate stress autonomic responses. To test this hypothesis, we microinjected an angiotensin-converting enzyme (ACE) inhibitor or angiotensin antagonists into the PL, prior to ARS. Male Wistar rats were used; guide cannulas were bilaterally implanted in the PL for microinjection of vehicle or drugs. A polyethylene catheter was introduced into the femoral artery to record cardiovascular parameters. Tail temperature was measured using a thermal camera. ARS was started 10 min after PL treatment with drugs. Pretreatment with ACE inhibitor lisinopril (0.5 nmol/100 nL) reduced the pressor response, but did not affect ARS-evoked tachycardia. At a dose of 1 nmol/100 nL, it reduced both ARS pressor and tachycardic responses. Pretreatment with candesartan, AT1 receptor antagonist reduced ARS-evoked pressor response, but not tachycardia. Pretreatment with PD123177, AT2 receptor antagonist, reduced tachycardia, but did not affect ARS pressor response. No treatment affected ARS fall in tail temperature. Results suggest involvement of PL angiotensin in the mediation of ARS cardiovascular responses, with participation of both AT1 and AT2 receptors. In conclusion, results indicate that PL AT1-receptors modulate the ARS-evoked pressor response, while AT2-receptors modulate the tachycardic component of the autonomic response.

Recurrent Early Cretaceous, Indo-Madagascar (89-86 Ma) and Deccan (66 Ma) alkaline magmatism in the Sarnu-Dandali complex, Rajasthan: 40Ar/39Ar age evidence and geodynamic significance

NASA Astrophysics Data System (ADS)

Sheth, Hetu; Pande, Kanchan; Vijayan, Anjali; Sharma, Kamal Kant; Cucciniello, Ciro

2017-07-01

The Sarnu-Dandali alkaline complex in Rajasthan, northwestern India, is considered to represent early, pre-flood basalt magmatism in the Deccan Traps province, based on a single 40Ar/39Ar age of 68.57 Ma. Rhyolites found in the complex are considered to be 750 Ma Malani basement. Our new 40Ar/39Ar ages of 88.9-86.8 Ma (for syenites, nephelinite, phonolite and rhyolite) and 66.3 ± 0.4 Ma (2σ, melanephelinite) provide clear evidence that whereas the complex has Deccan-age (66 Ma) components, it is dominantly an older (by 20 million years) alkaline complex, with rhyolites included. Basalt is also known to underlie the Early Cretaceous Sarnu Sandstone. Sarnu-Dandali is thus a periodically rejuvenated alkaline igneous centre, active twice in the Late Cretaceous and also earlier. Many such centres with recurrent continental alkaline magmatism (sometimes over hundreds of millions of years) are known worldwide. The 88.9-86.8 Ma 40Ar/39Ar ages for Sarnu-Dandali rocks fully overlap with those for the Indo-Madagascar flood basalt province formed during continental breakup between India (plus Seychelles) and Madagascar. Recent 40Ar/39Ar work on the Mundwara alkaline complex in Rajasthan, 120 km southeast of Sarnu-Dandali, has also shown polychronous emplacement (over ≥ 45 million years), and 84-80 Ma ages obtained from Mundwara also arguably represent post-breakup stages of the Indo-Madagascar flood basalt volcanism. Remnants of the Indo-Madagascar province are known from several localities in southern India but hitherto unknown from northwestern India 2000 km away. Additional equivalents buried under the vast Deccan Traps are highly likely.

Role of Penning ionization in the enhancement of streamer channel conductivity and Ar(1s{sub 5}) production in a He-Ar plasma jet

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sands, Brian L.; Huang, Shih K.; Speltz, Jared W.

2013-04-21

Plasma jet devices that use a helium gas flow mixed with a small percentage of argon have been shown to operate with a larger discharge current and enhanced production of the Ar(1s{sub 5}) metastable state, particularly in the discharge afterglow. In this experiment, time-resolved quantitative measurements of He(2{sup 3}S{sub 1}) and Ar(1s{sub 5}) metastable species were combined with current and spectrally resolved emission measurements to elucidate the role of Penning ionization in a helium plasma jet with a variable argon admixture. The plasma jet was enclosed in a glass chamber through which a flowing nitrogen background was maintained at 600more » Torr. At 3%-5% Ar admixture, we observed a {approx}50% increase in the peak circuit current and streamer velocity relative to a pure helium plasma jet for the same applied voltage. The streamer initiation delay also decreased by {approx}20%. Penning ionization of ground-state argon was found to be the dominant quenching pathway for He(2{sup 3}S{sub 1}) up to 2% Ar and was directly correlated with a sharp increase in both the circuit current and afterglow production of Ar(1s{sub 5}) for Ar admixtures up to 1%, but not necessarily with the streamer velocity, which increased more gradually with Ar concentration. Ar(1s{sub 5}) was produced in the afterglow through recombination of Ar{sup +} and dissociative recombination of Ar{sub 2}{sup +} as the local mean electron energy decreased in the plasma channel behind the streamer head. The discharge current and argon metastable enhancement are contingent on the rapid production of He(2{sup 3}S{sub 1}) near the streamer head, >5 Multiplication-Sign 10{sup 12} cm{sup -3} in 30 ns under the conditions of this experiment.« less

Flare onset at sites of maximum magnetic shear

NASA Technical Reports Server (NTRS)

Hagyard, M. J.; Smith, J. B., Jr.

1988-01-01

Observations of the transverse component of the Sun's photospheric magnetic field obtained with the MSFC vector magnetograph show where the fields are nonpotential. The correlation was studied between locations of nonpotential fields and sites of flare onset for four different active regions. The details of the active region AR 4711 are outlined. Similar results are presented for three other regions: AR 2372 (April 1980), AR 2776 (November 1980), and AR 4474 (April 1984). For all four regions it is shown that flares initiate at sites on the magnetic neutral line where the local field deviates the most from the potential field. The results of this study suggest that flares are likely to erupt where the shear is equal to or greater than 85 degrees, the field is equal to or greater than 10000 G, and there is strong shear (equal to or greater then 80 degress) extending over a length equal to or greater than 8000 km.

X-ray burst studies with the JENSA gas jet target

NASA Astrophysics Data System (ADS)

Schmidt, Konrad; Chipps, Kelly A.; Ahn, Sunghoon; Allen, Jacob M.; Ayoub, Sara; Bardayan, Daniel W.; Blackmon, Jeffrey C.; Blankstein, Drew; Browne, Justin; Cha, Soomi; Chae, Kyung YUK; Cizewski, Jolie; Deibel, Catherine M.; Deleeuw, Eric; Gomez, Orlando; Greife, Uwe; Hager, Ulrike; Hall, Matthew R.; Jones, Katherine L.; Kontos, Antonios; Kozub, Raymond L.; Lee, Eunji; Lepailleur, Alex; Linhardt, Laura E.; Matos, Milan; Meisel, Zach; Montes, Fernando; O'Malley, Patrick D.; Ong, Wei Jia; Pain, Steven D.; Sachs, Alison; Schatz, Hendrik; Schmitt, Kyle T.; Smith, Karl; Smith, Michael S.; Soares de Bem, Natã F.; Thompson, Paul J.; Toomey, Rebecca; Walter, David

2018-01-01

When a neutron star accretes hydrogen and helium from the outer layers of its companion star, thermonuclear burning enables the αp-process as a break out mechanism from the hot CNO cycle. Model calculations predict (α, p) reaction rates significantly affect both the light curves and elemental abundances in the burst ashes. The Jet Experiments in Nuclear Structure and Astrophysics (JENSA) gas jet target enables the direct measurement of previously inaccessible (α,p) reactions with radioactive beams provided by the rare isotope re-accelerator ReA3 at the National Superconducting Cyclotron Laboratory (NSCL), USA. JENSA is going to be the main target for the Recoil Separator for Capture Reactions (SECAR) at the Facility for Rare Isotope Beams (FRIB). Commissioning of JENSA and first experiments at Oak Ridge National Laboratory (ORNL) showed a highly localized, pure gas target with a density of ˜1019 atoms per square centimeter. Preliminary results are presented from the first direct cross section measurement of the 34Ar(α, p)37 K reaction at NSCL.

Efficient and dynamic nuclear localization of green fluorescent protein via RNA binding

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kitamura, Akira; Nakayama, Yusaku; Kinjo, Masataka, E-mail: kinjo@sci.hokudai.ac.jp

2015-07-31

Classical nuclear localization signal (NLS) sequences have been used for artificial localization of green fluorescent protein (GFP) in the nucleus as a positioning marker or for measurement of the nuclear-cytoplasmic shuttling rate in living cells. However, the detailed mechanism of nuclear retention of GFP-NLS remains unclear. Here, we show that a candidate mechanism for the strong nuclear retention of GFP-NLS is via the RNA-binding ability of the NLS sequence. GFP tagged with a classical NLS derived from Simian virus 40 (GFP-NLS{sup SV40}) localized not only in the nucleoplasm, but also to the nucleolus, the nuclear subdomain in which ribosome biogenesismore » takes place. GFP-NLS{sup SV40} in the nucleolus was mobile, and intriguingly, the diffusion coefficient, which indicates the speed of diffusing molecules, was 1.5-fold slower than in the nucleoplasm. Fluorescence correlation spectroscopy (FCS) analysis showed that GFP-NLS{sup SV40} formed oligomers via RNA binding, the estimated molecular weight of which was larger than the limit for passive nuclear export into the cytoplasm. These findings suggest that the nuclear localization of GFP-NLS{sup SV40} likely results from oligomerization mediated via RNA binding. The analytical technique used here can be applied for elucidating the details of other nuclear localization mechanisms, including those of several types of nuclear proteins. In addition, GFP-NLS{sup SV40} can be used as an excellent marker for studying both the nucleoplasm and nucleolus in living cells. - Highlights: • Nuclear localization signal-tagged GFP (GFP-NLS) showed clear nuclear localization. • The GFP-NLS dynamically localized not only in the nucleoplasm, but also to the nucleolus. • The nuclear localization of GFP-NLS results from transient oligomerization mediated via RNA binding. • Our NLS-tagging procedure is ideal for use in artificial sequestration of proteins in the nucleus.« less

Impaired helix 12 dynamics due to proline 892 substitutions in the androgen receptor are associated with complete androgen insensitivity.

PubMed

Elhaji, Youssef A; Stoica, Ileana; Dennis, Sheldon; Purisima, Enrico O; Lumbroso, Rose; Beitel, Lenore K; Trifiro, Mark A

2006-03-15

Structural studies of the ligand-binding domain (LBD) of several steroid receptors have revealed that the dynamic properties of the C-terminal helix 12 (H12) are the major determinant of the activation mode of these receptors. H12 exhibits high mobility and different conformations in the absence of ligand. Upon ligand binding, H12 is stabilized in a precise position to seal the ligand-binding pocket and finalize the assembly of the activation function (AF-2) domain. In this study, we investigated the role of the conserved proline 892 of the androgen receptor (AR) in directing the dynamic location and orientation of the AR-H12. We used a combined approach including kinetic and biochemical assays with molecular dynamic simulations to analyze two substitutions (P892A and P892L) identified in individuals with complete androgen insensitivity syndrome. Our analyses revealed distinct mechanisms by which these substitutions impair H12 function resulting in severely defective receptors. The AR-P892A receptor exhibited reduced ligand binding and transactivational potential because of an increased flexibility in H12. The AR-P892L substitution renders the receptor inactive due to a distorted, unstructured and misplaced H12. To confirm the mutants' inability to stabilize H12 in an active position, we have developed a novel in vivo assay to evaluate the accessibility of the H12-docking site on the AR-LBD surface. An extrinsic AR-H12 peptide was able to interact with wild-type and mutant LBDs in the absence of ligand. Ligand-induced proper positioning of the intrinsic H12 of wild-type AR prevented these interactions, whereas the misplacement of the mutants' H12 did not. Proline at this position may be critical for H12 dynamics not only in the AR, but also in other nuclear receptors where this proline is conserved.

Identification of novel nuclear localization signals of Drosophila myeloid leukemia factor.

PubMed

Sugano, Wakana; Yamaguchi, Masamitsu

2007-01-01

Myeloid leukemia factor 1 (MLF1) was first identified as part of a leukemic fusion protein produced by a chromosomal translocation, and MLF family proteins are present in many animals. In mammalian cells, MLF1 has been described as mainly cytoplasmic, but in Drosophila, one of the dMLF isoforms (dMLFA) localized mainly in the nucleus while the other isoform (dMLFB), that appears to be produced by the alternative splicing, displays both nuclear and cytoplasmic localization. To investigate the difference in subcellular localization between MLF family members, we examined the subcellular localization of deletion mutants of dMLFA isoform. The analyses showed that the C-terminal 40 amino acid region of dMLFA is necessary and sufficient for nuclear localization. Based on amino acid sequences, we hypothesized that two nuclear localization signals (NLSs) are present within the region. Site-directed mutagenesis of critical residues within the two putative NLSs leads to loss of nuclear localization, suggesting that both NLS motifs are necessary for nuclear localization.

Measures and Trends U.S. and U.S.S.R. Strategic Force Effectiveness. (Sanitized)

DTIC Science & Technology

1978-07-01

is limited by the uncer- tainties and inaccracies present in the data which are used to develop the moasure. In the main body of the text the...alplizan1e to the prvostwu noas;urO5 arc ar;ici~to tn; ~~z~ ’i.r 2ctwo mt- azurer i-rmores tne fact that t Cftl4t.0 av’curacy -f I tnk~ atv :a;r le... azured in aitica1 nilios, of all thv straregic nuclear weaorjzf in CaC!. forCe iS CO c~aztd. V. (U) in order to utlijZe .he stanl1ard qra:pl.ic re

THE ROLE OF TARGET ORGAN DIAGNOSTIC APPROACH IN SEASONAL ALLERGIC RHINITIS: NASAL SMEAR EOSINOPHILS.

PubMed

Nurkic, Jasmina; Ahmad, Mona Al; Arifhodzic, Nermina; Jusufovic, Edin

2016-04-01

Allergic rhinitis (AR) related to local weeds pollen sensitization (Chenopodiaceous family) is the most common cause of respiratory allergy in Kuwait. Local nasal accumulation of different cells typical of allergic inflammation is responsible for clinical symptoms of AR. Although nasal smear for Eosinophils (NSE) is one of the earliest included valuable test in diagnosis of AR, with time is underestimated. Explore possible correlation of natural pollen allergen stimulation with appearance and quantity of Eosinophils in nasal smear. A group of randomly selected patients with clinical history suggestive for seasonal AR (SAR), who came to Al Rashed Allergy Center in period from October 2014 to October 2015, obtain Nasal Smear for Eosinophils as a screening test before further diagnostic evaluation. Nasal samples were collected by passing a sterile swab, from each nasal cavity, along the medial surface of the inferior turbinate 2 to 3 times and the specimen smeared on a clear glass slide. Nasal smears were examined by light microscopy after staining with hematoxylin and eosin stain. Skin prick test is performed in all symptomatic patients with a battery of inhalant allergens that include local pollens. The control group was recruited, with their voluntary consent, from the medical stuff with a negative history of any allergic nasal symptoms. In this group we performed only nasal smear for Eosinophils. Air Biology Laboratory Kuwait provided us with daily pollen count. From total 158 study participants, 132 had SAR symptoms and are divided in four groups. Fifth, control, group is non symptomatic. For 38.6% of symptomatic patients NSE were positive, while 45% of these patients have negative SPT. From 62.1% NSE negative patients, 37.8% have negative SPT. Our results showed expected positive correlation of NSE positive patients with pollen season in Kuwait, in SPT positive group. However, presence of Eosinophils in nasal smear was moderate to high also in patients with negative SPT during the highest peak of season, in contrast to control group. NES showed moderate sensitivity, relatively high specificity and importance as screening test in SPT negative patients. Evaluation of AR demand wide and improved diagnostic approach due to significant number of SPT negative patients with positive NSE based on natural allergen stimulation. Our results emphasize locale allergic response of nasal mucosa and importance of target organ diagnostic approach.

Occurrence and in vitro bioactivity of estrogen, androgen, and glucocorticoid compounds in a nationwide screen of United States stream waters

EPA Science Inventory

In vitro bioassays are sensitive, effect-based tools used to quantitatively screen for chemicals with nuclear receptor activity in environmental samples. We measured in vitro estrogen (ER), androgen (AR), and glucocorticoid receptor (GR) activity, along with a suite of chemical a...

Identifying Environmental Chemicals as Agonists of the Androgen Receptor by Applying a Quantitative High-throughput Screening Platform

EPA Science Inventory

Background: The androgen receptor (AR, NR3C4) is a nuclear receptor whose main function is acting as a transcription factor regulating gene expression for male sexual development and maintaining accessory sexual organ function. It is also a necessary component of female fertility...

Structures and functions of proteins and nucleic acids in protein biosynthesis

NASA Astrophysics Data System (ADS)

Miyazawa, Tatsuo; Yokoyama, Shigeyuki

Infrared and Raman spectroscopy is useful for studying helical conformations of polypeptides, which are determined by molecular structure parameters. Nuclear magnetic resonance spectroscopy, as well as X-ray analysis, is now established to be important for conformation studies of proteins and nucleic acids in solution. This article is mainly concerned with the conformational aspect and function regulation in protein biosynthesis. The strict recognition of transfer ribonucleic acid (tRNA) by aminoacyl-tRNA synthetase (ARS) is achieved by multi-step mutual adaptation. The conformations of ARS-bound amino acids have been elucidated by transferred nuclear Overhauser effect analysis. Aminoacyl-tRNA takes the 3‧-isomeric form in the polypeptide chain elongation cycle. The regulation of codon recognition by post-transcriptional modification is achieved by conversion of the conformational characteristic of the anticodon of tRNA. The cytidine → lysidine modification of the anticodon of minor isoleucine tRNA concurrently converts the amino acid specificity and the codon specificity. As novel protein engineering, a basic strategy has been established for in vivo biosynthesis of proteins that are substituted with unnatural amino acids (alloproteins).

Shell-model computed cross sections for charged-current scattering of astrophysical neutrinos off 40Ar

NASA Astrophysics Data System (ADS)

Kostensalo, Joel; Suhonen, Jouni; Zuber, K.

2018-03-01

Charged-current (anti)neutrino-40Ar cross sections for astrophysical neutrinos have been calculated. The initial and final nuclear states were calculated using the nuclear shell model. The folded solar-neutrino scattering cross section was found to be 1.78 (23 ) ×10-42cm2 , which is higher than what the previous papers have reported. The contributions from the 1- and 2- multipoles were found to be significant at supernova-neutrino energies, confirming the random-phase approximation (RPA) result of a previous study. The effects of neutrino flavor conversions in dense stellar matter (matter oscillations) were found to enhance the neutrino-scattering cross sections significantly for both the normal and inverted mass hierarchies. For the antineutrino scattering, only a small difference between the nonoscillating and inverted-hierarchy cross sections was found, while the normal-hierarchy cross section was 2-3 times larger than that of the nonoscillating cross section, depending on the adopted parametrization of the Fermi-Dirac distribution. This property of the supernova-antineutrino signal could probably be used to distinguish between the two hierarchies in megaton LAr detectors.

Expression of androgen receptor and estrogen receptor-alpha in the developing pituitary gland of male sheep lamb.

PubMed

Huang, Li-Bo; Yuan, Xue-Jun

2011-09-01

To explore the expression of androgen receptor (AR) and estrogen receptor alpha (ERα) in the developing pituitary of male lamb, we detected AR and ERα expression in the anterior pituitary of lambs aged 2-7 months old by immunohistochemistry. The results showed that both AR immunoreactivity (AR-ir) and ERα immunoreactivity (ERα-ir) were localized in the nuclei of anterior pituitary cell. The percentage of the anterior pituitary cells expressing ERα fluctuated from 8.79±0.02% to 11.80±0.04% during the examined stages, but fell significantly to the lowest level at 6 months. While the proportion of AR-ir showed significant changes, it was in 11.52±1.26% at 2 months, it firstly increased to 19.86±1.03% at 3 months, and then significantly decreased to 8.18±1.17% at 6 months (P<0.05). The expression of both AR-ir and ERα-ir were the lowest level at 6 months old. By staining for PCNA, we observed that the changes in expression of AR and ERα at different lamb ages did not result from cell proliferation of anterior pituitary cells. These results indicate that both AR and ERα are important in regulation of secretary function of anterior pituitary in sheep lamb, although the related mechanism needs to be elucidated further. Copyright © 2011 Elsevier B.V. All rights reserved.

Behavioral Analysis of Genetically Modified Mice Indicates Essential Roles of Neurosteroidal Estrogen

PubMed Central

Honda, Shin-Ichiro; Wakatsuki, Toru; Harada, Nobuhiro

2011-01-01

Aromatase in the mouse brain is expressed only in the nerve cells of specific brain regions with a transient peak during the neonatal period when sexual behaviors become organized. The aromatase-knockout (ArKO) mouse, generated to shed light on the physiological functions of estrogen in the brain, exhibited various abnormal behaviors, concomitant with undetectable estrogen and increased androgen in the blood. To further elucidate the effects of neurosteroidal estrogens on behavioral phenotypes, we first prepared an brain-specific aromatase transgenic (bsArTG) mouse by introduction of a human aromatase transgene controlled under a −6.5 kb upstream region of the brain-specific promoter of the mouse aromatase gene into fertilized mouse eggs, because the −6.5 kb promoter region was previously shown to contain the minimal essential element responsible for brain-specific spatiotemporal expression. Then, an ArKO mouse expressing the human aromatase only in the brain was generated by crossing the bsArTG mouse with the ArKO mouse. The resulting mice (ArKO/bsArTG mice) nearly recovered from abnormal sexual, aggressive, and locomotive (exploratory) behaviors, in spite of having almost the same serum levels of estrogen and androgen as the adult ArKO mouse. These results suggest that estrogens locally synthesized in the specific neurons of the perinatal mouse brain directly act on the neurons and play crucial roles in the organization of neuronal networks participating in the control of sexual, aggressive, and locomotive (exploratory) behaviors. PMID:22654807

Characterization of extreme precipitation within atmospheric river events over California

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jeon, S.; Prabhat,; Byna, S.

Atmospheric rivers (ARs) are large, spatially coherent weather systems with high concentrations of elevated water vapor. These systems often cause severe downpours and flooding over the western coastal United States – and with the availability of more atmospheric moisture in the future under global warming we expect ARs to play an important role as potential causes of extreme precipitation changes. Therefore, we aim to investigate changes in extreme precipitation properties correlated with AR events in a warmer climate, which are large-scale meteorological patterns affecting the weather and climate of California. We have recently developed the TECA (Toolkit for Extreme Climatemore » Analysis) software for automatically identifying and tracking features in climate data sets. Specifically, we can now identify ARs that make landfall on the western coast of North America. Based on this detection procedure, we can investigate the impact of ARs by exploring the spatial extent of AR precipitation using climate model (CMIP5) simulations and characterize spatial patterns of dependence for future projections between AR precipitation extremes under climate change within the statistical framework. Our results show that AR events in the future RCP (Representative Concentration Pathway)8.5 scenario (2076–2100) tend to produce heavier rainfall with higher frequency and longer days than events from the historical run (1981–2005). We also find that the dependence between extreme precipitation events has a shorter spatial range, within localized areas in California, under the high future emissions scenario than under the historical run.« less

Characterization of extreme precipitation within atmospheric river events over California

DOE PAGES

Jeon, S.; Prabhat,; Byna, S.; ...

2015-11-17

Atmospheric rivers (ARs) are large, spatially coherent weather systems with high concentrations of elevated water vapor. These systems often cause severe downpours and flooding over the western coastal United States – and with the availability of more atmospheric moisture in the future under global warming we expect ARs to play an important role as potential causes of extreme precipitation changes. Therefore, we aim to investigate changes in extreme precipitation properties correlated with AR events in a warmer climate, which are large-scale meteorological patterns affecting the weather and climate of California. We have recently developed the TECA (Toolkit for Extreme Climatemore » Analysis) software for automatically identifying and tracking features in climate data sets. Specifically, we can now identify ARs that make landfall on the western coast of North America. Based on this detection procedure, we can investigate the impact of ARs by exploring the spatial extent of AR precipitation using climate model (CMIP5) simulations and characterize spatial patterns of dependence for future projections between AR precipitation extremes under climate change within the statistical framework. Our results show that AR events in the future RCP (Representative Concentration Pathway)8.5 scenario (2076–2100) tend to produce heavier rainfall with higher frequency and longer days than events from the historical run (1981–2005). We also find that the dependence between extreme precipitation events has a shorter spatial range, within localized areas in California, under the high future emissions scenario than under the historical run.« less

Androgen-androgen receptor system improves chronic inflammatory conditions by suppressing monocyte chemoattractant protein-1 gene expression in adipocytes via transcriptional regulation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Morooka, Nobukatsu, E-mail: amorooka@gunma-u.ac.jp; Ueguri, Kei; Yee, Karen Kar Lye

Age-related decreases in sex hormones are closely related to chronic inflammation in obesity and metabolic diseases. Particularly, the molecular basis of androgen activity in regulating inflammation and controlling metabolism remains largely unknown. Obese adipocytes secrete monocyte chemoattractant protein-1 (MCP-1), a key chemokine that promotes the infiltration of monocytes/macrophages into adipose tissue, thereby leading to metabolic disorders. Here, we studied the role of androgen-androgen receptor (AR) action in regulating MCP-1 expression in adipose tissue. We observed the induction of Mcp-1 expression in 3T3-L1 adipocytes co-cultured with RAW264.7 macrophages. Additionally, Mcp-1 expression was upregulated by culturing in conditioned medium derived from inflammatorymore » macrophages (M1-Mφ) containing tumor necrosis factor-alpha (TNF-α). We found that sex hormones downregulated TNF-α-induced Mcp-1 and interleukin (Il)-6 expression in 3T3-L1 adipocytes. Furthermore, luciferase-reporter analysis indicated that MCP-1 promoter activity was predominantly suppressed by dihydrotestosterone (DHT)-AR interactions through functional canonical nuclear factor-kappa B (NF-κB) sites, whereas non-canonical NF-κB site containing important flanking sequences exhibited minor contributions to DHT-AR transcriptional repression. These findings suggested that androgen-AR suppressed obesity-induced chronic inflammation in adipose tissue. - Highlights: • DHT, non-aromatizable androgen suppresses Mcp-1 expression in adipocytes. • Mcp-1 transcription was negatively regulated by DHT-AR action. • DHT-AR selectively regulates Mcp-1 transcription through distinct NF-κB sites.« less

Androgen Receptor Involvement in Rat Amelogenesis: An Additional Way for Endocrine-Disrupting Chemicals to Affect Enamel Synthesis.

PubMed

Jedeon, Katia; Loiodice, Sophia; Salhi, Khaled; Le Normand, Manon; Houari, Sophia; Chaloyard, Jessica; Berdal, Ariane; Babajko, Sylvie

2016-11-01

Endocrine-disrupting chemicals (EDCs) that interfere with the steroid axis can affect amelogenesis, leading to enamel hypomineralization similar to that of molar incisor hypomineralization, a recently described enamel disease. We investigated the sex steroid receptors that may mediate the effects of EDCs during rat amelogenesis. The expression of androgen receptor (AR), estrogen receptor (ER)-α, and progesterone receptor was dependent on the stage of ameloblast differentiation, whereas ERβ remained undetectable. AR was the only receptor selectively expressed in ameloblasts involved in final enamel mineralization. AR nuclear translocation and induction of androgen-responsive element-containing promoter activity upon T treatment, demonstrated ameloblast responsiveness to androgens. T regulated the expression of genes involved in enamel mineralization such as KLK4, amelotin, SLC26A4, and SLC5A8 but not the expression of genes encoding matrix proteins, which determine enamel thickness. Vinclozolin and to a lesser extent bisphenol A, two antiandrogenic EDCs that cause enamel defects, counteracted the actions of T. In conclusion, we show, for the first time, the following: 1) ameloblasts express AR; 2) the androgen signaling pathway is involved in the enamel mineralization process; and 3) EDCs with antiandrogenic effects inhibit AR activity and preferentially affect amelogenesis in male rats. Their action, through the AR pathway, may specifically and irreversibly affect enamel, potentially leading to the use of dental defects as a biomarker of exposure to environmental pollutants. These results are consistent with the steroid hormones affecting ameloblasts, raising the issue of the hormonal influence on amelogenesis and possible sexual dimorphism in enamel quality.

Proximal tubule sphingosine kinase-1 has a critical role in A1 adenosine receptor-mediated renal protection from ischemia

PubMed Central

Park, Sang Won; Kim, Mihwa; Kim, Joo Yun; Brown, Kevin M.; Haase, Volker H.; D’Agati, Vivette D.; Lee, H. Thomas

2012-01-01

Renal ischemia reperfusion injury is a major cause of acute kidney injury. We previously found that renal A1 adenosine receptor (A1AR) activation attenuated multiple cell death pathways including necrosis, apoptosis and inflammation. Here, we tested whether induction of cytoprotective sphingosine kinase (SK)-1 and sphingosine-1 phosphate (S1P) synthesis might be the mechanism of protection. A selective A1AR agonist (CCPA) increased the synthesis of S1P and selectively induced SK-1 in mouse kidney and HK-2 cells. This agonist failed to protect SK1-knockout but protected SK2-knockout mice against renal ischemia reperfusion injury indicating a critical role of SK1 in A1AR-mediated renal protection. Inhibition of SK prevented A1AR-mediated defense against necrosis and apoptosis in HK-2 cells. A selective S1P1R antagonist (W146) and global in vivo gene knockdown of S1P1Rs with small interfering RNA completely abolished the renal protection provided by CCPA. Mice selectively deficient in renal proximal tubule S1P1Rs (S1P1Rflox/flox PEPCKCre/−) were not protected against renal ischemia reperfusion injury by CCPA. Mechanistically, CCPA increased nuclear translocation of hypoxia inducible factor-1α in HK-2 cells and selective hypoxia inducible factor-1α inhibition blocked A1AR-mediated induction of SK1. Thus, proximal tubule SK-1 has a critical role in A1AR-mediated protection against renal ischemia reperfusion injury. PMID:22695326

32 CFR Appendix D to Part 651 - Public Participation Plan

Code of Federal Regulations, 2014 CFR

2014-07-01

...) ENVIRONMENTAL QUALITY ENVIRONMENTAL ANALYSIS OF ARMY ACTIONS (AR 200-2) Pt. 651, App. D Appendix D to Part 651... as news releases to local media, announcements to local citizens groups, and Commander's letters... have an interest in the environmental effects of the proposed action or activity (for example, hunters...

32 CFR Appendix D to Part 651 - Public Participation Plan

Code of Federal Regulations, 2011 CFR

2011-07-01

...) ENVIRONMENTAL QUALITY ENVIRONMENTAL ANALYSIS OF ARMY ACTIONS (AR 200-2) Pt. 651, App. D Appendix D to Part 651... as news releases to local media, announcements to local citizens groups, and Commander's letters... have an interest in the environmental effects of the proposed action or activity (for example, hunters...

32 CFR Appendix D to Part 651 - Public Participation Plan

Code of Federal Regulations, 2013 CFR

2013-07-01

...) ENVIRONMENTAL QUALITY ENVIRONMENTAL ANALYSIS OF ARMY ACTIONS (AR 200-2) Pt. 651, App. D Appendix D to Part 651... as news releases to local media, announcements to local citizens groups, and Commander's letters... have an interest in the environmental effects of the proposed action or activity (for example, hunters...

32 CFR Appendix D to Part 651 - Public Participation Plan

Code of Federal Regulations, 2012 CFR

2012-07-01

...) ENVIRONMENTAL QUALITY ENVIRONMENTAL ANALYSIS OF ARMY ACTIONS (AR 200-2) Pt. 651, App. D Appendix D to Part 651... as news releases to local media, announcements to local citizens groups, and Commander's letters... have an interest in the environmental effects of the proposed action or activity (for example, hunters...

Robust automatic P-phase picking: an on-line implementation in the analysis of broadband seismogram recordings

NASA Astrophysics Data System (ADS)

Sleeman, Reinoud; van Eck, Torild

1999-06-01

The onset of a seismic signal is determined through joint AR modeling of the noise and the seismic signal, and the application of the Akaike Information Criterion (AIC) using the onset time as parameter. This so-called AR-AIC phase picker has been tested successfully and implemented on the Z-component of the broadband station HGN to provide automatic P-phase picks for a rapid warning system. The AR-AIC picker is shown to provide accurate and robust automatic picks on a large experimental database. Out of 1109 P-phase onsets with signal-to-noise ratio (SNR) above 1 from local, regional and teleseismic earthquakes, our implementation detects 71% and gives a mean difference with manual picks of 0.1 s. An optimal version of the well-established picker of Baer and Kradolfer [Baer, M., Kradolfer, U., An automatic phase picker for local and teleseismic events, Bull. Seism. Soc. Am. 77 (1987) 1437-1445] detects less than 41% and gives a mean difference with manual picks of 0.3 s using the same dataset.

An alternative hypothesis for high-T 40Ar/39Ar age spectrum discordance in polyphase extraterrestrial materials

NASA Astrophysics Data System (ADS)

Cassata, W. S.; Shuster, D. L.; Renne, P. R.; Weiss, B. P.

2009-12-01

A common feature observed in 40Ar/39Ar age spectra of extraterrestrial (ET) rocks is a conspicuous decrease in the ages of high temperature extractions relative to lower temperature steps and a correlated increase in Ca/K, often succeeded by a monotonic increase in ages. This feature is routinely attributed to recoil-implanted 39Ar from a potassium (K)-rich donor phase into a K-poor receptor phase (e.g., 1,2). While 39Ar recoil redistribution is undoubtedly manifested in many terrestrial and ET 40Ar/39Ar whole-rock age spectra, it cannot easily explain the magnitude of high release temperature 40Ar*/39ArK anomalies observed in Martian meteorites ALH 84001 and Nakhla, as well as other course-grained meteorites and lunar rocks. Depending on the aliquot and sample, 50 - 100% of the pyroxene release spectra in ALH 84001 and Nakhla appear strongly perturbed to lower ages. As the mean recoil distance of 39Ar ~0.1 µm, the recoil hypothesis demands that a high-K phase be ubiquitously distributed amongst sub-micron to micron sized pyroxene crystals to account for the observed pyroxene age spectra. However, in both Nakhla and ALH 84001, pyroxene is often completely isolated from high-K phases and individual grains commonly exceed 100 µm in diameter. 40Ar/39Ar analyses of pyroxene-bearing terrestrial basalts, wherein fine-grained pyroxene and plagioclase are intimately adjoined, show that recoil-implanted 39Ar into pyroxene produces much less precipitous anomalies in 40Ar*/39ArK, as predicted by the recoil lengthscale. An alternative hypothesis is that whole-rock age spectra of ET samples with anomalously low ages at high temperatures may reflect diffusive 40Ar distributions within considerably degassed pyroxene grains. Owing to apparent differences in activation energies between glass and/or plagioclase and pyroxene, 40Ar may diffuse more rapidly from pyroxene under certain high-temperature conditions (i.e., above the temperature at which the extrapolated Ar Arrhenius relationships intersect). Thus, very brief, high-temperature shock-heating events may preferentially degas pyroxene without significantly resetting glass and plagioclase 40Ar/39Ar age spectra. This effect would be enhanced by highly localized shock-heating focused along pyroxene (sub)grain boundaries, as has been inferred in other cases (e.g., 3). The shock and impact origin of this feature may explain its frequent appearance in ET samples, regardless of grain size, as well as the general absence of terrestrial analogs. We will present new 40Ar/39Ar data from Martian meteorites and physical models to distinguish between these competing hypotheses. References Cited: 1. Turner & Cadogan, 1974, Possible effects of 39Ar recoil in 40Ar-39Ar dating. Proc. 5th LPSC, 1601- 1615. 2. Huneke & Smith, 1976, The realities of recoil: 39Ar recoil out of small grains and anomalous age patterns in 40Ar-39Ar dating. Proc. 7th LPSC, 1987-2008. 3. Min et al., 2003, Single grain (U-Th)/He ages from phosphates in Acapulco meteorite and implications for thermal history. EPSL 209, 323-336.

Regulatory mechanism of CCN2 production by serotonin (5-HT) via 5-HT2A and 5-HT2B receptors in chondrocytes.

PubMed

Hori, Ayaka; Nishida, Takashi; Takashiba, Shogo; Kubota, Satoshi; Takigawa, Masaharu

2017-01-01

Serotonin (5-hydroxytryptamine: 5-HT) is recognized as a neurotransmitter in the central nerve system and as a regulator of systemic blood pressure in the peripheral tissues. Recently, it was reported that 5-HT2 receptors (5-HT2Rs) were expressed in cartilage tissues lacking both vessels and neurons, suggesting possible novel functions of 5-HT during cartilage development and regeneration. Our previous data indicated that CCN family protein 2/connective tissue growth factor (CCN2/CTGF) plays a central role in cartilage development and regeneration. Therefore, the aim of this study was to investigate the effect of 5-HT on the production of CCN2 in chondrocytes. Firstly, we showed that the mRNAs of 5-HT2R subtypes 5-HT2AR and 5-HT2BR, were expressed in a human chondrocytic cell line, HCS-2/8; however, 5-HT2CR mRNA was not detected. In addition, exogenously added 5-HT did not affect the 5-HT2AR and 5-HT2BR expressions. Next, we demonstrated that CCN2 production was increased by treatment with a 5-HT2AR agonist and the combination of 5-HT and 5-HT2BR antagonist. In contrast, treatment with a 5-HT2BR agonist and the combination of 5-HT and 5-HT2AR antagonist decreased CCN2 production. Furthermore, we showed that phosphorylation of Akt and p38 MAPK were increased by treatment with 5-HT2AR agonist, and that phosphorylation of PKCε, PKCζ, ERK1/2 and JNK were increased by treatment with 5-HT2BR agonist. Finally, we found that 5-HT2AR was localized in the growth plate, whereas 5-HT2BR was localized in the articular cartilage. These findings suggest that 5-HT promotes CCN2 production through the 5-HT2AR in growth plates, and that it represses CCN2 production through the 5-HT2BR in articular cartilage for harmonized development of long bones.

Myosin-1C uses a novel phosphoinositide-dependent pathway for nuclear localization.

PubMed

Nevzorov, Ilja; Sidorenko, Ekaterina; Wang, Weihuan; Zhao, Hongxia; Vartiainen, Maria K

2018-02-01

Accurate control of macromolecule transport between nucleus and cytoplasm underlines several essential biological processes, including gene expression. According to the canonical model, nuclear import of soluble proteins is based on nuclear localization signals and transport factors. We challenge this view by showing that nuclear localization of the actin-dependent motor protein Myosin-1C (Myo1C) resembles the diffusion-retention mechanism utilized by inner nuclear membrane proteins. We show that Myo1C constantly shuttles in and out of the nucleus and that its nuclear localization does not require soluble factors, but is dependent on phosphoinositide binding. Nuclear import of Myo1C is preceded by its interaction with the endoplasmic reticulum, and phosphoinositide binding is specifically required for nuclear import, but not nuclear retention, of Myo1C. Our results therefore demonstrate, for the first time, that membrane association and binding to nuclear partners is sufficient to drive nuclear localization of also soluble proteins, opening new perspectives to evolution of cellular protein sorting mechanisms. © 2018 The Authors. Published under the terms of the CC BY NC ND 4.0 license.

The oestrogen receptor alpha-regulated lncRNA NEAT1 is a critical modulator of prostate cancer.

PubMed

Chakravarty, Dimple; Sboner, Andrea; Nair, Sujit S; Giannopoulou, Eugenia; Li, Ruohan; Hennig, Sven; Mosquera, Juan Miguel; Pauwels, Jonathan; Park, Kyung; Kossai, Myriam; MacDonald, Theresa Y; Fontugne, Jacqueline; Erho, Nicholas; Vergara, Ismael A; Ghadessi, Mercedeh; Davicioni, Elai; Jenkins, Robert B; Palanisamy, Nallasivam; Chen, Zhengming; Nakagawa, Shinichi; Hirose, Tetsuro; Bander, Neil H; Beltran, Himisha; Fox, Archa H; Elemento, Olivier; Rubin, Mark A

2014-11-21

The androgen receptor (AR) plays a central role in establishing an oncogenic cascade that drives prostate cancer progression. Some prostate cancers escape androgen dependence and are often associated with an aggressive phenotype. The oestrogen receptor alpha (ERα) is expressed in prostate cancers, independent of AR status. However, the role of ERα remains elusive. Using a combination of chromatin immunoprecipitation (ChIP) and RNA-sequencing data, we identified an ERα-specific non-coding transcriptome signature. Among putatively ERα-regulated intergenic long non-coding RNAs (lncRNAs), we identified nuclear enriched abundant transcript 1 (NEAT1) as the most significantly overexpressed lncRNA in prostate cancer. Analysis of two large clinical cohorts also revealed that NEAT1 expression is associated with prostate cancer progression. Prostate cancer cells expressing high levels of NEAT1 were recalcitrant to androgen or AR antagonists. Finally, we provide evidence that NEAT1 drives oncogenic growth by altering the epigenetic landscape of target gene promoters to favour transcription.

Retractions. Antioxidants and Redox Signaling (ARS).

PubMed

2012-04-01

Due to the recent findings of an investigation led by the U.S. Office of Research Integrity, and as a direct result of the falsification and manipulation of data in the articles listed below, Antioxidants and Redox Signaling (ARS) is officially retracting the following published papers, authored by Dipak K. Das. 1. Malik G, Gorbounov N, Das S, Gurusamy N, Otani H, Maulik N, Goswami S, Das DK. Ischemic preconditioning triggers nuclear translocation of thioredoxin and its interaction with Ref-1 potentiating a survival signal through the PI-3-kinase-Akt pathway. Antioxid Redox Signal 8:2101-2109, 2006. 2. Muinck ED, Nagy N, Tirziu D, Murakami M, Gurusamy N, Goswami SK, Ghatpande S, Engelman RM, Simons M, Das DK. Protection against myocardial ischemia-reperfusion injury by the angiogenic Masterswitch protein PR 39 gene therapy: the roles of HIF1alpha stabilization and FGFR1 signaling. Antioxid Redox Signal 9:437-445, 2007. These actions reinforce the high standards to which ARS is committed.

The oestrogen receptor alpha-regulated lncRNA NEAT1 is a critical modulator of prostate cancer

PubMed Central

Chakravarty, Dimple; Sboner, Andrea; Nair, Sujit S.; Giannopoulou, Eugenia; Li, Ruohan; Hennig, Sven; Mosquera, Juan Miguel; Pauwels, Jonathan; Park, Kyung; Kossai, Myriam; MacDonald, Theresa Y.; Fontugne, Jacqueline; Erho, Nicholas; Vergara, Ismael A.; Ghadessi, Mercedeh; Davicioni, Elai; Jenkins, Robert B.; Palanisamy, Nallasivam; Chen, Zhengming; Nakagawa, Shinichi; Hirose, Tetsuro; Bander, Neil H.; Beltran, Himisha; Fox, Archa H.; Elemento, Olivier; Rubin, Mark A.

2014-01-01

The androgen receptor (AR) plays a central role in establishing an oncogenic cascade that drives prostate cancer progression. Some prostate cancers escape androgen dependence and are often associated with an aggressive phenotype. The oestrogen receptor alpha (ERα) is expressed in prostate cancers, independent of AR status. However, the role of ERα remains elusive. Using a combination of chromatin immunoprecipitation (ChIP) and RNA-sequencing data, we identified an ERα-specific non-coding transcriptome signature. Among putatively ERα-regulated intergenic long non-coding RNAs (lncRNAs), we identified nuclear enriched abundant transcript 1 (NEAT1) as the most significantly overexpressed lncRNA in prostate cancer. Analysis of two large clinical cohorts also revealed that NEAT1 expression is associated with prostate cancer progression. Prostate cancer cells expressing high levels of NEAT1 were recalcitrant to androgen or AR antagonists. Finally, we provide evidence that NEAT1 drives oncogenic growth by altering the epigenetic landscape of target gene promoters to favour transcription. PMID:25415230

Excess Ar in biotites from the Broderick Falls (Webuye) area, western Kenya: implications for the tectonothermal history of the Mozambique Belt and its Archaean foreland

NASA Astrophysics Data System (ADS)

Shibata, K.; Suwa, K.; Uchiumi, S.; Agata, T.

1996-10-01

RbSr whole rock and KAr mineral age determinations were made on rocks from the Broderick Falls (Webuye) area, western Kenya. Granitic rocks yielded a RbSr whole rock isochron age of 2555 ± 101 Ma with an initial {87Sr}/{86Sr} ratio of 0.70121 ± 0.00038. This age represents the time of granitoid emplacement. KAr mineral ages range from 574 to 3420 Ma, which is very variable with respect to mineral type and locality. Mylonitic granodiorite very close to the Nandi Escarpment gave a KAr age of 916 Ma from biotite, suggesting the time of the activity of the Nandi Fault, which may be an earlier phase of the Pan-African Orogeny. Ages of biotites in a zone between 4 and 6 km northeast of the Nandi Fault are anomalously high compared to those of coexisting hornblende and the RbSr isochron age, confirming the existence of excess 40Ar in biotite. Excess 40Ar was probably introduced into biotite under the appropriate temperature conditions prevailing near the Nandi Fault. Taramite, a rare sodic-calcic amphibole, was found in a cordierite-biotite gneiss of the Kavirondian Supergroup and gave a typical Pan-African KAr age of 574 Ma. The last Pan-African metamorphism occurred in the terrane east of the Surongai Thrust.

MURC/Cavin-4 facilitates recruitment of ERK to caveolae and concentric cardiac hypertrophy induced by α1-adrenergic receptors.

PubMed

Ogata, Takehiro; Naito, Daisuke; Nakanishi, Naohiko; Hayashi, Yukiko K; Taniguchi, Takuya; Miyagawa, Kotaro; Hamaoka, Tetsuro; Maruyama, Naoki; Matoba, Satoaki; Ikeda, Koji; Yamada, Hiroyuki; Oh, Hidemasa; Ueyama, Tomomi

2014-03-11

The actions of catecholamines on adrenergic receptors (ARs) induce sympathetic responses, and sustained activation of the sympathetic nervous system results in disrupted circulatory homeostasis. In cardiomyocytes, α1-ARs localize to flask-shaped membrane microdomains known as "caveolae." Caveolae require both caveolin and cavin proteins for their biogenesis and function. However, the functional roles and molecular interactions of caveolar components in cardiomyocytes are poorly understood. Here, we showed that muscle-restricted coiled-coil protein (MURC)/Cavin-4 regulated α1-AR-induced cardiomyocyte hypertrophy through enhancement of ERK1/2 activation in caveolae. MURC/Cavin-4 was expressed in the caveolae and T tubules of cardiomyocytes. MURC/Cavin-4 overexpression distended the caveolae, whereas MURC/Cavin-4 was not essential for their formation. MURC/Cavin-4 deficiency attenuated cardiac hypertrophy induced by α1-AR stimulation in the presence of caveolae. Interestingly, MURC/Cavin-4 bound to α1A- and α1B-ARs as well as ERK1/2 in caveolae, and spatiotemporally modulated MEK/ERK signaling in response to α1-AR stimulation. Thus, MURC/Cavin-4 facilitates ERK1/2 recruitment to caveolae and efficient α1-AR signaling mediated by caveolae in cardiomyocytes, which provides a unique insight into the molecular mechanisms underlying caveola-mediated signaling in cardiac hypertrophy.

Storm orientation impacts on atmospheric river induced precipitation efficiency

NASA Astrophysics Data System (ADS)

Mehran, A.; Lettenmaier, D. P.

2016-12-01

Atmospheric Rivers (ARs) along the Pacific North coast are often associated with heavy winter precipitation and flooding. We analyze 35 years (1981 2016) of landfalling ARs over a transect along the U.S. West Coast consisting of four river basins from coastal Washington to Southern California (Chehalis, Russian, Santa Ana, and Santa Margarita Rivers) to assess the impact of storm orientation on precipitation rainout efficiency. We define precipitation rainout efficiency as the correlation coefficient between the net integrated vapor transport and precipitation rate. We use 6-hourly climate data from the Climate Forecast System Reanalysis (CFSR) for each of the landfalling ARs. We compute storm orientation from CFSR wind vectors (daily averaged over atmospheric levels between 1000 hPa and 300 hPa) associated with each AR event. We also compute integrated vapor transport (IVT) by multiplying precipitable water by the wind vector and compare with daily averaged precipitation averaged over the river basins, where daily precipitation is taken from Parameter-Elevation Relationships on Independent Slopes Model (PRISM) to evaluate the impact of storm orientation on rainfall efficiency. We calculate the local topographic orientation of each river basin (slope and aspect) from ArcGIS, which we related to storm orientation. To evaluate the impact of storm orientation on rainout efficiency over the Russian River basin (Northern California), we first calculated approaching IVT (for all of AR induced precipitations from 1981 to 2016) and daily averaged precipitation rate. Next, we calculated the correlation coefficient between IVT and precipitation rate (for all AR induced rainouts over the Russian River basin). Finally, by considering the local topographical changes (slope and aspect from ArcGIS) and integrating them into an effective IVT, we compared the correlation coefficients between actual and effective IVT and basin-average precipitation. We find that over the Russian River basin, the rainout efficiency increases from 55 to 75 % when we account for storm orientation relative to topography.

Structure, metamorphism, and geochronology of the Cosmos Hills and Ruby Ridge, Brooks Range schist belt, Alaska

USGS Publications Warehouse

Christiansen, Peter B.; Snee, Lawrence W.

1994-01-01

The boundary of the internal zones of the Brooks Range orogenic belt (the schist belt) is a fault contact that dips toward the hinterland (the Yukon-Koyukuk province). This fault, here referred to as the Cosmos Hills fault zone, juxtaposes oceanic rocks and unmetamorphosed sedimentary rocks structurally above blueschist-to-greenschist facies metamorphic rocks of the schist belt. Near the fault contact, schist belt rocks are increasingly affected by a prominent, subhorizontal transposition foliation that is locally mylonitic in the fault zone. Structural and petrologic observations combined with 40Ar/39Ar incremental-release geochronology give evidence for a polyphase metamorphic and deformational history beginning in the Middle Jurassic and continuing until the Late Cretaceous. Our 40Ar/39Ar cooling age for Jurassic metamorphism is consistent with stratigraphic and other evidence for the onset of Brooks Range orogenesis. Jurassic metamorphism is nearly everywhere overprinted by a regional greenschist-facies event dated at 130–125 Ma. Near the contact with the Cosmos Hills fault zone, the schist belt is increasingly affected by a younger greenschist metamorphism that is texturally related to a prominent foliation that folds and transposes an older fabric. The 40Ar/39Ar results on phengite and fuchsite that define this younger fabric give recrystallization ages ranging from 103 to less than 90 Ma. We conclude that metamorphism that formed the transposition fabric peaked around 100 Ma and may have continued until well after 90 Ma. This age for greenschist metamorphism is broadly synchronous with the depositional age of locally derived, shallow-marine clastic sedimentary strata in the hanging wall of the fault zone and thus substantiates the interpretation that the fault zone accommodated extension in the Late Cretaceous. This extension unroofed and exhumed the schist belt during relative subsidence of the Yukon-Koyukuk province.

Serotype-specific differences in dengue virus non-structural protein 5 nuclear localization.

PubMed

Hannemann, Holger; Sung, Po-Yu; Chiu, Han-Chen; Yousuf, Amjad; Bird, Jim; Lim, Siew Pheng; Davidson, Andrew D

2013-08-02

The four serotypes of dengue virus (DENV-1 to -4) cause the most important arthropod-borne viral disease of humans. DENV non-structural protein 5 (NS5) contains enzymatic activities required for capping and replication of the viral RNA genome that occurs in the host cytoplasm. However, previous studies have shown that DENV-2 NS5 accumulates in the nucleus during infection. In this study, we examined the nuclear localization of NS5 for all four DENV serotypes. We demonstrate for the first time that there are serotypic differences in NS5 nuclear localization. Whereas the DENV-2 and -3 proteins accumulate in the nucleus, DENV-1 and -4 NS5 are predominantly if not exclusively localized to the cytoplasm. Comparative studies on the DENV-2 and -4 NS5 proteins revealed that the difference in DENV-4 NS5 nuclear localization was not due to rapid nuclear export but rather the lack of a functional nuclear localization sequence. Interaction studies using DENV-2 and -4 NS5 and human importin-α isoforms failed to identify an interaction that supported the differential nuclear localization of NS5. siRNA knockdown of the human importin-α isoform KPNA2, corresponding to the murine importin-α isoform previously shown to bind to DENV-2 NS5, did not substantially affect DENV-2 NS5 nuclear localization, whereas knockdown of importin-β did. The serotypic differences in NS5 nuclear localization did not correlate with differences in IL-8 gene expression. The results show that NS5 nuclear localization is not strictly required for virus replication but is more likely to have an auxiliary function in the life cycle of specific DENV serotypes.

Serotype-specific Differences in Dengue Virus Non-structural Protein 5 Nuclear Localization*

PubMed Central

Hannemann, Holger; Sung, Po-Yu; Chiu, Han-Chen; Yousuf, Amjad; Bird, Jim; Lim, Siew Pheng; Davidson, Andrew D.

2013-01-01

The four serotypes of dengue virus (DENV-1 to -4) cause the most important arthropod-borne viral disease of humans. DENV non-structural protein 5 (NS5) contains enzymatic activities required for capping and replication of the viral RNA genome that occurs in the host cytoplasm. However, previous studies have shown that DENV-2 NS5 accumulates in the nucleus during infection. In this study, we examined the nuclear localization of NS5 for all four DENV serotypes. We demonstrate for the first time that there are serotypic differences in NS5 nuclear localization. Whereas the DENV-2 and -3 proteins accumulate in the nucleus, DENV-1 and -4 NS5 are predominantly if not exclusively localized to the cytoplasm. Comparative studies on the DENV-2 and -4 NS5 proteins revealed that the difference in DENV-4 NS5 nuclear localization was not due to rapid nuclear export but rather the lack of a functional nuclear localization sequence. Interaction studies using DENV-2 and -4 NS5 and human importin-α isoforms failed to identify an interaction that supported the differential nuclear localization of NS5. siRNA knockdown of the human importin-α isoform KPNA2, corresponding to the murine importin-α isoform previously shown to bind to DENV-2 NS5, did not substantially affect DENV-2 NS5 nuclear localization, whereas knockdown of importin-β did. The serotypic differences in NS5 nuclear localization did not correlate with differences in IL-8 gene expression. The results show that NS5 nuclear localization is not strictly required for virus replication but is more likely to have an auxiliary function in the life cycle of specific DENV serotypes. PMID:23770669

Nuclear Factor-κB Promotes Urothelial Tumorigenesis and Cancer Progression via Cooperation with Androgen Receptor Signaling.

PubMed

Inoue, Satoshi; Ide, Hiroki; Mizushima, Taichi; Jiang, Guiyang; Netto, George J; Gotoh, Momokazu; Miyamoto, Hiroshi

2018-06-01

We investigated the role of NF-κB in the development and progression of urothelial cancer as well as cross-talk between NF-κB and androgen receptor (AR) signals in urothelial cells. Immunohistochemistry in surgical specimens showed that the expression levels of NF-κB/p65 ( P = 0.015)/phospho-NF-κB/p65 ( P < 0.001) were significantly elevated in bladder tumors, compared with those in nonneoplastic urothelial tissues. The rates of phospho-NF-κB/p65 positivity were also significantly higher in high-grade ( P = 0.015)/muscle-invasive ( P = 0.033) tumors than in lower grade/non-muscle-invasive tumors. Additionally, patients with phospho-NF-κB/p65-positive muscle-invasive bladder cancer had significantly higher risks of disease progression ( P < 0.001) and cancer-specific mortality ( P = 0.002). In immortalized human normal urothelial SVHUC cells stably expressing AR, NF-κB activators and inhibitors accelerated and prevented, respectively, their neoplastic transformation induced by a chemical carcinogen 3-methylcholanthrene. Bladder tumors were identified in 56% (mock), 89% (betulinic acid), and 22% (parthenolide) of N -butyl- N -(4-hydroxybutyl)nitrosamine-treated male C57BL/6 mice at 22 weeks of age. NF-κB activators and inhibitors also significantly induced and reduced, respectively, cell proliferation/migration/invasion of AR-positive bladder cancer lines, but not AR-knockdown or AR-negative lines, and their growth in xenograft-bearing mice. In both nonneoplastic and neoplastic urothelial cells, NF-κB activators/inhibitors upregulated/downregulated, respectively, AR expression, whereas AR overexpression was associated with increases in the expression levels of NF-κB/p65 and phospho-NF-κB/p65. Thus, NF-κB appeared to be activated in bladder cancer, which was associated with tumor progression. NF-κB activators/inhibitors were also found to modulate tumorigenesis and tumor outgrowth in AR-activated urothelial cells. Accordingly, NF-κB inhibition, together with AR inactivation, has the potential of being an effective chemopreventive and/or therapeutic approach for urothelial carcinoma. Mol Cancer Ther; 17(6); 1303-14. ©2018 AACR . ©2018 American Association for Cancer Research.

Nuclear localization of Schizosaccharomyces pombe Mcm2/Cdc19p requires MCM complex assembly.

PubMed

Pasion, S G; Forsburg, S L

1999-12-01

The minichromosome maintenance (MCM) proteins MCM2-MCM7 are conserved eukaryotic replication factors that assemble in a heterohexameric complex. In fission yeast, these proteins are nuclear throughout the cell cycle. In studying the mechanism that regulates assembly of the MCM complex, we analyzed the cis and trans elements required for nuclear localization of a single subunit, Mcm2p. Mutation of any single mcm gene leads to redistribution of wild-type MCM subunits to the cytoplasm, and this redistribution depends on an active nuclear export system. We identified the nuclear localization signal sequences of Mcm2p and showed that these are required for nuclear targeting of other MCM subunits. In turn, Mcm2p must associate with other MCM proteins for its proper localization; nuclear localization of MCM proteins thus requires assembly of MCM proteins in a complex. We suggest that coupling complex assembly to nuclear targeting and retention ensures that only intact heterohexameric MCM complexes remain nuclear.

Nuclear Localization of Schizosaccharomyces pombe Mcm2/Cdc19p Requires MCM Complex Assembly

PubMed Central

Pasion, Sally G.; Forsburg, Susan L.

1999-01-01

The minichromosome maintenance (MCM) proteins MCM2–MCM7 are conserved eukaryotic replication factors that assemble in a heterohexameric complex. In fission yeast, these proteins are nuclear throughout the cell cycle. In studying the mechanism that regulates assembly of the MCM complex, we analyzed the cis and trans elements required for nuclear localization of a single subunit, Mcm2p. Mutation of any single mcm gene leads to redistribution of wild-type MCM subunits to the cytoplasm, and this redistribution depends on an active nuclear export system. We identified the nuclear localization signal sequences of Mcm2p and showed that these are required for nuclear targeting of other MCM subunits. In turn, Mcm2p must associate with other MCM proteins for its proper localization; nuclear localization of MCM proteins thus requires assembly of MCM proteins in a complex. We suggest that coupling complex assembly to nuclear targeting and retention ensures that only intact heterohexameric MCM complexes remain nuclear. PMID:10588642

Pollination Mode and Mating System Explain Patterns in Genetic Differentiation in Neotropical Plants

PubMed Central

Ballesteros-Mejia, Liliana; Lima, Natácia E.; Lima-Ribeiro, Matheus S.

2016-01-01

We studied genetic diversity and differentiation patterns in Neotropical plants to address effects of life history traits (LHT) and ecological attributes based on an exhaustive literature survey. We used generalized linear mixed models (GLMMs) to test the effects as fixed and random factors of growth form, pollination and dispersal modes, mating and breeding systems, geographical range and habitat on patterns of genetic diversity (HS, HeS, π and h), inbreeding coefficient (FIS), allelic richness (AR) and differentiation among populations (FST) for both nuclear and chloroplast genomes. In addition, we used phylogenetic generalized least squares (pGLS) to account for phylogenetic independence on predictor variables and verify the robustness of the results from significant GLMMs. In general, GLMM revealed more significant relationships among LHTs and genetic patterns than pGLS. After accounting for phylogenetic independence (i.e., using pGLS), FST for nuclear microsatellites was significantly related to pollination mode, mating system and habitat. Plants specifically with outcrossing mating system had lower FST. Moreover, AR was significantly related to pollination mode and geographical range and HeS for nuclear dominant markers was significantly related to habitat. Our findings showed that different results might be retrieved when phylogenetic non-independence is taken into account and that LHTs and ecological attributes affect substantially the genetic pattern in Neotropical plants, hence may drive key evolutionary processes in plants. PMID:27472384

Antibiotic Resistance in Animal and Environmental Samples Associated with Small-Scale Poultry Farming in Northwestern Ecuador

PubMed Central

Braykov, Nikolay P.; Eisenberg, Joseph N. S.; Grossman, Marissa; Zhang, Lixin; Vasco, Karla; Cevallos, William; Muñoz, Diana; Acevedo, Andrés; Moser, Kara A.; Marrs, Carl F.; Trostle, James; Trueba, Gabriel

2016-01-01

ABSTRACT The effects of animal agriculture on the spread of antibiotic resistance (AR) are cross-cutting and thus require a multidisciplinary perspective. Here we use ecological, epidemiological, and ethnographic methods to examine populations of Escherichia coli circulating in the production poultry farming environment versus the domestic environment in rural Ecuador, where small-scale poultry production employing nontherapeutic antibiotics is increasingly common. We sampled 262 “production birds” (commercially raised broiler chickens and laying hens) and 455 “household birds” (raised for domestic use) and household and coop environmental samples from 17 villages between 2010 and 2013. We analyzed data on zones of inhibition from Kirby-Bauer tests, rather than established clinical breakpoints for AR, to distinguish between populations of organisms. We saw significantly higher levels of AR in bacteria from production versus household birds; resistance to either amoxicillin-clavulanate, cephalothin, cefotaxime, and gentamicin was found in 52.8% of production bird isolates and 16% of household ones. A strain jointly resistant to the 4 drugs was exclusive to a subset of isolates from production birds (7.6%) and coop surfaces (6.5%) and was associated with a particular purchase site. The prevalence of AR in production birds declined with bird age (P < 0.01 for all antibiotics tested except tetracycline, sulfisoxazole, and trimethoprim-sulfamethoxazole). Farming status did not impact AR in domestic environments at the household or village level. Our results suggest that AR associated with small-scale poultry farming is present in the immediate production environment and likely originates from sources outside the study area. These outside sources might be a better place to target control efforts than local management practices. IMPORTANCE In developing countries, small-scale poultry farming employing antibiotics as growth promoters is being advanced as an inexpensive source of protein and income. Here, we present the results of a large ecoepidemiological study examining patterns of antibiotic resistance (AR) in E. coli isolates from small-scale poultry production environments versus domestic environments in rural Ecuador, where such backyard poultry operations have become established over the past decade. Our previous research in the region suggests that introduction of AR bacteria through travel and commerce may be an important source of AR in villages of this region. This report extends the prior analysis by examining small-scale production chicken farming as a potential source of resistant strains. Our results suggest that AR strains associated with poultry production likely originate from sources outside the study area and that these outside sources might be a better place to target control efforts than local management practices. PMID:27303705

Nuclear import of glucokinase in pancreatic beta-cells is mediated by a nuclear localization signal and modulated by SUMOylation.

PubMed

Johansson, Bente Berg; Fjeld, Karianne; Solheim, Marie Holm; Shirakawa, Jun; Zhang, Enming; Keindl, Magdalena; Hu, Jiang; Lindqvist, Andreas; Døskeland, Anne; Mellgren, Gunnar; Flatmark, Torgeir; Njølstad, Pål Rasmus; Kulkarni, Rohit N; Wierup, Nils; Aukrust, Ingvild; Bjørkhaug, Lise

2017-10-15

The localization of glucokinase in pancreatic beta-cell nuclei is a controversial issue. Although previous reports suggest such a localization, the mechanism for its import has so far not been identified. Using immunofluorescence, subcellular fractionation and mass spectrometry, we present evidence in support of glucokinase localization in beta-cell nuclei of human and mouse pancreatic sections, as well as in human and mouse isolated islets, and murine MIN6 cells. We have identified a conserved, seven-residue nuclear localization signal ( 30 LKKVMRR 36 ) in the human enzyme. Substituting the residues KK 31,32 and RR 35,36 with AA led to a loss of its nuclear localization in transfected cells. Furthermore, our data indicates that SUMOylation of glucokinase modulates its nuclear import, while high glucose concentrations do not significantly alter the enzyme nuclear/cytosolic ratio. Thus, for the first time, we provide data in support of a nuclear import of glucokinase mediated by a redundant mechanism, involving a nuclear localization signal, and which is modulated by its SUMOylation. These findings add new knowledge to the functional role of glucokinase in the pancreatic beta-cell. Copyright © 2017 Elsevier B.V. All rights reserved.

Acrosome reaction inducers impose alterations in repulsive strain and hydration barrier in human sperm membranes.

PubMed

Purohit, S B; Laloraya, M; Kumar, G P

1998-06-01

Spin labeling studies of the lipophilic domains of human spermatozoa during capacitation and during acrosome reaction (AR) under the influence of selected AR-inducers were performed. Significantly enhanced rotational function of molecules was obvious during capacitation, with no significant changes in membrane packaging or the lateral diffusion of molecules. The AR inducers appeared to restrict the rotational freedom of molecules, dramatically enhancing the lateral diffusion and ordering coefficients. A significant decrease in superoxide anion generation was observed in the acrosome reacted groups when compared to the non-acrosome reacted groups. A high level of superoxide anion radical (O2.-) level maintained in capacitated spermatozoa would add to the Van der Waal's repulsive forces at the polar head of phospholipids, holding the membrane in strain where the molecular enjoy little freedom for lateral motion. A sudden drop in the levels of O2.- in spermatozoa upon addition of AR inducers could abruptly release the local hydrophobic repulsive strain within the membrane. This loss of hydration barrier explains the observed enhancement in lateral diffusion profiles of lipids and the packaging of molecules. It is reasonable to assume that these phenomena could be amplified further by interplay of Ca2+ by modifying the local charge aggregation. Thus, we would conclude that AR inducers release the oxyradical load in capacitated spermatozoa, which would modify the repulsive strain and hydration barrier forces in the lipophilic domains permitting vesiculation of the membranes. It appears that various acrosome reaction inducers act as effectors of grossly similar physical alterations in sperm membranes and that the resulting signal cascades proceed through intercalating biochemical sequences.

Human testicular protein TPX1/CRISP-2: localization in spermatozoa, fate after capacitation and relevance for gamete interaction.

PubMed

Busso, D; Cohen, D J; Hayashi, M; Kasahara, M; Cuasnicú, P S

2005-04-01

Testicular protein Tpx-1, also known as CRISP-2, is a cysteine-rich secretory protein specifically expressed in the male reproductive tract. Since the information available on the human protein is limited to the identification and expression of its gene, in this work we have studied the presence and localization of human Tpx-1 (TPX1) in sperm, its fate after capacitation and acrosome reaction (AR), and its possible involvement in gamete interaction. Indirect immunofluorescence studies revealed the absence of significant staining in live or fixed non-permeabilized sperm, in contrast to a clear labelling in the acrosomal region of permeabilized sperm. These results, together with complementary evidence from protein extraction procedures strongly support that TPX1 would be mainly an intra-acrosomal protein in fresh sperm. After in vitro capacitation and ionophore-induced AR, TPX1 remained associated with the equatorial segment of the acrosome. The lack of differences in the electrophoretic mobility of TPX1 before and after capacitation and AR indicates that the protein would not undergo proteolytical modifications during these processes. The possible involvement of TPX1 in gamete interaction was evaluated by the hamster oocyte penetration test. The presence of anti-TPX1 during gamete co-incubation produced a significant and dose-dependent inhibition in the percentage of penetrated zona-free hamster oocytes without affecting sperm motility, the AR or sperm binding to the oolema. Together, these results indicate that human TPX1 would be a component of the sperm acrosome that remains associated with sperm after capacitation and AR, and is relevant for sperm-oocyte interaction.

Alpha1-adrenergic receptor blockade in the VTA modulates fear memories and stress responses.

PubMed

Solecki, Wojciech B; Szklarczyk, Klaudia; Klasa, Adam; Pradel, Kamil; Dobrzański, Grzegorz; Przewłocki, Ryszard

2017-08-01

Activity of the ventral tegmental area (VTA) and its terminals has been implicated in the Pavlovian associative learning of both stressful and rewarding stimuli. However, the role of the VTA noradrenergic signaling in fear responses remains unclear. We aimed to examine how alpha 1 -adrenergic receptor (α 1 -AR) signaling in the VTA affects conditioned fear. The role of α 1 -AR was assessed using the micro-infusions into the VTA of the selective antagonists (0.1-1µg/0.5µl prazosin and 1µg/0.5µl terazosin) in acquisition and expression of fear memory. In addition, we performed control experiments with α 1 -AR blockade in the mammillary bodies (MB) - a brain region with α 1 -AR expression adjacent to the VTA. Intra-VTA but not intra-MB α 1 -AR blockade prevented formation and retrieval of fear memories. Importantly, local administration of α 1 -AR antagonists did not influence footshock sensitivity, locomotion or anxiety-like behaviors. Similarly, α 1 -AR blockade in the VTA had no effects on negative affect measured as number of 22kHz ultrasonic vocalizations during fear conditioning training. We propose that noradrenergic signaling in the VTA via α 1 -AR regulates formation and retrieval of fear memories but not other behavioral responses to stressful environmental stimuli. It enhances the encoding of environmental stimuli by the VTA to form and retrieve conditioned fear memories and to predict future behavioral outcomes. Our results provide novel insight into the role of the VTA α 1 -AR signaling in the regulation of stress responsiveness and fear memory. Copyright © 2017 Elsevier B.V. and ECNP. All rights reserved.

Preclinical Efficacy and Safety Assessment of Artemisinin-Chemotherapeutic Agent Conjugates for Ovarian Cancer.

PubMed

Li, Xiaoguang; Zhou, Yu; Liu, Yanling; Zhang, Xu; Chen, Tao; Chen, Kerong; Ba, Qian; Li, Jingquan; Liu, Hong; Wang, Hui

2016-12-01

Artemisinin (ARS) and its derivatives, which are clinically used antimalarial agents, have shown antitumor activities. Their therapeutic potencies, however, are limited by their low solubility and poor bioavailability. Here, through a pharmacophore hybridization strategy, we synthesized ARS-drug conjugates, in which the marketed chemotherapeutic agents chlorambucil, melphalan, flutamide, aminoglutethimide, and doxifluridine, were separately bonded to Dihydroartemisinin (DHA) through various linkages. Of these, the artemisinin-melphalan conjugate, ARS4, exhibited most toxicity to human ovarian cancer cells but had low cytotoxicity to normal cells. ARS4 inhibited the growth and proliferation of ovarian cancer cells and resulted in S-phase arrest, apoptosis, and inhibition of migration; these effects were stronger than those of its parent drugs, DHA and melphalan. Furthermore, ARS4 modulated the expression of proteins involved in cell cycle progression, apoptosis, and the epithelial-mesenchymal transition (EMT). Moreover, in mice, ARS4 inhibited growth and intraperitoneal dissemination and metastasis of ovarian cancer cells without observable toxic effects. Our results provide a basis for development of the compound as a chemotherapeutic agent. Artemisinin compounds have recently received attention as anticancer agents because of their clinical safety profiles and broad efficacy. However, their therapeutic potencies are limited by low solubility and poor bioavailability. Here, we report that ARS4, an artemisinin-melphalan conjugate, possesses marked in-vitro and in-vivo antitumor activity against ovarian cancer, the effects of which are stronger than those for its parent drugs, Dihydroartemisinin and melphalan. In mice, ARS4 inhibits localized growth of ovarian cancer cells and intraperitoneal dissemination and metastasis without appreciable host toxicity. Thus, for patients with ovarian cancer, ARS4 is a promising chemotherapeutic agent. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Relationships Between Photospheric Flows and Solar Flares

NASA Astrophysics Data System (ADS)

Welsch, B. T.; Li, Y.

2013-12-01

Fourier Local Correlation Tracking (FLCT) has been applied to the entire database of 96-minute cadence line-of-sight (LOS) magnetograms from the SOHO/MDI mission, to derive photospheric transverse velocities (u_x,u_y). In a previous study, we applied FLCT to a few dozen active regions (ARs), and found that the "proxy Poynting flux" (PPF) --- the product u B^2, where u is the FLCT flow speed and B is the LOS field divided by the cosine of viewing angle, integrated over each AR --- was statistically related to flare activity. We will present preliminary results of our investigation of the relationship between PPF and flare activity from NOAA's GOES catalog for several hundred ARs identified in NOAA's daily Solar Region Summaries.

Conducting the Softer Side of Counterinsurgency

DTIC Science & Technology

2008-12-01

Donini , Larry Minear, Ian Smillie, Ted van Baarda and Anthony and Welch, Mapping the Security...Content Analysis Matrix In fo rm at io n O pe ra tio n S itu at io na l A w ar en es s C ul tu ra l A w ar en es s E m pa th y C om m an d In...Journal, no. JUL-AUG (2008): 42-44, 43. 90 Donini et al., Mapping the Security Environment: Understanding the perceptions of local communities,

Comprehensive Synchronization Elimination for Java (PREPRINT)

DTIC Science & Technology

2003-01-01

e : % thread-local % reentrant % enclosed Figure...0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 ca ss ow ar y ja va c ja va cu p ja va do c jg l jle x pi zz a ar ra y in st an td b jlo go pl as m a sl ic e Figure 6...1998. [DR98] P. Diniz and M. Rinard. Lock Coarsening: Eliminating Lock Overhead in Automatically Parallelized Object-based Programs. In Journal

Assessment of WWMCCS Performance in a Post-Nuclear Attack Environment. Sanitized

DTIC Science & Technology

1975-11-01

34cONTRACT No. 001-75-C-0217 * 1 THIS WORK SPONSOQRED BY THE DEFENSE NUCLEAR AGENC" UNDER RDT&E RMSS CODE X36075669 Q94OAXDDO01O1 H2590D. Pr p r d 1 rTHIS DOCUM...8217 < : " ! , . .I/• I V...... .... . . . . . . 1 "- 7 . . . • .tEPORT DOCJMENTATION PAGE "rAr, . Irt’. ±~ATSSIS9.C.7NF VMC EPPINEI 21 Jan 75-31 Oc- 75 IOST-I.CLLEA...U .. 4II4 .i %Iy•11 .4 @$ . .~ *󈧯.I . 1 . S $P.IL%-V ka"I 1 "- This work sponsored by the Defe.xse Nuclear Agency under %DT&E WISS Code X360075469 Q9

Nuclear Data Sheets for A=40

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, Jun

The experimental nuclear structure data and decay data are evaluated for the known nuclides of mass 40 (Mg, Al, Si, P, S, Cl, Ar, K, Ca, Sc, Ti). Detailed evaluated nuclear structure information is presented with the best values recommended for level energies, half-lives, γ-ray energies and intensities, decay properties (energies, intensities and placement of radiations), and other spectroscopic data. The {sup 40}Ca and {sup 40}K nuclides remain as the most extensively studied from many different reactions and decays; no excited states are known in {sup 40}Mg, {sup 40}Al, {sup 40}P and {sup 40}Ti. This work supersedes the earlier fullmore » evaluation of A=40 by J. Cameron and B. Singh (2004Ca38).« less

32 CFR 516.78 - Status, fees, and expenses.

Code of Federal Regulations, 2010 CFR

2010-07-01

... PUBLIC RELATIONS LITIGATION Soldiers Summoned To Serve on State and Local Juries § 516.78 Status, fees, and expenses. (a) Soldiers who are required to comply with summons to serve on state or local juries will be placed on permissive TDY under the provisions of AR 630-5. (b) Jury fees accruing to soldiers...

Marker-Based Multi-Sensor Fusion Indoor Localization System for Micro Air Vehicles.

PubMed

Xing, Boyang; Zhu, Quanmin; Pan, Feng; Feng, Xiaoxue

2018-05-25

A novel multi-sensor fusion indoor localization algorithm based on ArUco marker is designed in this paper. The proposed ArUco mapping algorithm can build and correct the map of markers online with Grubbs criterion and K-mean clustering, which avoids the map distortion due to lack of correction. Based on the conception of multi-sensor information fusion, the federated Kalman filter is utilized to synthesize the multi-source information from markers, optical flow, ultrasonic and the inertial sensor, which can obtain a continuous localization result and effectively reduce the position drift due to the long-term loss of markers in pure marker localization. The proposed algorithm can be easily implemented in a hardware of one Raspberry Pi Zero and two STM32 micro controllers produced by STMicroelectronics (Geneva, Switzerland). Thus, a small-size and low-cost marker-based localization system is presented. The experimental results show that the speed estimation result of the proposed system is better than Px4flow, and it has the centimeter accuracy of mapping and positioning. The presented system not only gives satisfying localization precision, but also has the potential to expand other sensors (such as visual odometry, ultra wideband (UWB) beacon and lidar) to further improve the localization performance. The proposed system can be reliably employed in Micro Aerial Vehicle (MAV) visual localization and robotics control.

Polymer Characterization by 13C Nuclear Magnetic Resonance (NMR) spectroscopy: Acryloid K125-EA and High Molecular Weight PIBM

DTIC Science & Technology

1980-02-01

average sequence length Butyl acrylate Methyl methacrylate PIBM Carbon-13 Monomer distribution PMMA (Continued on reverse side) 120. ASTACT (VC•T e m...TACTEC Attic SARPH.FTA 1 505 KIng Avenue Ihlle ithlt, AR 71611 Columbus, OH 43201 US ARMY TRAINING & DOCTRINE COMMAND Director or Toxicology

Distribution of androgen receptor mRNA expression in vocal, auditory, and neuroendocrine circuits in a teleost fish.

PubMed

Forlano, Paul M; Marchaterre, Margaret; Deitcher, David L; Bass, Andrew H

2010-02-15

Across all major vertebrate groups, androgen receptors (ARs) have been identified in neural circuits that shape reproductive-related behaviors, including vocalization. The vocal control network of teleost fishes presents an archetypal example of how a vertebrate nervous system produces social, context-dependent sounds. We cloned a partial cDNA of AR that was used to generate specific probes to localize AR expression throughout the central nervous system of the vocal plainfin midshipman fish (Porichthys notatus). In the forebrain, AR mRNA is abundant in proposed homologs of the mammalian striatum and amygdala, and in anterior and posterior parvocellular and magnocellular nuclei of the preoptic area, nucleus preglomerulosus, and posterior, ventral and anterior tuberal nuclei of the hypothalamus. Many of these nuclei are part of the known vocal and auditory circuitry in midshipman. The midbrain periaqueductal gray, an essential link between forebrain and hindbrain vocal circuitry, and the lateral line recipient nucleus medialis in the rostral hindbrain also express abundant AR mRNA. In the caudal hindbrain-spinal vocal circuit, high AR mRNA is found in the vocal prepacemaker nucleus and along the dorsal periphery of the vocal motor nucleus congruent with the known pattern of expression of aromatase-containing glial cells. Additionally, abundant AR mRNA expression is shown for the first time in the inner ear of a vertebrate. The distribution of AR mRNA strongly supports the role of androgens as modulators of behaviorally defined vocal, auditory, and neuroendocrine circuits in teleost fish and vertebrates in general. 2009 Wiley-Liss, Inc.

Effects of a Proteasome Inhibitor on Cardiomyocytes in a Pressure-Overload Hypertrophy Rat Model: An Animal Study.

PubMed

Kim, In-Sub; Jo, Won-Min

2017-06-01

The ubiquitin-proteasome system (UPS) is an important pathway of proteolysis in pathologic hypertrophic cardiomyocytes. We hypothesize that MG132, a proteasome inhibitor, might prevent hypertrophic cardiomyopathy (CMP) by blocking the UPS. Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and androgen receptor (AR) have been reported to be mediators of CMP and heart failure. This study drew upon pathophysiologic studies and the analysis of NF-κB and AR to assess the cardioprotective effects of MG132 in a left ventricular hypertrophy (LVH) rat model. We constructed a transverse aortic constriction (TAC)-induced LVH rat model with 3 groups: sham (TAC-sham, n=10), control (TAC-cont, n=10), and MG132 administration (TAC-MG132, n=10). MG-132 (0.1 mg/kg) was injected for 4 weeks in the TAC-MG132 group. Pathophysiologic evaluations were performed and the expression of AR and NF-κB was measured in the left ventricle. Fibrosis was prevalent in the pathologic examination of the TAC-cont model, and it was reduced in the TAC-MG132 group, although not significantly. Less expression of AR, but not NF-κB, was found in the TAC-MG132 group than in the TAC-cont group (p<0.05). MG-132 was found to suppress AR in the TAC-CMP model by blocking the UPS, which reduced fibrosis. However, NF-κB expression levels were not related to UPS function.

Resveratrol, 4′ Acetoxy Resveratrol, R-equol, Racemic Equol or S-equol as Cosmeceuticals to Improve Dermal Health

PubMed Central

Lephart, Edwin D.

2017-01-01

Phytochemicals are botanical compounds used in dermatology applications as cosmeceuticals to improve skin health. Resveratrol and equol are two of the best-known polyphenolic or phytoestrogens having similar chemical structures and some overlapping biological functions to 17β-estradiol. Human skin gene expression was reviewed for 28 different biomarkers when resveratrol, 4′ acetoxy resveratrol (4AR), R-equol, racemic equol or S-equol were tested. Sirtuin 1 activator (SIRT 1) was stimulated by resveratrol and 4AR only. Resveratrol, R-equol and racemic equol were effective on the aging biomarkers proliferating cell nuclear factor (PCNA), nerve growth factor (NGF), 5α-reductase and the calcium binding proteins S100 A8 and A9. Racemic equol and 4AR displayed among the highest levels for the collagens, elastin and tissue inhibitor of the matrix metalloproteinase 1 (TIMP 1). S-equol displayed the lowest level of effectiveness compared to the other compounds. The 4AR analog was more effective compared to resveratrol by 1.6-fold. R-equol and racemic equol were almost equal in potency displaying greater inhibition vs. resveratrol or its 4′ analog for the matrix metalloproteinases (MMPs), but among the inflammatory biomarkers, resveratrol, 4AR, R-equol and racemic equol displayed high inhibition. Thus, these cosmeceuticals display promise to improve dermal health; however, further study is warranted to understand how phytochemicals protect/enhance the skin. PMID:28587197

Adipogenesis stimulates the nuclear localization of EWS with an increase in its O-GlcNAc glycosylation in 3T3-L1 cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Qiang; Kamemura, Kazuo, E-mail: k_kamemura@nagahama-i-bio.ac.jp

2014-07-18

Highlights: • The majority of EWS localizes stably in the cytosol in 3T3-L1 preadipocytes. • Adipogenic stimuli induce the nuclear localization of EWS. • Adipogenesis promotes O-GlcNAcylation of EWS. • O-GlcNAcylation stimulates the recruitment of EWS to the nuclear periphery. - Abstract: Although the Ewing sarcoma (EWS) proto-oncoprotein is found in the nucleus and cytosol and is associated with the cell membrane, the regulatory mechanisms of its subcellular localization are still unclear. Here we found that adipogenic stimuli induce the nuclear localization of EWS in 3T3-L1 cells. Tyrosine phosphorylation in the C-terminal PY-nuclear localization signal of EWS was negative throughoutmore » adipogenesis. Instead, an adipogenesis-dependent increase in O-linked β-N-acetylglucosamine (O-GlcNAc) glycosylation of EWS was observed. Pharmacological inactivation of O-GlcNAcase in preadipocytes promoted perinuclear localization of EWS. Our findings suggest that the nuclear localization of EWS is partly regulated by the glycosylation.« less

Mass Measurements Demonstrate a Strong N = 28 Shell Gap in Argon

DOE PAGES

Meisel, Z.; George, S.; Ahn, S.; ...

2015-01-15

We present results from recent time-of-flight nuclear mass measurements at the National Superconducting Cyclotron Laboratory at Michigan State University. We report the first mass measurements of 48Ar and 49Ar and find atomic mass excesses of -22.28(31) MeV and -17.8(1.1) MeV, respectively. These masses provide strong evidence for the closed shell nature of neutron number N = 28 in argon, which is therefore the lowest even-Z element exhibiting the N = 28 closed shell. The resulting trend in binding-energy differences, which probes the strength of the N = 28 shell, compares favorably with shell-model calculations in the sd-pf shell using SDPF-Umore » and SDPF-MU Hamiltonians.« less

Image analysis of androgen receptor immunostaining in metastatic prostate cancer. Heterogeneity as a predictor of response to hormonal therapy.

PubMed

Sadi, M V; Barrack, E R

1993-04-15

Reliable predictors of the response of prostate cancer to androgen ablation therapy are lacking. The goals of this study were to determine whether nuclear androgen receptor (AR) concentrations in metastatic prostate cancer varied within and between specimens and to correlate this information with the response to therapy. AR concentration was evaluated by computer-assisted image analysis of immunohistochemical staining intensity in 200 malignant epithelial nuclei of each of 17 specimens of Stage D2 prostate cancer obtained before hormonal therapy. The data were correlated with the time to tumor progression (relapse) after hormonal therapy. AR staining intensity varied within specimens, and the variance of staining intensity was significantly greater (P = 0.03) in the poor responders (n = 8; time to progression, < 20 months) than in the good responders (n = 9; time to progression, > or = 20 months). The kurtosis was significantly lower in poor responders (P = 0.04). However, the mean AR staining intensity was not significantly different among patients. The frequency distribution plots of good responders were generally uniform and unimodal, but those of poor responders were flattened (more platykurtic), dispersed, and highly variable. Thus, the AR concentration per cell was significantly more heterogeneous in poor responders. Variance was a significant predictor of response. Five of 6 patients with a high variance (defined as variance greater than the mean) were poor responders, whereas 8 of 11 patients with a low variance were good responders (an overall classification accuracy of 13 of 17, 76%). The greater AR heterogeneity in poor responders may reflect a greater genetic instability in tumors that have progressed further toward androgen independence and may be a valuable predictor of progression.

Suppression of osteoclastogenesis via α2-adrenergic receptors

PubMed Central

Hamajima, Kosuke; Hamamura, Kazunori; Chen, Andy; Yokota, Hiroki; Mori, Hironori; Yo, Shoyoku; Kondo, Hisataka; Tanaka, Kenjiro; Ishizuka, Kyoko; Kodama, Daisuke; Hirai, Takao; Miyazawa, Ken; Goto, Shigemi; Togari, Akifumi

2018-01-01

The sympathetic nervous system is known to regulate osteoclast development. However, the involvement of α2-adrenergic receptors (α2-ARs) in osteoclastogenesis is not well understood. In the present study, their potential role in osteoclastogenesis was investigated. Guanabenz, clonidine and xylazine were used as agonists of α2-ARs, while yohimbine and idazoxan were employed as antagonists. Using RAW264.7 pre-osteoclast and primary bone marrow cells, the mRNA expression of the osteoclast-related genes nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), tartrate-resistant acid phosphatase (TRAP) and cathepsin K was evaluated following induction with receptor activator of nuclear factor κB ligand (RANKL). TRAP staining was also conducted to assess effects on osteoclastogenesis in mouse bone marrow cells in vitro. Administration of 5–20 µM guanabenz (P<0.01, for RANKL-only treatment), 20 µM clonidine (P<0.05, for RANKL-only treatment) and 20 µM xylazine (P<0.05, for RANKL-only treatment) attenuated RANKL-induced upregulation of NFATc1, TRAP and cathepsin K mRNA. Furthermore, the reductions in these mRNAs by 10 µM guanabenz and 20 µM clonidine in the presence of RANKL were attenuated by 20 µM yohimbine or idazoxan (P<0.05). The administration of 5–20 µM guanabenz (P<0.01, for RANKL-only treatment) and 10–20 µM clonidine (P<0.05, for RANKL-only treatment) also decreased the number of TRAP-positive multi-nucleated osteoclasts. Collectively, the present study demonstrates that α2-ARs may be involved in the regulation of osteoclastogenesis. PMID:29725523

Sex differences in neuromuscular androgen receptor expression and sociosexual behavior in a sex changing fish

PubMed Central

Pradhan, Devaleena S.; Thonkulpitak, Kevin; Drilling, Cathleen; Black, Michael; Grober, Matthew S.

2017-01-01

Androgen signaling, via receptor binding, is critical for regulating the physiological and morphological foundations of male-typical reproductive behavior in vertebrates. Muscles essential for male courtship behavior and copulation are highly sensitive to androgens. Differences in the distribution and density of the androgen receptor (AR) are important for maintaining dimorphic musculature and thus may provide for anatomical identification of sexually selected traits. In Lythrypnus dalli, a bi-directional hermaphroditic teleost fish, both sexes produce agonistic approach displays, but reproductive behavior is sexually dimorphic. The male-specific courtship behavior is characterized by rapid jerky movements (involving dorsal fin erection) towards a female or around their nest. Activation of the supracarinalis muscle is involved in dorsal fin contributions to both agonistic and sociosexual behavior in other fishes, suggesting that differences in goby sexual behavior may be reflected in sexual dimorphism in AR signaling in this muscle. We examined sex differences in the local distribution of AR in supracarinalis muscle and spinal cord. Our results demonstrate that males do express more AR in the supracarinalis muscle relative to females, but there was no sex difference in the number of spinal motoneurons expressing AR. Interestingly, AR expression in the supracarinalis muscle was also related to rates of sociosexual behavior in males, providing evidence that sexual selection may influence muscle androgenic sensitivity to enhance display vigor. Sex differences in the distribution and number of cells expressing AR in the supracarinalis muscle may underlie the expression of dimorphic behaviors in L. dalli. PMID:28520775

High androgen receptor immunoexpression in human "Sertoli cell only" testis.

PubMed

Loukil, L Hadjkacem; Boudawara, T Sellami; Ayadi, I; Bahloul, A; Jlidi, R; Ayadi, H; Keskes, L Ammar

2005-01-01

Our purpose was to evaluate cellular androgen receptor (AR) distribution and intensity of immunostaining in the human azoospermic testis. Thirty six biopsy specimens from azoospermic men were immunostained, using a monoclonal antibody of human AR. The localization and the intensity of AR immunostaining was evaluated in Sertoli Cell Only (SCO) testis (G1, n = 21), in spermatogenesis arrest testis (G2, n = 11) and in histologically normal testis (G3, n = 4). We found an AR immunostaining in Sertoli, peritubular myoid and Leydig cells, but not in germ cells. The intensity of the immunostaining varied substantially between biopsy specimens of different patients. Sertoli and Leydig cells AR immunostaining (score and intensity) in SCO group was higher than in the other groups. For Sertoli cells, the score means of AR immunoreactivity were 20 +/- 2.36, 10.18 +/- 1.0 and 1 +/- 1, for G1, G2 and G3 groups, respectively. For Leydig cells, the score means were 10.24 +/- 1.37, 6 +/- 0.71 and 0, for G1, G2 and G3 groups, respectively. We found significant differences between G1 and G2 (p = 0.0008), between G1 and G3 (p = 1.54 10-7) and G2 and G3 (p = 0.00032). These results suggest that in the testis AR is located exclusively in somatic cells and its expression is higher in SCO syndrome than in normal and in arrest spermatogenesis testes.

Targeting congestion in allergic rhinitis: the importance of intranasal corticosteroids.

PubMed

Marple, Bradley F

2008-01-01

The cardinal nasal symptoms of allergic rhinitis (AR) are sustained by an underlying inflammatory process. Congestion is one of the most prominent and distressing symptoms for patients and is strongly associated with a broadly deteriorated quality of life and significant losses in productivity. The purpose of this study was to explore the role of intranasal corticosteroids (INSs) in down-regulating the inflammatory response to allergen and their clinical efficacy on AR symptoms, particularly congestion. AR is characterized by an influx of inflammatory cells and mediators into the nasal mucosa after antigen exposure. The response is biphasic, encompassing an early and a late phase. Antigen exposure has a priming effect, decreasing the threshold for subsequent allergic reaction on rechallenge and increasing the responsiveness of the nasal mucosa. INSs are a mainstay of therapy for AR and the most effective intervention for nasal congestion and other nasal symptoms, with established superiority to antihistamines, decongestants, and leukotriene antagonists. In addition to symptom relief, INSs suppress numerous stages of the inflammatory cascade, inhibiting the influx of inflammatory cells and mediators. Topical nasal corticosteroids have a low incidence of local adverse effects, negligible systemic absorption, and excellent safety. Congestion is one of the most bothersome symptoms of AR. INS therapy improves AR symptoms, with particular efficacy in relieving congestion, by attenuating nasal hyperresponsiveness. Pretreatment with INSs has been shown to relieve early and late-phase clinical symptoms of AR. Modification of the disease process results in significant relief of symptoms and leads to fewer disease exacerbations.

ADRA2A is involved in neuro-endocrine regulation of bone resorption.

PubMed

Mlakar, Vid; Jurkovic Mlakar, Simona; Zupan, Janja; Komadina, Radko; Prezelj, Janez; Marc, Janja

2015-07-01

Adrenergic stimulation is important for osteoclast differentiation and bone resorption. Previous research shows that this happens through β2-adrenergic receptor (AR), but there are conflicting evidence on presence and role of α2A-AR in bone. The aim of this study was to investigate the presence of α2A-AR and its involvement in neuro-endocrine signalling of bone remodelling in humans. Real-time polymerase chain reaction (PCR) and immunohistochemistry were used to investigate α2A-AR receptor presence and localization in bone cells. Functionality of rs553668 and rs1800544 single nucleotide polymorphism SNPs located in α2A-AR gene was analysed by qPCR expression on bone samples and luciferase reporter assay in human osteosarcoma HOS cells. Using real-time PCR, genetic association study between rs553668 A>G and rs1800544 C>G SNPs and major bone markers was performed on 661 Slovenian patients with osteoporosis. α2A-AR is expressed in osteoblasts and lining cells but not in osteocytes. SNP rs553668 has a significant influence on α2A-AR mRNA level in human bone samples through the stability of mRNA. α2A-AR gene locus associates with important bone remodelling markers (BMD, CTX, Cathepsin K and pOC). The results of this study are providing comprehensive new evidence that α2A-AR is involved in neuro-endocrine signalling of bone turnover and development of osteoporosis. As shown by our results the neurological signalling is mediated through osteoblasts and result in bone resorption. Genetic study showed association of SNPs in α2A-AR gene locus with bone remodelling markers, identifying the individuals with higher risk of development of osteoporosis. © 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

The 40Ar/39Ar age record and geodynamic significance of Indo-Madagascar and Deccan flood basalt volcanism in the Sarnu-Dandali alkaline complex, Rajasthan, northwestern India

NASA Astrophysics Data System (ADS)

Vijayan, Anjali; Pande, Kanchan; Sheth, Hetu; Kant Sharma, Kamal

2017-04-01

The Sarnu-Dandali alkaline complex in Rajasthan, northwestern India, is considered to represent early, pre-tholeiite magmatism in the Deccan Traps continental flood basalt (CFB) province, based on a single 40Ar/39Ar age of 68.57 Ma. Rhyolites found in the complex are considered to be 750 Ma Malani basement. Our new 40Ar/39Ar ages of 88.9-86.8 Ma (for syenites, nephelinite, phonolite and rhyolite) and 66.3 ± 0.4 Ma (2σ, melanephelinite) provide clear evidence that whereas the Sarnu-Dandali complex has Deccan-age components, it is dominantly an older (by ˜20 million years) alkaline complex, with rhyolites included. Sarnu-Dandali is thus an alkaline igneous center active at least twice in the Late Cretaceous, and also much before as suggested by a basalt flow underlying the Early Cretaceous Sarnu Sandstone. The 89-86 Ma 40Ar/39Ar ages fully overlap with those for the Indo-Madagascar CFB province formed during continental break-up between India (plus Seychelles) and Madagascar. Recent 40Ar/39Ar work has shown polychronous emplacement (over ≥ 45 million years) of the Mundwara alkaline complex in Rajasthan, 100 km from Sarnu-Dandali, and 84-80 Ma ages obtained from Mundwara also arguably represent late stages of the Indo-Madagascar CFB volcanism. Remnants of the Indo-Madagascar CFB province are known from several localities in southern India but hitherto unknown from northwestern India 2000 km away. Additional equivalents buried under the vast Deccan Traps are highly likely. We relate the Sarnu-Dandali and Mundwara complexes to decompression melting of ancient, subduction-fluxed, enriched mantle lithosphere due to periodic lithospheric extension during much of the Cretaceous, and hundreds of kilometers inland from the India-Madagascar and India-Seychelles rifted margins.

40Ar/ 39Ar dating of Late Permian evaporites, southeastern New Mexico, USA

NASA Astrophysics Data System (ADS)

Renne, Paul R.; Sharp, Warren D.; Montañez, Isabel P.; Becker, Tim A.; Zierenberg, Robert A.

2001-12-01

40Ar/ 39Ar dating of the potassium-magnesium sulfate mineral langbeinite from Permian evaporites of the Salado formation near Carlsbad, New Mexico, provides quantitative evidence that some salts in these deposits have not recrystallized for 251 Myr since deposition. Survival of Permian salts supports the possibility that Bacillus bacteria recovered from nearby halite was isolated in a closed system and represents a sample of uncontaminated Permian life. Local recrystallization of langbeinite and other nearby minerals is also indicated by the dating, suggesting both the need and the opportunity to document closed system behavior more rigorously. The shoaling and desiccation event recorded by the Salado formation began at least 1 Myr before the Permian-Triassic boundary. Temporal correlation of the Salado with the Zechstein evaporites of north-central Europe supports previously inferred regression models for the origin of these deposits. Significant paleoenvironmental change at the Permian-Triassic boundary thus occurred on a time scale more protracted than that implied by geologically instantaneous events such as bolide impacts.

Augmented Reality Tool for the Situational Awareness Improvement of UAV Operators

PubMed Central

Ruano, Susana; Cuevas, Carlos; Gallego, Guillermo; García, Narciso

2017-01-01

Unmanned Aerial Vehicles (UAVs) are being extensively used nowadays. Therefore, pilots of traditional aerial platforms should adapt their skills to operate them from a Ground Control Station (GCS). Common GCSs provide information in separate screens: one presents the video stream while the other displays information about the mission plan and information coming from other sensors. To avoid the burden of fusing information displayed in the two screens, an Augmented Reality (AR) tool is proposed in this paper. The AR system has two functionalities for Medium-Altitude Long-Endurance (MALE) UAVs: route orientation and target identification. Route orientation allows the operator to identify the upcoming waypoints and the path that the UAV is going to follow. Target identification allows a fast target localization, even in the presence of occlusions. The AR tool is implemented following the North Atlantic Treaty Organization (NATO) standards so that it can be used in different GCSs. The experiments show how the AR tool improves significantly the situational awareness of the UAV operators. PMID:28178189

Campaign datasets for ARM Cloud Aerosol Precipitation Experiment (ACAPEX)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Leung, L. Ruby; Mei, Fan; Comstock, Jennifer

This campaign consisted of the deployment of the DOE ARM Mobile Facility 2 (AMF2) and the ARM Aerial Facility (AAF) G-1 in a field campaign called ARM Cloud Aerosol Precipitation Experiment (ACAPEX), which took place in conjunction with CalWater 2- a NOAA field campaign. The joint CalWater 2/ACAPEX field campaign aimed to improve understanding and modeling of large-scale dynamics and cloud and precipitation processes associated with ARs and aerosol-cloud interactions that influence precipitation variability and extremes in the western U.S. The observational strategy consisted of the use of land and offshore assets to monitor: 1. the evolution and structure ofmore » ARs from near their regions of development 2. the long-range transport of aerosols in the eastern North Pacific and potential interactions with ARs 3. how aerosols from long-range transport and local sources influence cloud and precipitation in the U.S. West Coast where ARs make landfall and post-frontal clouds are frequent.« less

Arabic sign language recognition based on HOG descriptor

NASA Astrophysics Data System (ADS)

Ben Jmaa, Ahmed; Mahdi, Walid; Ben Jemaa, Yousra; Ben Hamadou, Abdelmajid

2017-02-01

We present in this paper a new approach for Arabic sign language (ArSL) alphabet recognition using hand gesture analysis. This analysis consists in extracting a histogram of oriented gradient (HOG) features from a hand image and then using them to generate an SVM Models. Which will be used to recognize the ArSL alphabet in real-time from hand gesture using a Microsoft Kinect camera. Our approach involves three steps: (i) Hand detection and localization using a Microsoft Kinect camera, (ii) hand segmentation and (iii) feature extraction using Arabic alphabet recognition. One each input image first obtained by using a depth sensor, we apply our method based on hand anatomy to segment hand and eliminate all the errors pixels. This approach is invariant to scale, to rotation and to translation of the hand. Some experimental results show the effectiveness of our new approach. Experiment revealed that the proposed ArSL system is able to recognize the ArSL with an accuracy of 90.12%.

New resonances from the coherence of Auger and intercoulombic (ICD) processes in the photoionization of endohedral fullerenes

NASA Astrophysics Data System (ADS)

Chakraborty, Himadri; Wise, Jacob; de, Ruma; Javani, Mohammad; Manson, Steve; Madjet, Mohamed

2014-05-01

Considering the photoionization of Ar@C60 , we predict resonant femtosecond decays of both Ar and C60 vacancies through the continua of atom-fullerene hybrid final states. The resulting resonances emerge from the interference between simultaneous autoionizing and intercoulombic decay (ICD) processes. For Ar 3s --> np excitations, these resonances are far stronger than the Ar-to-C60 resonant ICDs, while for C60 excitations they are strikingly larger than the corresponding Auger features. The results indicate the power of hybridization to enhance decay rates, and modify lifetimes and line profiles. These decays are also likely to exist generally in the ionization of molecules, nano-dimers and -polymers, and fullerene onions that support hybridized electrons as well. A jellium based time-dependent local density approximation (TDLDA), with the Leeuwen and Baerends exchange-correlation functional to produce accurate asymptotic behavior, is employed to calculate the dynamical response of the system to the photon field.

Augmented Reality Tool for the Situational Awareness Improvement of UAV Operators.

PubMed

Ruano, Susana; Cuevas, Carlos; Gallego, Guillermo; García, Narciso

2017-02-06

Unmanned Aerial Vehicles (UAVs) are being extensively used nowadays. Therefore, pilots of traditional aerial platforms should adapt their skills to operate them from a Ground Control Station (GCS). Common GCSs provide information in separate screens: one presents the video stream while the other displays information about the mission plan and information coming from other sensors. To avoid the burden of fusing information displayed in the two screens, an Augmented Reality (AR) tool is proposed in this paper. The AR system has two functionalities for Medium-Altitude Long-Endurance (MALE) UAVs: route orientation and target identification. Route orientation allows the operator to identify the upcoming waypoints and the path that the UAV is going to follow. Target identification allows a fast target localization, even in the presence of occlusions. The AR tool is implemented following the North Atlantic Treaty Organization (NATO) standards so that it can be used in different GCSs. The experiments show how the AR tool improves significantly the situational awareness of the UAV operators.

A MIS 15-MIS 12 record of environmental changes and Lower Palaeolithic occupation from Valle Giumentina, central Italy

NASA Astrophysics Data System (ADS)

Villa, Valentina; Pereira, Alison; Chaussé, Christine; Nomade, Sébastien; Giaccio, Biagio; Limondin-Lozouet, Nicole; Fusco, Fabio; Regattieri, Eleonora; Degeai, Jean-Philippe; Robert, Vincent; Kuzucuoglu, Catherine; Boschian, Giovanni; Agostini, Silvano; Aureli, Daniele; Pagli, Marina; Bahain, Jean Jacques; Nicoud, Elisa

2016-11-01

An integrated geological study, including sedimentology, stable isotope analysis (δ18O, δ13C), geochemistry, micromorphology, biomarker analysis, 40Ar/39Ar geochronology and tephrochronology, was undertaken on the Quaternary infill of the Valle Giumentina basin in Central Italy, which also includes an outstanding archaeological succession, composed of nine human occupation levels ascribed to the Lower and Middle Palaeolithic. 40Ar/39Ar dating, and other palaeoenvironmental and tephrochronological data, constrain the sedimentary history of the whole succession to the MIS 15-MIS 12 interval, between 618 ± 13 ka and 456 ± 2 ka. Palaeoenvironmental proxies suggest that over this time interval of about 150 ka, sedimentary and pedogenic processes were mainly influenced by climatic changes, in particular by the pulsing of local mountain glaciers of the Majella massif. Specifically, the Valle Giumentina succession records glacio-fluvial and lacustrine sedimentation during the colder glacial periods and pedogenesis and/or alluvial sedimentation during the warmer interglacial and/or interstadial periods. During this interval, tectonics played a negligible role as a driving factor of local morphogenesis and sedimentation, whereas the general regional uplift experienced in the Middle Pleistocene led to capture of the basin and its definitive extinction after MIS 12. These data substantially improve previous knowledge of the chronology and sedimentary evolution of the succession, providing for the first time, a well constrained chronological and palaeoenvironmental framework for the archaeological and human palaeoecological record of Valle Giumentina.

Local dynamic nuclear polarization using quantum point contacts

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wald, K.R.; Kouwenhoven, L.P.; McEuen, P.L.

1994-08-15

We have used quantum point contacts (QPCs) to locally create and probe dynamic nuclear polarization (DNP) in GaAs heterostructures in the quantum Hall regime. DNP is created via scattering between spin-polarized Landau level electrons and the Ga and As nuclear spins, and it leads to hysteresis in the dc transport characteristics. The nuclear origin of this hysteresis is demonstrated by nuclear magnetic resonance (NMR). Our results show that QPCs can be used to create and probe local nuclear spin populations, opening up new possibilities for mesoscopic NMR experiments.

Growth hormone-specific induction of the nuclear localization of porcine growth hormone receptor in porcine hepatocytes.

PubMed

Lan, H N; Hong, P; Li, R N; Shan, A S; Zheng, X

2017-10-01

The phenomenon of nuclear translocation of growth hormone receptor (GHR) in human, rat, and fish has been reported. To date, this phenomenon has not been described in a domestic animal (such as pig). In addition, the molecular mechanisms of GHR nuclear translocation have not been thoroughly elucidated. To this end, porcine hepatocytes were isolated and used as a cell model. We observed that porcine growth hormone (pGH) can induce porcine GHR's nuclear localization in porcine hepatocytes. Subsequently, the dynamics of pGH-induced pGHR's nuclear localization were analyzed and demonstrated that pGHR's nuclear localization occurs in a time-dependent manner. Next, we explored the mechanism of pGHR nuclear localization using different pGHR ligands, and we demonstrated that pGHR's nuclear translocation is GH(s)-dependent. We also observed that pGHR translocates into cell nuclei in a pGH dimerization-dependent fashion, whereas further experiments indicated that IMPα/β is involved in the nuclear translocation of the pGH-pGHR dimer. The pGH-pGHR dimer may form a pGH-GHR-JAK2 multiple complex in cell nuclei, which would suggest that similar to its function in the cell membrane, the nuclear-localized pGH-pGHR dimer might still have the ability to signal. Copyright © 2017 Elsevier Inc. All rights reserved.

Prm3p is a pheromone-induced peripheral nuclear envelope protein required for yeast nuclear fusion.

PubMed

Shen, Shu; Tobery, Cynthia E; Rose, Mark D

2009-05-01

Nuclear membrane fusion is the last step in the mating pathway of the yeast Saccharomyces cerevisiae. We adapted a bioinformatics approach to identify putative pheromone-induced membrane proteins potentially required for nuclear membrane fusion. One protein, Prm3p, was found to be required for nuclear membrane fusion; disruption of PRM3 caused a strong bilateral defect, in which nuclear congression was completed but fusion did not occur. Prm3p was localized to the nuclear envelope in pheromone-responding cells, with significant colocalization with the spindle pole body in zygotes. A previous report, using a truncated protein, claimed that Prm3p is localized to the inner nuclear envelope. Based on biochemistry, immunoelectron microscopy and live cell microscopy, we find that functional Prm3p is a peripheral membrane protein exposed on the cytoplasmic face of the outer nuclear envelope. In support of this, mutations in a putative nuclear localization sequence had no effect on full-length protein function or localization. In contrast, point mutations and deletions in the highly conserved hydrophobic carboxy-terminal domain disrupted both protein function and localization. Genetic analysis, colocalization, and biochemical experiments indicate that Prm3p interacts directly with Kar5p, suggesting that nuclear membrane fusion is mediated by a protein complex.

Heat asymptotics for nonminimal Laplace type operators and application to noncommutative tori

NASA Astrophysics Data System (ADS)

Iochum, B.; Masson, T.

2018-07-01

Let P be a Laplace type operator acting on a smooth hermitean vector bundle V of fiber CN over a compact Riemannian manifold given locally by P = - [gμν u(x) ∂μ∂ν +vν(x) ∂ν + w(x) ] where u ,vν , w are MN(C) -valued functions with u(x) positive and invertible. For any a ∈ Γ(End(V)) , we consider the asymptotics Tr(ae-tP) ∼ t↓0+ ∑r=0∞ ar(a , P) t (r - d) / 2 where the coefficients ar(a , P) can be written as an integral of the functions ar(a , P) (x) = tr [ a(x) Rr(x) ] . The computation of R2 is performed opening the opportunity to calculate the modular scalar curvature for noncommutative tori.

Non-Nuclear Validation Test Results of a Closed Brayton Cycle Test-Loop

NASA Astrophysics Data System (ADS)

Wright, Steven A.

2007-01-01

Both NASA and DOE have programs that are investigating advanced power conversion cycles for planetary surface power on the moon or Mars, or for next generation nuclear power plants on earth. Although open Brayton cycles are in use for many applications (combined cycle power plants, aircraft engines), only a few closed Brayton cycles have been tested. Experience with closed Brayton cycles coupled to nuclear reactors is even more limited and current projections of Brayton cycle performance are based on analytic models. This report describes and compares experimental results with model predictions from a series of non-nuclear tests using a small scale closed loop Brayton cycle available at Sandia National Laboratories. A substantial amount of testing has been performed, and the information is being used to help validate models. In this report we summarize the results from three kinds of tests. These tests include: 1) test results that are useful for validating the characteristic flow curves of the turbomachinery for various gases ranging from ideal gases (Ar or Ar/He) to non-ideal gases such as CO2, 2) test results that represent shut down transients and decay heat removal capability of Brayton loops after reactor shut down, and 3) tests that map a range of operating power versus shaft speed curve and turbine inlet temperature that are useful for predicting stable operating conditions during both normal and off-normal operating behavior. These tests reveal significant interactions between the reactor and balance of plant. Specifically these results predict limited speed up behavior of the turbomachinery caused by loss of load, the conditions for stable operation, and for direct cooled reactors, the tests reveal that the coast down behavior during loss of power events can extend for hours provided the ultimate heat sink remains available.

Antiandrogenic mechanisms of pesticides in human LNCaP prostate and H295R adrenocortical carcinoma cells.

PubMed

Robitaille, Christina N; Rivest, Patricia; Sanderson, J Thomas

2015-01-01

Several pesticides suspected or known to have endocrine disrupting effects were screened for pro- or antiandrogenic properties by determining their effects on proliferation, prostatic-specific antigen (PSA) secretion and androgen receptor (AR) expression, and AR phosphorylation in androgen-dependent LNCaP human prostate cancer cells, as well as on the expression and catalytic activity of the enzyme CYP17 in H295R human adrenocortical carcinoma cells, an in vitro model of steroidogenesis. Effects on SRD5A gene expression were determined in both cell lines. Benomyl, vinclozolin, and prochloraz, but not atrazine, concentration dependently (1-30 μM) decreased dihydrotestosterone (DHT)-stimulated proliferation of LNCaP cells. All pesticides except atrazine decreased DHT-stimulated PSA secretion, AR nuclear accumulation, and AR phosphorylation on serines 81 and 213 in LNCaP cells. Benomyl and prochloraz, but not vinclozolin or atrazine, decreased levels of CYP17 gene and protein expression, as well as catalytic activity in H295R cells. In the case of prochloraz, some of these effects corresponded with cytotoxicity. H295R cells expressed AR protein and SRD5A1, but not SRD5A2 transcripts. SRD5A1 gene expression in H295R cells was increased by 10 nM DHT, whereas in LNCaP cells significant induction was observed by 0.1 nM DHT. AR protein expression in H295R cells was not increased by DHT. Vinclozolin decreased DHT-induced SRD5A1 gene expression in LNCaP, but not H295R cells, indicating a functional difference of AR between the cell lines. In conclusion, pesticides may exert antiandrogenic effects through several mechanisms that are cell type-specific, including AR antagonism and down-regulation or catalytic inhibition of androgen biosynthetic enzymes, such as CYP17 and SRD5A1. © The Author 2014. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Identification and functional characterization of a novel bipartite nuclear localization sequence in ARID1A.

PubMed

Bateman, Nicholas W; Shoji, Yutaka; Conrads, Kelly A; Stroop, Kevin D; Hamilton, Chad A; Darcy, Kathleen M; Maxwell, George L; Risinger, John I; Conrads, Thomas P

2016-01-01

AT-rich interactive domain-containing protein 1A (ARID1A) is a recently identified nuclear tumor suppressor frequently altered in solid tumor malignancies. We have identified a bipartite-like nuclear localization sequence (NLS) that contributes to nuclear import of ARID1A not previously described. We functionally confirm activity using GFP constructs fused with wild-type or mutant NLS sequences. We further show that cyto-nuclear localized, bipartite NLS mutant ARID1A exhibits greater stability than nuclear-localized, wild-type ARID1A. Identification of this undescribed functional NLS within ARID1A contributes vital insights to rationalize the impact of ARID1A missense mutations observed in patient tumors. Copyright © 2015 Elsevier Inc. All rights reserved.

Identification and functional characterization of a novel bipartite nuclear localization sequence in ARID1A

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bateman, Nicholas W.; The John P. Murtha Cancer Center, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda 20889, MD; Shoji, Yutaka

2016-01-01

AT-rich interactive domain-containing protein 1A (ARID1A) is a recently identified nuclear tumor suppressor frequently altered in solid tumor malignancies. We have identified a bipartite-like nuclear localization sequence (NLS) that contributes to nuclear import of ARID1A not previously described. We functionally confirm activity using GFP constructs fused with wild-type or mutant NLS sequences. We further show that cyto-nuclear localized, bipartite NLS mutant ARID1A exhibits greater stability than nuclear-localized, wild-type ARID1A. Identification of this undescribed functional NLS within ARID1A contributes vital insights to rationalize the impact of ARID1A missense mutations observed in patient tumors. - Highlights: • We have identified a bipartitemore » nuclear localization sequence (NLS) in ARID1A. • Confirmation of the NLS was performed using GFP constructs. • NLS mutant ARID1A exhibits greater stability than wild-type ARID1A.« less

A Comparison Study of Augmented Reality versus Interactive Simulation Technology to Support Student Learning of a Socio-Scientific Issue

ERIC Educational Resources Information Center

Chang, Hsin-Yi; Hsu, Ying-Shao; Wu, Hsin-Kai

2016-01-01

We investigated the impact of an augmented reality (AR) versus interactive simulation (IS) activity incorporated in a computer learning environment to facilitate students' learning of a socio-scientific issue (SSI) on nuclear power plants and radiation pollution. We employed a quasi-experimental research design. Two classes (a total of 45…

Discrimination between NL1- and NL2-Mediated Nuclear Localization of the Glucocorticoid Receptor

PubMed Central

Savory, Joanne G. A.; Hsu, Brian; Laquian, Ian R.; Giffin, Ward; Reich, Terry; Haché, Robert J. G.; Lefebvre, Yvonne A.

1999-01-01

Glucocorticoid receptor (GR) cycles between a free liganded form that is localized to the nucleus and a heat shock protein (hsp)-immunophilin-complexed, unliganded form that is usually localized to the cytoplasm but that can also be nuclear. In addition, rapid nucleocytoplasmic exchange or shuttling of the receptor underlies its localization. Nuclear import of liganded GR is mediated through a well-characterized sequence, NL1, adjacent to the receptor DNA binding domain and a second, uncharacterized motif, NL2, that overlaps with the ligand binding domain. In this study we report that rapid nuclear import (half-life [t1/2] of 4 to 6 min) of agonist- and antagonist-treated GR and the localization of unliganded, hsp-associated GRs to the nucleus in G0 are mediated through NL1 and correlate with the binding of GR to pendulin/importin α. By contrast, NL2-mediated nuclear transfer of GR occurred more slowly (t1/2 = 45 min to 1 h), was agonist specific, and appeared to be independent of binding to importin α. Together, these results suggest that NL2 mediates the nuclear import of GR through an alternative nuclear import pathway. Nuclear export of GR was inhibited by leptomycin B, suggesting that the transfer of GR to the cytoplasm is mediated through the CRM1-dependent pathway. Inhibition of GR nuclear export by leptomycin B enhanced the nuclear localization of both unliganded, wild-type GR and hormone-treated NL1− GR. These results highlight that the subcellular localization of both liganded and unliganded GRs is determined, at least in part, by a flexible equilibrium between the rates of nuclear import and export. PMID:9891038

Arachidonate 15-Lipoxygenase 2 as an Endogenous Inhibitor of Prostate Cancer Development

DTIC Science & Technology

2006-03-01

dehydrogenase; NHP, normal human prostate epithelial cells; PCa, prostate cancer; NLS, nuclear localization signal; PPAR -, peroxisome proliferator...cloned, i.e., 15-LOX2sv-a/b/c, are mostly excluded from the nucleus. A potential bi-partite nuclear localization signal (NLS...only partially involved in the nuclear import of 15-LOX2. To elucidate the relationship between nuclear localization , enzymatic activity, and tumor

A continuously self regenerating high-flux neutron-generator facility

NASA Astrophysics Data System (ADS)

Rogers, A. M.; Becker, T. A.; Bernstein, L. A.; van Bibber, K.; Bleuel, D. L.; Chen, A. X.; Daub, B. H.; Goldblum, B. L.; Firestone, R. B.; Leung, K.-N.; Renne, P. R.; Waltz, C.

2013-10-01

A facility based on a next-generation, high-flux D-D neutron generator (HFNG) is being constructed at UC Berkeley. The current generator, designed around two RF-driven multicusp deuterium ion sources, is capable of producing a neutron output of >1011 n/s. A specially designed titanium-coated copper target located between the ion sources accelerates D+ ions up to 150 keV, generating 2.45 MeV neutrons through the d(d,3He)n fusion reaction. Deuterium in the target is self loaded and regenerating through ion implantation, enabling stable and continuous long-term operation. The proposed science program is focused on pioneering advances in the 40Ar/39Ar dating technique for geochronology, new nuclear data measurements, basic nuclear science research including statistical model studies of radiative-strength functions and level densities, and education. An overview of the facility and its unique capabilities as well as first measurements from the HFNG commissioning will be presented. Work supported by NSF Grant No. EAR-0960138, U.S. DOE LBL Contract No. DE-AC02-05CH11231, and U.S. DOE LLNL Contract No. DE-AC52-07NA27344.

Modeling study of radiation characteristics with different impurity species seeding in EAST

NASA Astrophysics Data System (ADS)

Liu, X. J.; Deng, G. Z.; Wang, L.; Liu, S. C.; Zhang, L.; Li, G. Q.; Gao, X.

2017-12-01

A critical issue for EAST and future tokamak machines such as ITER and China Fusion Engineering Testing Reactor is the handling of excessive heat load on the divertor target plates. As an effective means of actively reducing and controlling the power fluxes to the target plates, localized impurity (N, Ne, and Ar) gas puffing from the lower dome is investigated by using SOLPS5.0 for an L-mode discharge on EAST with double null configuration. The radiative efficiency and distribution of different impurities are compared. The effect of N, Ne, and Ar seeding on target power load, the power entering into scrape-off layer (SOL), Psep, and their concentration in SOL along the poloidal length and edge effective ion charge number (Zeff) which are closely related to core plasma performance are presented. The simulation results indicate that N, Ne, and Ar seeding can effectively reduce the peak heat load and electron temperature at divertor targets similarly. N seeding can reach the highest radiative loss fraction and both N and Ar strongly radiate power in the divertor region, while the radiative power inside the separatrix for Ar seeding is also significant. Ne radiates power mainly around the separatrix and X-point. Ne and Ar impurities' puffing results in a faster decrease of Psep than N seeding case; the reduction of Psep can eventually degrade the core performance of fusion plasma. Additionally, seeding with Ne has a totally larger concentration at the outer midplane and edge Zeff than those in N and Ar seeding cases; it suggests that N and Ar impurities are more acceptable than Ne in terms of fuel dilution for this discharge.

On the function of chitin synthase extracellular domains in biomineralization.

PubMed

Weiss, Ingrid M; Lüke, Florian; Eichner, Norbert; Guth, Christina; Clausen-Schaumann, Hauke

2013-08-01

Molluscs with various shell architectures evolved around 542-525 million years ago, as part of a larger phenomenon related to the diversification of metazoan phyla. Molluscs deposit minerals in a chitin matrix. The mollusc chitin is synthesized by transmembrane enzymes that contain several unique extracellular domains. Here we investigate the assembly mechanism of the chitin synthase Ar-CS1 via its extracellular domain ArCS1_E22. The corresponding transmembrane protein ArCS1_E22TM accumulates in membrane fractions of the expression host Dictyostelium discoideum. Soluble recombinant ArCS1_E22 proteins can be purified as monomers only at basic pH. According to confocal fluorescence microscopy experiments, immunolabeled ArCS1_E22 proteins adsorb preferably to aragonitic nacre platelets at pH 7.75. At pH 8.2 or pH 9.0 the fluorescence signal is less intense, indicating that protein-mineral interaction is reduced with increasing pH. Furthermore, ArCS1_E22 forms regular nanostructures on cationic substrates as revealed by atomic force microscopy (AFM) experiments on modified mica cleavage planes. These experiments suggest that the extracellular domain ArCS1_E22 is involved in regulating the multiple enzyme activities of Ar-CS1 such as chitin synthesis and myosin movements by interaction with mineral surfaces and eventually by protein assembly. The protein complexes could locally probe the status of mineralization according to pH unless ions and pCO2 are balanced with suitable buffer substances. Taking into account that the intact enzyme could act as a force sensor, the results presented here provide further evidence that shell formation is coordinated physiologically with precise adjustment of cellular activities to the structure, topography and stiffness at the mineralizing interface. Copyright © 2013 Elsevier Inc. All rights reserved.

Eocene and Miocene extension, meteoric fluid infiltration, and core complex formation in the Great Basin (Raft River Mountains, Utah)

USGS Publications Warehouse

Methner, Katharina; Mulch, Andreas; Teyssier, Christian; Wells, Michael L.; Cosca, Michael A.; Gottardi, Raphael; Gebelin, Aude; Chamberlain, C. Page

2015-01-01

Metamorphic core complexes (MCCs) in the North American Cordillera reflect the effects of lithospheric extension and contribute to crustal adjustments both during and after a protracted subduction history along the Pacific plate margin. While the Miocene-to-recent history of most MCCs in the Great Basin, including the Raft River-Albion-Grouse Creek MCC, is well documented, early Cenozoic tectonic fabrics are commonly severely overprinted. We present stable isotope, geochronological (40Ar/39Ar), and microstructural data from the Raft River detachment shear zone. Hydrogen isotope ratios of syntectonic white mica (δ2Hms) from mylonitic quartzite within the shear zone are very low (−90‰ to −154‰, Vienna SMOW) and result from multiphase synkinematic interaction with surface-derived fluids. 40Ar/39Ar geochronology reveals Eocene (re)crystallization of white mica with δ2Hms ≥ −154‰ in quartzite mylonite of the western segment of the detachment system. These δ2Hms values are distinctively lower than in localities farther east (δ2Hms ≥ −125‰), where 40Ar/39Ar geochronological data indicate Miocene (18–15 Ma) extensional shearing and mylonitic fabric formation. These data indicate that very low δ2H surface-derived fluids penetrated the brittle-ductile transition as early as the mid-Eocene during a first phase of exhumation along a detachment rooted to the east. In the eastern part of the core complex, prominent top-to-the-east ductile shearing, mid-Miocene 40Ar/39Ar ages, and higher δ2H values of recrystallized white mica, indicate Miocene structural and isotopic overprinting of Eocene fabrics.

Role of androgen receptor and associated lysine-demethylase coregulators, LSD1 and JMJD2A, in localized and advanced human bladder cancer.

PubMed

Kauffman, Eric C; Robinson, Brian D; Downes, Martin J; Powell, Leagh G; Lee, Ming Ming; Scherr, Douglas S; Gudas, Lorraine J; Mongan, Nigel P

2011-12-01

Bladder cancer is approximately three times more common in men as compared to women. We and others have previously investigated the contribution of androgens and the androgen receptor (AR) to bladder cancer. JMJD2A and LSD1 are recently discovered AR coregulator proteins that mediate AR-dependent transcription via recently described histone lysine-demethylation (KDM) mechanisms. We used immunohistochemistry to examine JMJD2A, LSD1, and AR expression in 72 radical cystectomy specimens, resulting in evaluation of 129 tissue samples (59 urothelial carcinoma, 70 benign). We tested levels of these proteins for statistical association with clinicopathologic variables and patient survival. Expression of these markers was also assessed in human bladder cancer cell lines. The effects of pharmacological inhibition of LSD1 on the proliferation of these bladder cancer cells was determined. JMJD2A and AR levels were significantly lower in malignant versus benign urothelium, while increased LSD1 levels were observed in malignant urothelium relative to benign. A significant reduction in all three proteins occurred with cancer stage progression, including muscle invasion (JMJD2A/LSD1/AR), extravesical extension (JMJD2A/LSD1), and lymph node metastasis (JMJD2A/AR). Lower JMJD2A intensity correlated with additional poor prognostic features, including lymphovascular invasion, concomitant carcinoma in situ and tobacco usage, and predicted significantly worse overall survival. Pharmacological inhibition of LSD1 suppressed bladder cancer cell proliferation and androgen-induced transcription. Our results support a novel role for the AR-KDM complex in bladder cancer initiation and progression, identify JMJD2A as a promising prognostic biomarker, and demonstrate targeting of the KDM activity as an effective potential approach for bladder cancer growth inhibition. Copyright © 2011 Wiley Periodicals, Inc.

Androgen receptor-mediated non-genomic effects of vinclozolin on porcine ovarian follicles and isolated granulosa cells: Vinclozolin and non-genomic effects in porcine ovarian follicles.

PubMed

Wartalski, Kamil; Knet-Seweryn, Malgorzata; Hoja-Lukowicz, Dorota; Tabarowski, Zbigniew; Duda, Malgorzata

2016-05-01

The present study investigated the influence of the androgen receptor (AR) agonists testosterone (T) and dihydrotestosterone (DHT), and vinclozolin (Vnz), a fungicide with antiandrogenic activity, on non-genomic signal transduction within ovarian follicles. Porcine granulosa cells (GCs) isolated from mature follicles were cultured for 48h. For the last 24h of culture, they were exposed to T (10(-7)M), DHT (10(-7)M), Vnz (1.4×10(-5)M), T and Vnz (T+Vnz), or DHT and Vnz (DHT+Vnz) at the same concentrations. To better imitate in vivo conditions, whole follicles (4-6mm in diameter) were incubated (24h) in an organ culture system with the same factors. Expression of AR mRNA and protein was determined by real-time PCR and western blot analyses. To demonstrate AR localization in cultured GCs and whole follicles, immunocytochemistry and immunohistochemistry were performed, respectively. To elucidate the possible non-genomic action of Vnz in GCs, protein expression and the activity of ERK1/2 and Akt kinases were determined by western blot and ELISA analyses. The immunocytochemistry and immunohistochemistry results showed that exposure of GCs and follicles to Vnz resulted in cytoplasmic and perinuclear AR localization. Real-time PCR and western blot analysis showed that AR mRNA and protein expression increased (P≤0.001) in GC cultures after combined treatment with an androgen and Vnz. In whole follicles, such treatment also increased AR mRNA with a decrease in the respective protein expression (P≤0.001). Moreover, addition of T or DHT with Vnz increased the activity of ERK1/2 and Akt kinases in cultured GCs (P≤0.001). The results suggest a novel mechanism for Vnz action in porcine ovarian follicles on both AR mRNA and protein levels. Thus, this environmental antiandrogen activates non-genomic signaling pathways, as indicated by the increased activity of both investigated kinases observed within minutes of Vnz addition. Given the widespread presence of Vnz in the environment, elucidation of its non-genomic action should be the subject of studies on female fertility. Copyright © 2016 Elsevier GmbH. All rights reserved.

MURC/Cavin-4 facilitates recruitment of ERK to caveolae and concentric cardiac hypertrophy induced by α1-adrenergic receptors

PubMed Central

Ogata, Takehiro; Naito, Daisuke; Nakanishi, Naohiko; Hayashi, Yukiko K.; Taniguchi, Takuya; Miyagawa, Kotaro; Hamaoka, Tetsuro; Maruyama, Naoki; Matoba, Satoaki; Ikeda, Koji; Yamada, Hiroyuki; Oh, Hidemasa; Ueyama, Tomomi

2014-01-01

The actions of catecholamines on adrenergic receptors (ARs) induce sympathetic responses, and sustained activation of the sympathetic nervous system results in disrupted circulatory homeostasis. In cardiomyocytes, α1-ARs localize to flask-shaped membrane microdomains known as “caveolae.” Caveolae require both caveolin and cavin proteins for their biogenesis and function. However, the functional roles and molecular interactions of caveolar components in cardiomyocytes are poorly understood. Here, we showed that muscle-restricted coiled-coil protein (MURC)/Cavin-4 regulated α1-AR–induced cardiomyocyte hypertrophy through enhancement of ERK1/2 activation in caveolae. MURC/Cavin-4 was expressed in the caveolae and T tubules of cardiomyocytes. MURC/Cavin-4 overexpression distended the caveolae, whereas MURC/Cavin-4 was not essential for their formation. MURC/Cavin-4 deficiency attenuated cardiac hypertrophy induced by α1-AR stimulation in the presence of caveolae. Interestingly, MURC/Cavin-4 bound to α1A- and α1B-ARs as well as ERK1/2 in caveolae, and spatiotemporally modulated MEK/ERK signaling in response to α1-AR stimulation. Thus, MURC/Cavin-4 facilitates ERK1/2 recruitment to caveolae and efficient α1-AR signaling mediated by caveolae in cardiomyocytes, which provides a unique insight into the molecular mechanisms underlying caveola-mediated signaling in cardiac hypertrophy. PMID:24567387

The analytical methods used in examining resistance of hydrogeological systems to anthropogenic pollution

NASA Astrophysics Data System (ADS)

Najman, Joanna; Bielewski, Jarosław; Śliwka, Ireneusz

2013-04-01

key words: gas chromatography (GC) measurement method, groundwater dating, He, SF6, F-11, F-12, Ar, Ne. In this work the method for evaluating resistance hydrogeological systems to anthropogenic pollution using environmental tracers is described. Resistance groundwater systems to anthropogenic pollution is correlated with the age of water, which can be determined by means of environmental tracers SF6, F-11, F-12 [1] and He. To correct measured values of He and SF6 the temperature of recharge and the excess air is needed and can be determined by measuring Ne and Ar concentrations in groundwater. This paper describes three measurement GC systems to determine the concentrations of greenhouse gases: sulfur hexafluoride (SF6) and chlorofluorocarbons F-11, F-12 [2], the noble gases neon (Ne), argon (Ar) [3] and helium (He) [4] in groundwater. The first system for measurements of the concentration of SF6, F-11 and F-12 consists of a gas chromatograph, type N504 is supplied with nitrogen carrier gas with a purity of 6.0. It is equipped with two packed columns K1 and K2 running at 60°C with the use of the "back-flush" column switching and electron capture detector (ECD) operating at 300°C. Second system for measuring the concentration of the noble gases argon and neon, is composed of a dual Shimadzu gas chromatograph. It is equipped with two columns K4 and K5 operating at 30°C, thermalconductivity detector (TCD) for analysis of argon and helium detector with pulse discharge (PDHID) for analysis of neon. This chromatograph is powered by helium carrier gas 6.0. The third system measures the concentration of helium, consists of a gas chromatograph equipped with a TCD detector and three packed columns filled with molecular sieve type 5A and activated carbon. The carrier gas in this system is argon 6.0. Detection limit, LOD for each measurement systems for the tested compounds are: 0,06 fmol/L for SF6, 15 fmol/L for F-11, 10 fmol/L for F-12, 1,9•10-8 cm3STP/cm3 for Ne, 3,1•10-6 cm3STP/cm3 for Ar and 1,2•10-8cm3STP/gH2O for He. Work performed within the strategic research project "Technologies supporting the development of safe nuclear power" financed by the National Centre for Research and Development (NCBiR). Research Task "Development of methods to assure nuclear safety and radiation protection for current and future needs of nuclear power plants", contract No. SP/J/6/143339/11. This work was also supported by grant No. N N525 3488 38 from the Polish National Science Centre. [1] I. Śliwka, et al., Long-Term Measurements of CFCs and SF6 Concentration in Air, Polish J. of Eviron. Stud. Vol. 19, No. 4, 811-815, 2010. [2] I. Śliwka, et al., Headspace Extraction Method for Simultaneus Determination of SF6, CCl3F2, CCl2F2 and CCl2FCClF2 in Water, Chem. Anal. (Warsaw) 49,535, 2004. [3] P. Mochalski, Chromatographic method for the determination of Ar, Ne and N2 in water, Ph.D. thesis, Institute of Nuclear Physics Polish Academy of Sciences in Krakow, 2003 (in polish). [4] J. Najman, Development of chromatographic measurement method of helium concentration in groundwater for the purpose of dating in the hydrological issues, Ph.D. thesis, Institute of Nuclear Physics Polish Academy of Sciences in Krakow, 2008, http://www.ifj.edu.pl/SD/rozprawy_dr/rozpr_Najman.pdf?lang=pl (in polish).

The emerging roles of orphan nuclear receptors in prostate cancer.

PubMed

Wu, Dinglan; Cheung, Alyson; Wang, Yuliang; Yu, Shan; Chan, Franky L

2016-08-01

Orphan nuclear receptors are members of the nuclear receptor (NR) superfamily and are so named because their endogenous physiological ligands are either unknown or may not exist. Because of their important regulatory roles in many key physiological processes, dysregulation of signalings controlled by these receptors is associated with many diseases including cancer. Over years, studies of orphan NRs have become an area of great interest because their specific physiological and pathological roles have not been well-defined, and some of them are promising drug targets for diseases. The recently identified synthetic small molecule ligands, acting as agonists or antagonists, to these orphan NRs not only help to understand better their functional roles but also highlight that the signalings mediated by these ligand-independent NRs in diseases could be therapeutically intervened. This review is a summary of the recent advances in elucidating the emerging functional roles of orphan NRs in cancers, especially prostate cancer. In particular, some orphan NRs, RORγ, TR2, TR4, COUP-IFII, ERRα, DAX1 and SHP, exhibit crosstalk or interference with androgen receptor (AR) signaling in either normal or malignant prostatic cells, highlighting their involvement in prostate cancer progression as androgen and AR signaling pathway play critical roles in this process. We also propose that a better understanding of the mechanism of actions of these orphan NRs in prostate gland or prostate cancer could help to evaluate their potential value as therapeutic targets for prostate cancer. Copyright © 2016 Elsevier B.V. All rights reserved.

Role of regulatory subunits and protein kinase inhibitor (PKI) in determining nuclear localization and activity of the catalytic subunit of protein kinase A.

PubMed

Wiley, J C; Wailes, L A; Idzerda, R L; McKnight, G S

1999-03-05

Regulation of protein kinase A by subcellular localization may be critical to target catalytic subunits to specific substrates. We employed epitope-tagged catalytic subunit to correlate subcellular localization and gene-inducing activity in the presence of regulatory subunit or protein kinase inhibitor (PKI). Transiently expressed catalytic subunit distributed throughout the cell and induced gene expression. Co-expression of regulatory subunit or PKI blocked gene induction and prevented nuclear accumulation. A mutant PKI lacking the nuclear export signal blocked gene induction but not nuclear accumulation, demonstrating that nuclear export is not essential to inhibit gene induction. When the catalytic subunit was targeted to the nucleus with a nuclear localization signal, it was not sequestered in the cytoplasm by regulatory subunit, although its activity was completely inhibited. PKI redistributed the nuclear catalytic subunit to the cytoplasm and blocked gene induction, demonstrating that the nuclear export signal of PKI can override a strong nuclear localization signal. With increasing PKI, the export process appeared to saturate, resulting in the return of catalytic subunit to the nucleus. These results demonstrate that both the regulatory subunit and PKI are able to completely inhibit the gene-inducing activity of the catalytic subunit even when the catalytic subunit is forced to concentrate in the nuclear compartment.

Risk assessment for public–private partnerships : a primer.

DOT National Transportation Integrated Search

2014-01-01

The Federal Highway Administrations (FHWAs) Office of Innovative Program Delivery (IPD) assists States and local governments in developing knowledge, skills, and abilities in innovative finance techniques. Publicprivate partnerships (P3s) ar...

2.7 MeV Ar11+ ion irradiation induced structural evolution in Lu2(Ti2-xLux)O7-x/2 pyrochlores

NASA Astrophysics Data System (ADS)

Yang, D. Y.; Liu, C. G.; Zhang, K. Q.; Xia, Y.; Chen, L. J.; Liu, H.; Li, Y. H.

2015-11-01

This paper aims to study the radiation effects of nonstoichiometric pyrochlore series Lu2(Ti2-xLux)O7-x/2 (x = 0-0.667). Polycrystalline Lu2(Ti2-xLux)O7-x/2 samples were irradiated with 2.7 MeV Ar11+ ions up to a fluence of 8 × 1014 ions/cm2. The irradiated samples were characterized using grazing incidence X-ray diffraction technique. The results reveal that Lu2(Ti2-xLux)O7-x/2 samples undergo significant amorphization and lattice swelling upon irradiation. Specifically, the amorphization process is predominantly driven by ballistic nuclear energy deposition of Ar11+ ions at this energy regime, which can be well described by a direct-impact/defect-stimulated model. Both the amorphization fraction and the relative variation of lattice parameter decrease with increasing x, showing a strong dependence on the chemical composition. The results are then discussed in the framework of the structural disorder and recovery ability from damage, applying an atomic layer model.

Synthesis and biological evaluation of novel selective androgen receptor modulators (SARMs) Part III: Discovery of 4-(5-oxopyrrolidine-1-yl)benzonitrile derivative 2f as a clinical candidate.

PubMed

Aikawa, Katsuji; Asano, Moriteru; Ono, Koji; Habuka, Noriyuki; Yano, Jason; Wilson, Keith; Fujita, Hisashi; Kandori, Hitoshi; Hara, Takahito; Morimoto, Megumi; Santou, Takashi; Yamaoka, Masuo; Nakayama, Masaharu; Hasuoka, Atsushi

2017-07-01

We previously reported that 4-(pyrrolidin-1-yl)benzonitrile derivative 1b was a selective androgen receptor modulator (SARM) that exhibited anabolic effects on organs such as muscles and the central nervous system (CNS), but neutral effects on the prostate. From further modification, we identified that 4-(5-oxopyrrolidine-1-yl)benzonitrile derivative 2a showed strong AR binding affinity with improved metabolic stabilities. Based on these results, we tried to enhance the AR agonistic activities by modifying the substituents of the 5-oxopyrrolidine ring. As a consequence, we found that 4-[(2S,3S)-2-ethyl-3-hydroxy-5-oxopyrrolidin-1-yl]-2-(trifluoromethyl)benzonitrile (2f) had ideal SARM profiles in Hershberger assay and sexual behavior induction assay. Furthermore, 2f showed good pharmacokinetic profiles in rats, dogs, monkeys, excellent nuclear selectivity and acceptable toxicological profiles. We also determined its binding mode by obtaining the co-crystal structures with AR. Copyright © 2017 Elsevier Ltd. All rights reserved.

Energy levels, lifetimes, and transition rates for the selenium isoelectronic sequence Pd XIII-Te XIX, Xe XXI-Nd XXVII, W XLI

NASA Astrophysics Data System (ADS)

Wang, K.; Yang, X.; Chen, Z. B.; Si, R.; Chen, C. Y.; Yan, J.; Zhao, X. H.; Dang, W.

2017-09-01

Energy levels, wavelengths, lifetimes, oscillator strengths, and electric dipole (E1), magnetic dipole (M1), electric quadrupole (E2), magnetic quadrupole (M2) transition rates among the 46 fine structure levels belonging to the ([ Ar ] 3d10) 4s2 4p4, ([ Ar ] 3d10) 4s2 4p3 4 d, and ([ Ar ] 3d10) 4 s 4p5 configurations for the selenium isoelectronic sequence Pd XIII-Te XIX, Xe XXI-Nd XXVII, W XLI are reported. These data are determined in the multi-configuration Dirac-Fock (MCDF) approach, in which relativistic effects, main electron correlations within the n = 7 complex, Breit interaction (BI), and quantum electrodynamic (QED) corrections are included. The many-body perturbation theory (MBPT) method is also employed as an independent calculation to confirm the present accuracy, taking W XLI as an example. Comparisons and analysis are made between the present results and available experimental and theoretical ones, and good agreements are obtained. These accurate data are expected to be useful in nuclear fusion research and astrophysical applications.

Hematopoietic recovery of acute radiation syndrome by human superoxide dismutase-expressing umbilical cord mesenchymal stromal cells.

PubMed

Gan, Jingyi; Meng, Fanwei; Zhou, Xin; Li, Chan; He, Yixin; Zeng, Xiaoping; Jiang, Xingen; Liu, Jia; Zeng, Guifang; Tang, Yunxia; Liu, Muyun; Mrsny, Randall J; Hu, Xiang; Hu, Jifan; Li, Tao

2015-04-01

Acute radiation syndrome (ARS) leads to pancytopenia and multi-organ failure. Transplantation of hematopoietic stem cells provides a curative option for radiation-induced aplasia, but this therapy is limited by donor availability. We examined an alternative therapeutic approach to ARS with the use of human extracellular superoxide dismutase (ECSOD)-modified umbilical cord mesenchymal stromal cells (UCMSCs). This treatment combines the unique regenerative role of UCMSCs with the anti-oxidative activity of ECSOD. We demonstrated that systemically administered ECSOD-UCMSCs are able to protect mice from sub-lethal doses of radiation and improve survival by promoting multilineage hematopoietic recovery. The therapeutic effect of this treatment is related to the decrease in radiation-induced O(2)(-) and apoptosis. Our data highlight the clinical potential of this two-pronged approach to the treatment of ARS, thereby serving as a rapid and effective first-line strategy to combat the hematopoietic failure resulting from a radiation accident, nuclear terrorism and other radiologic emergencies. Copyright © 2015 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Profile of apalutamide in the treatment of metastatic castration-resistant prostate cancer: evidence to date.

PubMed

Chong, Julio T; Oh, William K; Liaw, Bobby C

2018-01-01

Advances in therapies have led to the approval of six therapeutic agents since 2004, each demonstrating overall survival benefit in randomized studies, and these have significantly improved the outlook for men facing metastatic castration-resistant prostate cancer (CRPC). More recently, efforts have been directed at trying to effect change at earlier phases of the disease. Apalutamide (ARN-509), a second-generation androgen receptor antagonist, recently received approval in the nonmetastatic (M0) CRPC space. Similar to enzalutamide, apalutamide inhibits the binding of androgen to androgen receptor (AR), nuclear translocation of the androgen-AR complex, and binding of AR transcription complex to DNA-binding sites and transcription elements. Phase I and II trial experience demonstrates the safety and tolerability of apalutamide, as well as its efficacy in effecting prostate-specific antigen response and radiographic-free survival in CRPC. US Food and Drug Administration approval in M0 CRPC was granted following positive results from the phase III SPARTAN study, where apalutamide demonstrated significant improvements in metastasis-free survival and time to symptomatic progression as compared to placebo.

The fate of the duplicated androgen receptor in fishes: a late neofunctionalization event?

PubMed Central

2008-01-01

Background Based on the observation of an increased number of paralogous genes in teleost fishes compared with other vertebrates and on the conserved synteny between duplicated copies, it has been shown that a whole genome duplication (WGD) occurred during the evolution of Actinopterygian fish. Comparative phylogenetic dating of this duplication event suggests that it occurred early on, specifically in teleosts. It has been proposed that this event might have facilitated the evolutionary radiation and the phenotypic diversification of the teleost fish, notably by allowing the sub- or neo-functionalization of many duplicated genes. Results In this paper, we studied in a wide range of Actinopterygians the duplication and fate of the androgen receptor (AR, NR3C4), a nuclear receptor known to play a key role in sex-determination in vertebrates. The pattern of AR gene duplication is consistent with an early WGD event: it has been duplicated into two genes AR-A and AR-B after the split of the Acipenseriformes from the lineage leading to teleost fish but before the divergence of Osteoglossiformes. Genomic and syntenic analyses in addition to lack of PCR amplification show that one of the duplicated copies, AR-B, was lost in several basal Clupeocephala such as Cypriniformes (including the model species zebrafish), Siluriformes, Characiformes and Salmoniformes. Interestingly, we also found that, in basal teleost fish (Osteoglossiformes and Anguilliformes), the two copies remain very similar, whereas, specifically in Percomorphs, one of the copies, AR-B, has accumulated substitutions in both the ligand binding domain (LBD) and the DNA binding domain (DBD). Conclusion The comparison of the mutations present in these divergent AR-B with those known in human to be implicated in complete, partial or mild androgen insensitivity syndrome suggests that the existence of two distinct AR duplicates may be correlated to specific functional differences that may be connected to the well-known plasticity of sex determination in fish. This suggests that three specific events have shaped the present diversity of ARs in Actinopterygians: (i) early WGD, (ii) parallel loss of one duplicate in several lineages and (iii) putative neofunctionalization of the same duplicate in percomorphs, which occurred a long time after the WGD. PMID:19094205

Kar5p is required for multiple functions in both inner and outer nuclear envelope fusion in Saccharomyces cerevisiae.

PubMed

Rogers, Jason V; Rose, Mark D

2014-12-02

During mating in the budding yeast Saccharomyces cerevisiae, two haploid nuclei fuse via two sequential membrane fusion steps. SNAREs (i.e., soluble N-ethylmaleimide-sensitive factor attachment protein receptors) and Prm3p mediate outer nuclear membrane fusion, but the inner membrane fusogen remains unknown. Kar5p is a highly conserved transmembrane protein that localizes adjacent to the spindle pole body (SPB), mediates nuclear envelope fusion, and recruits Prm3p adjacent to the SPB. To separate Kar5p's functions, we tested localization, Prm3p recruitment, and nuclear fusion efficiency in various kar5 mutants. All domains and the conserved cysteine residues were essential for nuclear fusion. Several kar5 mutant proteins localized properly but did not mediate Prm3p recruitment; other kar5 mutant proteins localized and recruited Prm3p but were nevertheless defective for nuclear fusion, demonstrating additional functions beyond Prm3p recruitment. We identified one Kar5p domain required for SPB localization, which is dependent on the half-bridge protein Mps3p. Electron microscopy revealed a kar5 mutant that arrests with expanded nuclear envelope bridges, suggesting that Kar5p is required after outer nuclear envelope fusion. Finally, a split-GFP assay demonstrated that Kar5p localizes to both the inner and outer nuclear envelope. These insights suggest a mechanism by which Kar5p mediates inner nuclear membrane fusion. Copyright © 2015 Rogers and Rose.

Kar5p Is Required for Multiple Functions in Both Inner and Outer Nuclear Envelope Fusion in Saccharomyces cerevisiae

PubMed Central

Rogers, Jason V.; Rose, Mark D.

2014-01-01

During mating in the budding yeast Saccharomyces cerevisiae, two haploid nuclei fuse via two sequential membrane fusion steps. SNAREs (i.e., soluble N-ethylmaleimide–sensitive factor attachment protein receptors) and Prm3p mediate outer nuclear membrane fusion, but the inner membrane fusogen remains unknown. Kar5p is a highly conserved transmembrane protein that localizes adjacent to the spindle pole body (SPB), mediates nuclear envelope fusion, and recruits Prm3p adjacent to the SPB. To separate Kar5p’s functions, we tested localization, Prm3p recruitment, and nuclear fusion efficiency in various kar5 mutants. All domains and the conserved cysteine residues were essential for nuclear fusion. Several kar5 mutant proteins localized properly but did not mediate Prm3p recruitment; other kar5 mutant proteins localized and recruited Prm3p but were nevertheless defective for nuclear fusion, demonstrating additional functions beyond Prm3p recruitment. We identified one Kar5p domain required for SPB localization, which is dependent on the half-bridge protein Mps3p. Electron microscopy revealed a kar5 mutant that arrests with expanded nuclear envelope bridges, suggesting that Kar5p is required after outer nuclear envelope fusion. Finally, a split-GFP assay demonstrated that Kar5p localizes to both the inner and outer nuclear envelope. These insights suggest a mechanism by which Kar5p mediates inner nuclear membrane fusion. PMID:25467943

Type 1 IGF Receptor Localization in Paediatric Gliomas: Significant Association with WHO Grading and Clinical Outcome.

PubMed

Clément, Florencia; Martin, Ayelen; Venara, Marcela; de Luján Calcagno, Maria; Mathó, Cecilia; Maglio, Silvana; Lombardi, Mercedes García; Bergadá, Ignacio; Pennisi, Patricia A

2018-06-01

Nuclear localization of insulin-like growth factor receptor type 1 (IGF-1R) has been described as adverse prognostic factor in some cancers. We studied the expression and localization of IGF-1R in paediatric patients with gliomas, as well as its association with World Health Organization (WHO) grading and survival. We conducted a single cohort, prospective study of paediatric patients with gliomas. Samples were taken at the time of the initial surgery; IGF-1R expression and localization were characterized by immunohistochemistry (IHC), subcellular fractionation and western blotting. Tumours (47/53) showed positive staining for IGF-1R by IHC. IGF-1R nuclear labelling was observed in 10/47 cases. IGF-1R staining was mostly non-nuclear in low-grade tumours, while IGF-1R nuclear labelling was predominant in high-grade gliomas (p = 0.0001). Survival was significantly longer in patients with gliomas having non-nuclear IGF-1R localization than in patients with nuclear IGF-1R tumours (p = 0.016). In gliomas, IGF-1R nuclear localization was significantly associated with both high-grade tumours and increased risk of death. Based on a prospective design, we provide evidence of a potential usefulness of intracellular localization of IGF-1R as prognostic factor in paediatric patients with gliomas.

Authigenic potassium feldspar: a tracer for the timing of palaeofluid flow in carbonate rocks, Northern Calcareous Alps, Austria

USGS Publications Warehouse

Spotl, C.; Kunk, Michael J.; Ramseyer, K.; Longstaffe, F.J.

1998-01-01

This paper is included in the Special Publication entitled 'Dating and duration of fluid flow and fluid-rock interaction', edited by J. Parnell. Feldspar is a common authigenic constituent in Permian carbonate rocks which occur as tectonically isolated blocks within the evaporitic Haselgebirge melange in the Northern Calcareous Alps (NCA). Coexisting with pyrite, anhydrite, (saddle) dolomite, magnesite, fluorite and calcite, K-feldspar and minor albite record an event of regionally extensive interaction of hot brines with carbonate rocks. Detailed petrographic, crystallographic and geochemical studies reveal a variability in crystal size and shape, Al-Si ordering, elemental and stable isotopic compositions of the K-feldspar, which is only partially consistent with the traditional view of authigenic feldspar as a well-ordered, compositionally pure mineral. 40Ar-39Ar step- heating measurements of authigenic potassium feldspar from several localities yield two age populations, an older one of 145-154 Ma, and a younger one of c.90-97 Ma. Most age spectra reflect cooling through the argon retention temperature interval, which was rapid in some localities (as indicated by plateau ages) and slower in others. Rb-Sr isotope data are more difficult to interpret, because in many K-feldspar samples they are controlled largely by Sr-bearing inclusions. The Jurassic 40Ar-39Ar dates are interpreted as minimum ages of feldspar growth and hence imply that fluid-rock interaction is likely to be simultaneous with or to slightly predate melange formation. Deformation associated with the closure and subduction of the Meliata-Hallstatt ocean south of the NCA during the Upper Jurassic is regarded as the principal geodynamic driving force for both enhanced fluid circulation and melange formation. Some localities were reheated beyond the argon retention temperature for microcline during mid-Cretaceous nappe stacking of the NCA, thus obliterating the older signal.

Astronomical calibration of 40Ar/39Ar reference minerals using high-precision, multi-collector (ARGUSVI) mass spectrometry

NASA Astrophysics Data System (ADS)

Phillips, D.; Matchan, E. L.; Honda, M.; Kuiper, K. F.

2017-01-01

The new generation of multi-collector mass spectrometers (e.g. ARGUSVI) permit ultra-high precision (<0.1%) 40Ar/39Ar geochronology of rocks and minerals. At the same time, the 40Ar/39Ar method is limited by relatively large uncertainties (>1%) in 40K decay constants and the ages of natural reference minerals that form the basis of the technique. For example, reported ages for widely used 40Ar/39Ar reference materials, such as the ca. 28 Ma Fish Canyon Tuff sanidine (FCTs) and the ca. 1.2 Ma Alder Creek Rhyolite sanidine (ACRs), vary by >1%. Recent attempts to independently calibrate these reference minerals have focused on K-Ar analyses of the same minerals and inter-comparisons with astronomically tuned tephras in sedimentary sequences and U-Pb zircon ages from volcanic rocks. Most of these studies used older generation (effectively single-collector) mass spectrometers that employed peak-jumping analytical methods to acquire 40Ar/39Ar data. In this study, we reassess the inter-calibration and ages of commonly used 40Ar/39Ar reference minerals Fish Canyon Tuff sanidine (FCTs), Alder Creek Rhyolite sanidine (ACRs) and Mount Dromedary biotite (MD2b; equivalent to GA-1550 biotite), relative to the astronomically tuned age of A1 Tephra sanidine (A1Ts), Faneromeni section, Crete (Rivera et al., 2011), using a multi-collector ARGUSVI mass spectrometer. These analyses confirm the exceptional precision capability (<0.1%) of this system, compared to most previous studies. All sanidine samples (FCTs, ACRs and A1Ts) exhibit discordant 40Ar/39Ar step-heating spectra, with generally monotonically increasing ages (∼1% gradients). The similarity in these patterns, mass-dependent fractionation modeling, and results from step-crushing experiments on FCTs, which yield younger apparent ages, suggest that the discordance may be due to a combination of recoil loss and redistribution of 39ArK and isotope mass fractionation. In contrast to our previous inferences, these results imply that the sanidine samples are suitable 40Ar/39Ar reference materials, provided appropriate corrections are included for differential recoil loss of 39ArK and contributions from xenocrysts/antecrysts can be resolved. Relative to an age of 6.943 ± 0.005 Ma for A1Ts, we calculate astronomically tuned ages for FCTs, ACRs and MD2b of 28.126 ± 0.019 (0.066%) Ma, 1.18144 ± 0.00068 (0.058%) Ma and 99.125 ± 0.076 (0.077%) Ma, respectively (95% internal errors). These results are consistent with recent 238U/206Pb age data from these localities, but are marginally younger (∼0.2%) than previous 40Ar/39Ar ages inter-calibrated with astronomically tuned tephra from the Mediterranean, and distinctly younger (0.6%) than results optimized against a broad array of 238U/206Pb zircon ages. Consideration of published and assumed recoil loss 39ArK proportions (0.18-0.40%), yields recoil-corrected age estimates of 28.187 ± 0.019 Ma, 1.18404 ± 0.00068 Ma and 99.204 ± 0.076 Ma, respectively. This comparison indicates inherent uncertainties of >0.1% in the 40Ar/39Ar ages of reference minerals without consideration of recoil artefacts, thus limiting the benefits of high precision multi-collector analyses. Significant improvement to the accuracy of the 40Ar/39Ar method (<0.1%) will require further inter-laboratory 40Ar/39Ar studies utilizing multi-collector mass spectrometry, additional constraints on recoil 39ArK loss from reference minerals, further resolution of discrepancies between astronomically tuned sedimentary successions and refinement of the 238U/206Pb zircon age cross-calibration approach.

Apollo 12 ropy glasses revisited

NASA Technical Reports Server (NTRS)

Wentworth, S. J.; Mckay, D. S.; Lindstrom, D. J.; Basu, A.; Martinez, R. R.; Bogard, D. D.; Garrison, D. H.

1994-01-01

We analyzed ropy glasses from Apollo 12 soils 12032 and 12033 by a variety of techniques including SEM/EDX, electron microprobe analysis, INAA, and Ar-39-Ar-40 age dating. The ropy glasses have potassium rare earth elements phosphorous (KREEP)-like compositions different from those of local Apollo 12 mare soils; it is likely that the ropy glasses are of exotic origin. Mixing calculations indicate that the ropy glasses formed from a liquid enriched in KREEP and that the ropy glass liquid also contained a significant amount of mare material. The presence of solar Ar and a trace of regolith-derived glass within the ropy glasses are evidence that the ropy glasses contain a small regolith component. Anorthosite and crystalline breccia (KREEP) clasts occur in some ropy glasses. We also found within these glasses clasts of felsite (fine-grained granitic fragments) very similar in texture and composition to the larger Apollo 12 felsites, which have a Ar-39-Ar-40 degassing age of 800 +/- 15 Ma. Measurements of 39-Ar-40-Ar in 12032 ropy glass indicate that it was degassed at the same time as the large felsite although the ropy glass was not completely degassed. The ropy glasses and felsites, therefore, probably came from the same source. Most early investigators suggested that the Apollo 12 ropy glasses were part of the ejecta deposited at the Apollo 12 site from the Copernicus impact. Our new data reinforce this model. If these ropy glasses are from Copernicus, they provide new clues to the nature of the target material at the Copernicus site, a part of the Moon that has not been sampled directly.

Gigantol from Dendrobium chrysotoxum Lindl. binds and inhibits aldose reductase gene to exert its anti-cataract activity: An in vitro mechanistic study.

PubMed

Wu, Jie; Li, Xue; Wan, Wencheng; Yang, Qiaohong; Ma, Weifeng; Chen, Dan; Hu, Jiangmiao; Chen, C-Y Oliver; Wei, Xiaoyong

2017-02-23

Dendrobium. chrysotoxum Lindl is a commonly used species of medicinal Dendrobium which belongs to the family of Orchidaceae, locally known as "Shihu" or "Huangcao". D. chrysotoxum Lindl is widely known for medicinal values in traditional Chinese medicine as it possesses anti-inflammatory, anti-hyperglycemic induction, antitumor and antioxidant properties. To characterize the interaction between gigantol extracted from D. chrysotoxum Lindl and the AR gene, and determine gigantol's efficacy against cataractogenesis. Human lens epithelial cells (HLECs) were induced by glucose as the model group. Reverse transcription polymerase chain reaction (RT-PCR) was used to assess AR gene expression. Then, the mode of interaction of gigantol with the AR gene was evaluated by UV-visible spectroscopy, atomic force microscope (AFM) and surface-enhanced Raman spectroscopy (SERS). The binding constant was determined by UV-visible. Gigantol depressed AR gene expression in HLECs. UV-visible spectra preliminarily indicated that interaction between the AR gene and gigantol may follow the groove mode, with a binding constant of 1.85×10 3 L/mol. Atomic force microscope (AFM) data indicated that gigantol possibly bound to insert AR gene base pairs of the double helix. Surface-enhanced Raman spectroscopy (SERS) studies further supported these observations. Gigantol extracted from D. chrysotoxum Lindl not only has inhibitory effects on aldose reductase, but also inhibits AR gene expression. These findings provide a more comprehensive theoretical basis for the use of Dendrobium for the treatment of diabetic cataract. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

An in-situ K-Ar isochron dating method for planetary landers using a spot-by-spot laser-ablation technique

NASA Astrophysics Data System (ADS)

Cho, Yuichiro; Sugita, Seiji; Miura, Yayoi N.; Okazaki, Ryuji; Iwata, Naoyoshi; Morota, Tomokatsu; Kameda, Shingo

2016-09-01

Age is essential information for interpreting the geologic record on planetary surfaces. Although crater counting has been widely used to estimate the planetary surface ages, crater chronology in the inner solar system is largely built on radiometric age data from limited sites on the Moon. This has resulted in major uncertainty in planetary chronology. Because opportunities for sample-return missions are limited, in-situ geochronology measurements from one-way lander/rover missions are extremely valuable. Here we developed an in-situ isochron-based dating method using the K-Ar system, with K and Ar in a single rock sample extracted locally by laser ablation and measured using laser-induced breakdown spectroscopy (LIBS) and a quadrupole mass spectrometer (QMS), respectively. We built an experimental system combining flight-equivalent instruments and measured K-Ar ages for mineral samples with known ages (~1.8 Ga) and K contents (1-8 wt%); we achieved precision of 20% except for a mineral with low mechanical strength. Furthermore, validation measurements with two natural rocks (gneiss slabs) obtained K-Ar isochron ages and initial 40Ar consistent with known values for both cases. This result supports that our LIBS-MS approach can derive both isochron ages and contributions of non-in situ radiogenic 40Ar from natural rocks. Error assessments suggest that the absolute ages of key geologic events including the Noachian/Hesperian- and the Hesperian/Amazonian-transition can be dated with 10-20% errors for a rock containing ~1 wt% K2O, greatly reducing the uncertainty of current crater chronology models on Mars.

Apollo 12 ropy glasses revisited

NASA Astrophysics Data System (ADS)

Wentworth, S. J.; McKay, D. S.; Lindstrom, D. J.; Basu, A.; Martinez, R. R.; Bogard, D. D.; Garrison, D. H.

1994-05-01

We analyzed ropy glasses from Apollo 12 soils 12032 and 12033 by a variety of techniques including SEM/EDX, electron microprobe analysis, INAA, and Ar-39-Ar-40 age dating. The ropy glasses have potassium rare earth elements phosphorous (KREEP)-like compositions different from those of local Apollo 12 mare soils; it is likely that the ropy glasses are of exotic origin. Mixing calculations indicate that the ropy glasses formed from a liquid enriched in KREEP and that the ropy glass liquid also contained a significant amount of mare material. The presence of solar Ar and a trace of regolith-derived glass within the ropy glasses are evidence that the ropy glasses contain a small regolith component. Anorthosite and crystalline breccia (KREEP) clasts occur in some ropy glasses. We also found within these glasses clasts of felsite (fine-grained granitic fragments) very similar in texture and composition to the larger Apollo 12 felsites, which have a Ar-39-Ar-40 degassing age of 800 +/- 15 Ma. Measurements of 39-Ar-40-Ar in 12032 ropy glass indicate that it was degassed at the same time as the large felsite although the ropy glass was not completely degassed. The ropy glasses and felsites, therefore, probably came from the same source. Most early investigators suggested that the Apollo 12 ropy glasses were part of the ejecta deposited at the Apollo 12 site from the Copernicus impact. Our new data reinforce this model. If these ropy glasses are from Copernicus, they provide new clues to the nature of the target material at the Copernicus site, a part of the Moon that has not been sampled directly.

Nuclear Data Sheets for A=36

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nica N.; Nica,N.; Cameron,J.

2012-01-01

Nuclear spectroscopic information for experimentally investigated nuclides of mass 36 (Mg, Al, Si, P, S, Cl, Ar, K, Ca) has been evaluated. The principal sources of the 'adopted levels' presented for nuclides close to the stability line are Endt's evaluations (1990En08, 1978En02). The data sets for reactions and decays, including all available gamma-ray data, are based mostly on the original literature. The {sup 36}Na has been looked for but not yet experimentally detected. There are no data available for the excited states in {sup 36}Al, and for {sup 36}Mg and {sup 36}Ca, only one excited state is known.

Slip localization on the southern Alpine Fault, New Zealand

NASA Astrophysics Data System (ADS)

Barth, N. C.; Boulton, C.; Carpenter, B. M.; Batt, G. E.; Toy, V. G.

2013-06-01

of a detailed field study of the southern onshore portion of New Zealand's Alpine Fault reveal that for 75 km along-strike, dextral-normal slip on this long-lived structure is highly localized in phyllosilicate-rich fault core gouges and along their contact with more competent rocks. At three localities (Martyr River, McKenzie Creek, and Hokuri Creek), we document complete cross sections through the fault. New 40Ar/39Ar dates on mylonites, combined with microstructural and mechanical data on phyllosilicate-rich fault core gouges show that modern slip is localized onto a single, steeply dipping 1 to 12 m-thick fault core composed of impermeable (k = 10-20 to 10-22 m2), frictionally weak (μs = 0.12-0.37), velocity-strengthening, illite-chlorite, and saponite-chlorite-lizardite fault gouges. Fault core materials are (1) comparable to those of other major weak-cored faults (e.g., San Andreas Fault) and (2) most compatible with fault creep, despite paleoseismic evidence of quasiperiodic large magnitude earthquakes (Mw > 7) on this portion of the Alpine Fault. We conclude that frictional properties of gouges at the surface do not characterize the overall seismogenic behavior of the southern Alpine Fault.

Clozapine Reverses Phencyclidine-Induced Desynchronization of Prefrontal Cortex through a 5-HT1A Receptor-Dependent Mechanism

PubMed Central

Kargieman, Lucila; Riga, Maurizio S; Artigas, Francesc; Celada, Pau

2012-01-01

The non-competitive NMDA receptor (NMDA-R) antagonist phencyclidine (PCP)—used as a pharmacological model of schizophrenia—disrupts prefrontal cortex (PFC) activity. PCP markedly increased the discharge rate of pyramidal neurons and reduced slow cortical oscillations (SCO; 0.15–4 Hz) in rat PFC. Both effects were reversed by classical (haloperidol) and atypical (clozapine) antipsychotic drugs. Here we extended these observations to mice brain and examined the potential involvement of 5-HT2A and 5-HT1A receptors (5-HT2AR and 5-HT1AR, respectively) in the reversal by clozapine of PCP actions. Clozapine shows high in vitro affinity for 5-HT2AR and behaves as partial agonist in vivo at 5-HT1AR. We used wild-type (WT) mice and 5-HT1AR and 5-HT2AR knockout mice of the same background (C57BL/6) (KO-1A and KO-2A, respectively). Local field potentials (LFPs) were recorded in the PFC of WT, KO-1A, and KO-2A mice. PCP (10 mg/kg, intraperitoneally) reduced SCO equally in WT, KO-2A, and KO-1A mice (58±4%, 42±7%, and 63±7% of pre-drug values, n=23, 13, 11, respectively; p<0.0003). Clozapine (0.5 mg/kg, intraperitoneally) significantly reversed PCP effect in WT and KO-2A mice, but not in KO-1A mice nor in WT mice pretreated with the selective 5-HT1AR antagonist WAY-100635.The PCP-induced disorganization of PFC activity does not appear to depend on serotonergic function. However, the lack of effect of clozapine in KO-1A mice and the prevention by WAY-100635 indicates that its therapeutic action involves 5-HT1AR activation without the need to block 5-HT2AR, as observed with clozapine-induced cortical dopamine release. PMID:22012474

Arabidopsis SHR and SCR transcription factors and AUX1 auxin influx carrier control the switch between adventitious rooting and xylogenesis in planta and in in vitro cultured thin cell layers.

PubMed

Della Rovere, F; Fattorini, L; D'Angeli, S; Veloccia, A; Del Duca, S; Cai, G; Falasca, G; Altamura, M M

2015-03-01

Adventitious roots (ARs) are essential for vegetative propagation. The Arabidopsis thaliana transcription factors SHORT ROOT (SHR) and SCARECROW (SCR) affect primary/lateral root development, but their involvement in AR formation is uncertain. LAX3 and AUX1 auxin influx carriers contribute to primary/lateral root development. LAX3 expression is regulated by SHR, and LAX3 contributes to AR tip auxin maximum. In contrast, AUX1 involvement in AR development is unknown. Xylogenesis is induced by auxin plus cytokinin as is AR formation, but the genes involved are largely unknown. Stem thin cell layers (TCLs) form ARs and undergo xylogenesis under the same auxin plus cytokinin input. The aim of this research was to investigate SHR, SCR, AUX1 and LAX3 involvement in AR formation and xylogenesis in intact hypocotyls and stem TCLs in arabidopsis. Hypocotyls of scr-1, shr-1, lax3, aux1-21 and lax3/aux1-21 Arabidopsis thaliana null mutant seedlings grown with or without auxin plus cytokinin were examined histologically, as were stem TCLs cultured with auxin plus cytokinin. SCR and AUX1 expression was monitored using pSCR::GFP and AUX1::GUS lines, and LAX3 expression and auxin localization during xylogenesis were monitored by using LAX3::GUS and DR5::GUS lines. AR formation was inhibited in all mutants, except lax3. SCR was expressed in pericycle anticlinally derived AR-forming cells of intact hypocotyls, and in cell clumps forming AR meristemoids of TCLs. The apex was anomalous in shr and scr ARs. In all mutant hypocotyls, the pericycle divided periclinally to produce xylogenesis. Xylary element maturation was favoured by auxin plus cytokinin in shr and aux1-21. Xylogenesis was enhanced in TCLs, and in aux1-21 and shr in particular. AUX1 was expressed before LAX3, i.e. in the early derivatives leading to either ARs or xylogenesis. AR formation and xylogenesis are developmental programmes that are inversely related, but they involve fine-tuning by the same proteins, namely SHR, SCR and AUX1. Pericycle activity is central for the equilibrium between xylary development and AR formation in the hypocotyl, with a role for AUX1 in switching between, and balancing of, the two developmental programmes. © The Author 2015. Published by Oxford University Press on behalf of the Annals of Botany Company.

A geochronological 40Ar/39Ar and 87Rb/81Sr study of K-Mn oxides from the weathering sequence of Azul, Brazil

NASA Astrophysics Data System (ADS)

Ruffet, G.; Innocent, C.; Michard, A.; Féraud, G.; Beauvais, A.; Nahon, D.; Hamelin, B.

1996-06-01

KMn oxides of hollandite group minerals such as cryptomelane (K 1-2(Mn 3+, Mn 4+) 8O 16nH 2O) are often precipitated authigenically in weathering profiles. The presence of structural K allows these minerals to be dated by the KAr and 40Ar/ 39Ar methods, making it possible to study the progression of oxidation fronts during weathering processes. Within the context of a recent 40Ar/ 39Ar study of cryptomelane from the Azul Mn deposit in the Carajàs region (Amazônia, Brazil), Vasconcelos et al. (1994) defined three age clusters (65-69, 51-56, and 40-43 Ma) and proposed that they correspond to the episodic precipitation of the three generations of Mn oxide that have been identified in the deposit (Beauvais et al., 1987). We performed a laser probe 40Ar/ 39Ar and 87Rb/ 87Sr study on new samples from the same Mn deposit. Our 40Ar/ 39Ar data confirm that cryptomelane is a suitable mineral for 40Ar/ 39Ar dating, although in some cases we clearly identify the existence of 39Ar recoil effects. Although the corresponding age spectra are generally strongly disturbed, our results also confirm that the earliest cryptomelane generation is of Upper Cretaceous-Paleocene age. We obtained good plateau ages from veins and concretions of the second cryptomelane generation. Some of these results allow definition of a well-constrained age cluster at 46.7-48.1 Ma not observed by Vasconcelos et al. (1994). A petrographic study confirms that none of the samples analyzed in the present study contained material associated with the third generation of cryptomelane. We propose that these new results support the idea of a more or less continuous crystallization of KMn oxides, mainly constrained by local factors, rather than the model advanced by Vasconcelos et al. (1994), which suggests that each cryptomelane generation corresponds to distinct weathering events related to global climatic changes. 87Sr/ 86Sr data show large variations, clearly inherited from the 2.1 Ga parent rock of the Mn protore. The Rb/Sr results demonstrate that minimum fractionation occurs during cryptomelane crystallization, except for the latest generation, which is depleted in Sr. This precludes use of the Rb/Sr radiochronometer for dating secondary Mn oxides in laterites.

Financial structuring and assessment for public–private partnerships : a primer.

DOT National Transportation Integrated Search

2013-12-01

The Federal Highway Administrations (FHWAs) Office of Innovative Program Delivery (IPD) assists States and local governments in developing knowledge, skills, and abilities in innovative finance techniques. Publicprivate partnerships (P3s) ar...

Nuclear localization signal-dependent and -independent movements of Drosophila melanogaster dUTPase isoforms during nuclear cleavage

DOE Office of Scientific and Technical Information (OSTI.GOV)

Muha, Villo; Zagyva, Imre; Venkei, Zsolt

2009-04-03

Two dUTPase isoforms (23 kDa and 21 kDa) are present in the fruitfly with the sole difference of an N-terminal extension. In Drosophila embryo, both isoforms are detected inside the nucleus. Here, we investigated the function of the N-terminal segment using eYFP-dUTPase constructs. In Schneider 2 cells, only the 23 kDa construct showed nuclear localization arguing that it may contain a nuclear localization signal (NLS). Sequence comparisons identified a lysine-rich nonapeptide with similarity to the human c-myc NLS. In Drosophila embryos during nuclear cleavages, the 23 kDa isoform showed the expected localization shifts. Contrariwise, although the 21 kDa isoform wasmore » excluded from the nuclei during interphase, it was shifted to the nucleus during prophase and forthcoming mitotic steps. The observed dynamic localization character showed strict timing to the nuclear cleavage phases and explained how both isoforms can be present within the nuclear microenvironment, although at different stages of cell cycle.« less

Constraining in-medium nucleon-nucleon interactions via nucleus-nucleus reactions

NASA Astrophysics Data System (ADS)

Sammarruca, Francesca; White, Larz

2010-11-01

The nuclear equation of state is a broadly useful tool. Besides being the main input of stellar structure calculations, it allows a direct connection to the physics of nuclei. For instance, an energy functional (such as a mass formula), together with the energy/particle in nuclear matter, can be used to predict nuclear energies and radii [1]. The single-particle properties are also a key point to link infinite nuclear matter and actual nuclei. The parameters of the single-particle potential, in particular the effective mass, enter the calculations of, for instance, in-medium effective cross sections. From the well-known Glauber reaction theory, the total nucleus-nucleus reaction cross section is expressed in terms of the nuclear transparency, which, in turn, depends on the overlap of the nuclear density distributions and the elementary nucleon-nucleon (NN) cross sections. We explore the sensitivity of the reaction calculation to medium modifications of the NN cross sections to estimate the likelihood of constraining the latter through nuclear reactions. Ultimately, we wish to incorporate isospin asymmetry in the reaction model, having in mind connections with rare isotopes. [1] F. Sammarruca, arXiv:1002.00146 [nucl-th]; International Journal of Modern Physics, in press.

Targeting the androgen receptor pathway in castration-resistant prostate cancer: progresses and prospects

PubMed Central

Ferraldeschi, R; Welti, J; Luo, J; Attard, G; de Bono, JS

2015-01-01

Androgen receptor (AR) signaling is a critical pathway for prostate cancer cells, and androgen-deprivation therapy (ADT) remains the principal treatment for patients with locally advanced and metastatic disease. However, over time, most tumors become resistant to ADT. The view of castration-resistant prostate cancer (CRPC) has changed dramatically in the last several years. Progress in understanding the disease biology and mechanisms of castration resistance led to significant advancements and to paradigm shift in the treatment. Accumulating evidence showed that prostate cancers develop adaptive mechanisms for maintaining AR signaling to allow for survival and further evolution. The aim of this review is to summarize molecular mechanisms of castration resistance and provide an update in the development of novel agents and strategies to more effectively target the AR signaling pathway. PMID:24837363

SiRNAs conjugated with aromatic compounds induce RISC-mediated antisense strand selection and strong gene-silencing activity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kubo, Takanori, E-mail: kubo-t@yasuda-u.ac.jp; Yanagihara, Kazuyoshi; Division of Genetics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045

2012-10-05

Highlights: Black-Right-Pointing-Pointer SiRNAs conjugated with aromatic compounds (Ar-siRNAs) at 5 Prime -sense strand were synthesized. Black-Right-Pointing-Pointer Ar-siRNAs increased resistance against nuclease degradation. Black-Right-Pointing-Pointer Ar-siRNAs were thermodynamically stable compared with the unmodified siRNA. Black-Right-Pointing-Pointer High levels of cellular uptake and cytoplasmic localization were found. Black-Right-Pointing-Pointer Strong gene-silencing efficacy was exhibited in the Ar-siRNAs. -- Abstract: Short interference RNA (siRNA) is a powerful tool for suppressing gene expression in mammalian cells. In this study, we focused on the development of siRNAs conjugated with aromatic compounds in order to improve the potency of RNAi and thus to overcome several problems with siRNAs, suchmore » as cellular delivery and nuclease stability. The siRNAs conjugated with phenyl, hydroxyphenyl, naphthyl, and pyrenyl derivatives showed strong resistance to nuclease degradation, and were thermodynamically stable compared with unmodified siRNA. A high level of membrane permeability in HeLa cells was also observed. Moreover, these siRNAs exhibited enhanced RNAi efficacy, which exceeded that of locked nucleic acid (LNA)-modified siRNAs, against exogenous Renilla luciferase in HeLa cells. In particular, abundant cytoplasmic localization and strong gene-silencing efficacy were found in the siRNAs conjugated with phenyl and hydroxyphenyl derivatives. The novel siRNAs conjugated with aromatic compounds are promising candidates for a new generation of modified siRNAs that can solve many of the problems associated with RNAi technology.« less

Gold Ultrathin Nanorods with Controlled Aspect Ratios and Surface Modifications: Formation Mechanism and Localized Surface Plasmon Resonance.

PubMed

Takahata, Ryo; Yamazoe, Seiji; Koyasu, Kiichirou; Imura, Kohei; Tsukuda, Tatsuya

2018-05-30

We synthesized gold ultrathin nanorods (AuUNRs) by slow reductions of gold(I) in the presence of oleylamine (OA) as a surfactant. Transmission electron microscopy revealed that the lengths of AuUNRs were tuned in the range of 5-20 nm while keeping the diameter constant (∼2 nm) by changing the relative concentration of OA and Au(I). It is proposed on the basis of time-resolved optical spectroscopy that AuUNRs are formed via the formation of small (<2 nm) Au spherical clusters followed by their one-dimensional attachment in OA micelles. The surfactant OA on AuUNRs was successfully replaced with glutathionate or dodecanethiolate by the ligand exchange approach. Optical extinction spectroscopy on a series of AuUNRs with different aspect ratios (ARs) revealed a single intense extinction band in the near-IR (NIR) region due to the longitudinal localized surface plasmon resonance (LSPR), the peak position of which is red-shifted with the AR. The NIR bands of AuUNRs with AR < 5 were blue-shifted upon the ligand exchange from OA to thiolates, in sharp contrast to the red shift observed in the conventional Au nanorods and nanospheres (diameter >10 nm). This behavior suggests that the NIR bands of thiolate-protected AuUNRs with AR < 5 are not plasmonic in nature, but are associated with a single-electron excitation between quantized states. The LSPR band was attenuated by thiolate passivation that can be explained by the direct decay of plasmons into an interfacial charge transfer state (chemical interface damping). The LSPR wavelengths of AuUNRs are remarkably longer than those of the conventional AuNRs with the same AR, demonstrating that the miniaturization of the diameter to below ∼2 nm significantly affects the optical response. The red shift of the LSPR band can be ascribed to the increase in the effective mass of electrons in AuUNRs.

Nickel nanowires mesh fabricated by ion beam irradiation-induced nanoscale welding for transparent conducting electrodes

NASA Astrophysics Data System (ADS)

Honey, S.; Ahmad, I.; Madhuku, M.; Naseem, S.; Maaza, M.; Kennedy, J. V.

2017-07-01

In this report, random nickel nanowires (Ni-NWs) meshes are fabricated by ions beam irradiation-induced nanoscale welding of NWs on intersecting positions. Ni-NWs are exposed to beam of 50 KeV Argon (Ar+) ions at various fluencies in the range ~1015 ions cm-2 to 1016 ions cm-2 at room temperature. Ni-NWs are welded due to accumulation of Ar+ ions beam irradiation-induced sputtered atoms on crossing positions. Ar+ ions irradiated Ni-NWs meshes are optically transparent and optical transparency is enhanced with increase in beam fluence of Ar+ ions. Ar+ ions beam irradiation-induced welded and optically transparent mesh is then exposed to 2.75 MeV hydrogen (H+) ions at fluencies 1  ×  1015 ions cm-2, 3  ×  1015 ions cm-2 and 1  ×  1016 ions cm-2 at room temperature. MeV H+ ions irradiation-induced local heat cause melting and fusion of NWs on intersecting points and eventually lead to reduce contact resistance between Ni-NWs. Electrical conductivity is enhanced with increase in beam fluence of H+ ions. These welded highly transparent and electrically conductive Ni-NWs meshes can be employed as transparent conducting electrodes in optoelectronic devices.

Platelets Express Activated P2Y12 Receptor in Patients With Diabetes Mellitus.

PubMed

Hu, Liang; Chang, Lin; Zhang, Yan; Zhai, Lili; Zhang, Shenghui; Qi, Zhiyong; Yan, Hongmei; Yan, Yan; Luo, Xinping; Zhang, Si; Wang, Yiping; Kunapuli, Satya P; Ye, Hongying; Ding, Zhongren

2017-08-29

Platelets from patients with diabetes mellitus are hyperactive. Hyperactivated platelets may contribute to cardiovascular complications and inadequate responses to antiplatelet agents in the setting of diabetes mellitus. However, the underlying mechanism of hyperactivated platelets is not completely understood. We measured P2Y 12 expression on platelets from patients with type 2 diabetes mellitus and on platelets from rats with diabetes mellitus. We also assayed platelet P2Y 12 activation by measuring cAMP and VASP phosphorylation. The antiplatelet and antithrombotic effects of AR-C78511 and cangrelor were compared in rats. Finally, we explored the role of the nuclear factor-κB pathway in regulating P2Y 12 receptor expression in megakaryocytes. Platelet P2Y 12 levels are 4-fold higher in patients with type 2 diabetes mellitus compared with healthy subjects. P2Y 12 expression correlates with ADP-induced platelet aggregation (r=0.89, P <0.01). P2Y 12 in platelets from patients with diabetes mellitus is constitutively activated. Although both AR-C78511, a potent P2Y 12 inverse agonist, and cangrelor have similar antiplatelet efficacy on platelets from healthy subjects, AR-C78511 exhibits more powerful antiplatelet effects on diabetic platelets than cangrelor (aggregation ratio 36±3% versus 49±5%, respectively, P <0.05). Using a FeCl 3 -injury mesenteric arteriole thrombosis model in rats and an arteriovenous shunt thrombosis model in rats, we found that the inverse agonist AR-C78511 has greater antithrombotic effects on GK rats with diabetes mellitus than cangrelor (thrombus weight 4.9±0.3 mg versus 8.3±0.4 mg, respectively, P <0.01). We also found that a pathway involving high glucose-reactive oxygen species-nuclear factor-κB increases platelet P2Y 12 receptor expression in diabetes mellitus. Platelet P2Y 12 receptor expression is significantly increased and the receptor is constitutively activated in patients with type 2 diabetes mellitus, which contributes to platelet hyperactivity and limits antiplatelet drug efficacy in type 2 diabetes mellitus. © 2017 American Heart Association, Inc.

New Aminoacyl-tRNA Synthetase-like Protein in Insecta with an Essential Mitochondrial Function*♦

PubMed Central

Guitart, Tanit; Leon Bernardo, Teresa; Sagalés, Jessica; Stratmann, Thomas; Bernués, Jordi; Ribas de Pouplana, Lluís

2010-01-01

Aminoacyl-tRNA synthetases (ARS) are modular enzymes that aminoacylate transfer RNAs (tRNA) for their use by the ribosome during protein synthesis. ARS are essential and universal components of the genetic code that were almost completely established before the appearance of the last common ancestor of all living species. This long evolutionary history explains the growing number of functions being discovered for ARS, and for ARS homologues, beyond their canonical role in gene translation. Here we present a previously uncharacterized paralogue of seryl-tRNA synthetase named SLIMP (seryl-tRNA synthetase-like insect mitochondrial protein). SLIMP is the result of a duplication of a mitochondrial seryl-tRNA synthetase (SRS) gene that took place in early metazoans and was fixed in Insecta. Here we show that SLIMP is localized in the mitochondria, where it carries out an essential function that is unrelated to the aminoacylation of tRNA. The knockdown of SLIMP by RNA interference (RNAi) causes a decrease in respiration capacity and an increase in mitochondrial mass in the form of aberrant mitochondria. PMID:20870726

Numerical dating of the Eckfeld maar fossil site, Eifel, Germany: a calibration mark for the Eocene time scale.

PubMed

Mertz, D F; Swisher, C C; Franzen, J L; Neuffer, F O; Lutz, H

2000-06-01

Sediments of the Eckfeld maar (Eifel, Germany) bear a well-preserved Eocene fauna and flora. Biostratigraphically, Eckfeld corresponds to the Middle Eocene mammal reference level MP (Mammals Paleogene) 13 of the ELMA (European Land Mammal Age) Geiseltalian. In the maar crater, basalt fragments were drilled, representing explosion crater eruption products. By 40Ar/39Ar dating of the basalt, for the first time a direct numerical calibration mark for an Eocene European mammal locality has been established. The Eckfeld basalt inverse isochron date of 44.3 +/- 0.4 Ma suggests an age for the Geiseltalian/Robiacian boundary at 44 Ma and, together with the 1995 time scale of Berggren et al., a time span ranging from 49 to 44 Ma for the Geiseltalian and from 44 to 37 Ma for the Robiacian, respectively. Additional 40Ar/39Ar dating on a genetically related basalt occurrence close to the maar confirms a period of volcanism of ca. 0.6 m.y. in the Eckfeld area, matching the oldest Eocene volcanic activity of the Hocheifel volcanic field.

Application of Interface Technology in Nonlinear Analysis of a Stitched/RFI Composite Wing Stub Box

NASA Technical Reports Server (NTRS)

Wang, John T.; Ransom, Jonathan B.

1997-01-01

A recently developed interface technology was successfully employed in the geometrically nonlinear analysis of a full-scale stitched/RFI composite wing box loaded in bending. The technology allows mismatched finite element models to be joined in a variationally consistent manner and reduces the modeling complexity by eliminating transition meshing. In the analysis, local finite element models of nonlinearly deformed wide bays of the wing box are refined without the need for transition meshing to the surrounding coarse mesh. The COMET-AR finite element code, which has the interface technology capability, was used to perform the analyses. The COMET-AR analysis is compared to both a NASTRAN analysis and to experimental data. The interface technology solution is shown to be in good agreement with both. The viability of interface technology for coupled global/local analysis of large scale aircraft structures is demonstrated.

Thermostabilization of the β1-adrenergic receptor correlates with increased entropy of the inactive state.

PubMed

Niesen, Michiel J M; Bhattacharya, Supriyo; Grisshammer, Reinhard; Tate, Christopher G; Vaidehi, Nagarajan

2013-06-20

The dynamic nature of GPCRs is a major hurdle in their purification and crystallization. Thermostabilization can facilitate GPCR structure determination, as has been shown by the structure of the thermostabilized β1-adrenergic receptor (β1AR) mutant, m23-β1AR, which has been thermostabilized in the inactive state. However, it is unclear from the structure how the six thermostabilizing mutations in m23-β1AR affect receptor dynamics. We have used molecular dynamics simulations in explicit solvent to compare the conformational ensembles for both wild type β1AR (wt-β1AR) and m23-β1AR. Thermostabilization results in an increase in the number of accessible microscopic conformational states within the inactive state ensemble, effectively increasing the side chain entropy of the inactive state at room temperature, while suppressing large-scale main chain conformational changes that lead to activation. We identified several diverse mechanisms of thermostabilization upon mutation. These include decrease of long-range correlated movement between residues in the G-protein coupling site to the extracellular region (Y227A(5.58), F338M(7.48)), formation of new hydrogen bonds (R68S), and reduction of local stress (Y227(5.58), F327(7.37), and F338(7.48)). This study provides insights into microscopic mechanisms underlying thermostability that leads to an understanding of the effect of these mutations on the structure of the receptor.

Use of augmented reality in laparoscopic gynecology to visualize myomas.

PubMed

Bourdel, Nicolas; Collins, Toby; Pizarro, Daniel; Debize, Clement; Grémeau, Anne-Sophie; Bartoli, Adrien; Canis, Michel

2017-03-01

To report the use of augmented reality (AR) in gynecology. AR is a surgical guidance technology that enables important hidden surface structures to be visualized in endoscopic images. AR has been used for other organs, but never in gynecology and never with a very mobile organ like the uterus. We have developed a new AR approach specifically for uterine surgery and demonstrated its use for myomectomy. Tertiary university hospital. Three patients with one, two, and multiple myomas, respectively. AR was used during laparoscopy to localize the myomas. Three-dimensional (3D) models of the patient's uterus and myomas were constructed before surgery from T2-weighted magnetic resonance imaging. The intraoperative 3D shape of the uterus was determined. These models were automatically aligned and "fused" with the laparoscopic video in real time. The live fused video made the uterus appear semitransparent, and the surgeon can see the location of the myoma in real time while moving the laparoscope and the uterus. With this information, the surgeon can easily and quickly decide on how best to access the myoma. We developed an AR system for gynecologic surgery and have used it to improve laparoscopic myomectomy. Technically, the software we developed is very different to approaches tried for other organs, and it can handle significant challenges, including image blur, fast motion, and partial views of the organ. Copyright © 2016 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Spatial variations in focused exhumation along a continental-scale strike-slip fault: The Denali fault of the eastern Alaska Range

USGS Publications Warehouse

Benowitz, J.A.; Layer, P.W.; Armstrong, P.; Perry, S.E.; Haeussler, Peter J.; Fitzgerald, P.G.; VanLaningham, S.

2011-01-01

40Ar/39Ar, apatite fission-track, and apatite (U-Th)/He thermochronological techniques were used to determine the Neogene exhumation history of the topographically asymmetric eastern Alaska Range. Exhumation cooling ages range from ~33 Ma to ~18 Ma for 40Ar/39Ar biotite, ~18 Ma to ~6 Ma for K-feldspar minimum closure ages, and ~15 Ma to ~1 Ma for apatite fission-track ages, and apatite (U-Th)/He cooling ages range from ~4 Ma to ~1 Ma. There has been at least ~11 km of exhumation adjacent to the north side of Denali fault during the Neogene inferred from biotite 40Ar/39Ar thermochronology. Variations in exhumation history along and across the strike of the fault are influenced by both far-field effects and local structural irregularities. We infer deformation and rapid exhumation have been occurring in the eastern Alaska Range since at least ~22 Ma most likely related to the continued collision of the Yakutat microplate with the North American plate. The Nenana Mountain region is the late Pleistocene to Holocene (~past 1 Ma) primary locus of tectonically driven exhumation in the eastern Alaska Range, possibly related to variations in fault geometry. During the Pliocene, a marked increase in climatic instability and related global cooling is temporally correlated with an increase in exhumation rates in the eastern Alaska Range north of the Denali fault system.

Cargo-mediated regulation of a rapid Rab4-dependent recycling pathway.

PubMed

Yudowski, Guillermo A; Puthenveedu, Manojkumar A; Henry, Anastasia G; von Zastrow, Mark

2009-06-01

Membrane trafficking is well known to regulate receptor-mediated signaling processes, but less is known about whether signaling receptors conversely regulate the membrane trafficking machinery. We investigated this question by focusing on the beta-2 adrenergic receptor (B2AR), a G protein-coupled receptor whose cellular signaling activity is controlled by ligand-induced endocytosis followed by recycling. We used total internal reflection fluorescence microscopy (TIR-FM) and tagging with a pH-sensitive GFP variant to image discrete membrane trafficking events mediating B2AR endo- and exocytosis. Within several minutes after initiating rapid endocytosis of B2ARs by the adrenergic agonist isoproterenol, we observed bright "puffs" of locally increased surface fluorescence intensity representing discrete Rab4-dependent recycling events. These events reached a constant frequency in the continuous presence of isoproterenol, and agonist removal produced a rapid (observed within 1 min) and pronounced (approximately twofold) increase in recycling event frequency. This regulation required receptor signaling via the cAMP-dependent protein kinase (PKA) and a specific PKA consensus site located in the carboxyl-terminal cytoplasmic tail of the B2AR itself. B2AR-mediated regulation was not restricted to this membrane cargo, however, as transferrin receptors packaged in the same population of recycling vesicles were similarly affected. In contrast, net recycling measured over a longer time interval (10 to 30 min) was not detectably regulated by B2AR signaling. These results identify rapid regulation of a specific recycling pathway by a signaling receptor cargo.

Differential expression of androgen, estrogen, and progesterone receptors in benign prostatic hyperplasia

PubMed Central

Song, Lingmin; Shen, Wenhao; Zhang, Heng; Wang, Qiwu; Wang, Yongquan; Zhou, Zhansong

2016-01-01

This study aimed to identify the differential expression levels of androgen receptor (AR), estrogen receptors (ERα, ERβ), and progesterone receptor (PGR) between normal prostate and benign prostatic hyperplasia (BPH). The combination of immunohistochemistry, quantitative real-time reverse transcription polymerase chain reaction, and Western blotting assay was used to identify the distribution and differential expression of these receptors at the immunoactive biomarker, transcriptional, and protein levels between 5 normal human prostate tissues and 40 BPH tissues. The results were then validated in a rat model of BPH induced by testosterone propionate and estradiol benzoate. In both human and rat prostate tissues, AR was localized mainly to epithelial and stromal cell nuclei; ERα was distributed mainly to stromal cells, but not exclusively; ERβ was interspersed in the basal layer of epithelium, but sporadically in epithelial and stromal cells; PGR was expressed abundantly in cytoplasm of epithelial and stromal cells. There were decreased expression of ERα and increased expression of PGR, but no difference in the expression of ERβ in the BPH compared to the normal prostate of both human and rat. Increased expression of AR in the BPH compared to the normal prostate of human was observed, however, the expression of AR in the rat prostate tissue was decreased. This study identified the activation of AR and PGR and repression of ERα in BPH, which indicate a promoting role of AR and PGR and an inhibitory role of ERα in the pathogenesis of BPH. PMID:27294569

Influences of Regional Climate Change on Air Quality Across the Continental U.S. Projected from Downscaling IPCC AR5 Simulations. Chapter 2

NASA Technical Reports Server (NTRS)

Nolte, Christopher; Otte, Tanya; Pinder, Robert; Bowden, J.; Herwehe, J.; Faluvegi, Gregory; Shindell, Drew

2013-01-01

Projecting climate change scenarios to local scales is important for understanding, mitigating, and adapting to the effects of climate change on society and the environment. Many of the global climate models (GCMs) that are participating in the Intergovernmental Panel on Climate Change (IPCC) Fifth Assessment Report (AR5) do not fully resolve regional-scale processes and therefore cannot capture regional-scale changes in temperatures and precipitation. We use a regional climate model (RCM) to dynamically downscale the GCM's large-scale signal to investigate the changes in regional and local extremes of temperature and precipitation that may result from a changing climate. In this paper, we show preliminary results from downscaling the NASA/GISS ModelE IPCC AR5 Representative Concentration Pathway (RCP) 6.0 scenario. We use the Weather Research and Forecasting (WRF) model as the RCM to downscale decadal time slices (1995-2005 and 2025-2035) and illustrate potential changes in regional climate for the continental U.S. that are projected by ModelE and WRF under RCP6.0. The regional climate change scenario is further processed using the Community Multiscale Air Quality modeling system to explore influences of regional climate change on air quality.

Properties of Localized Protons in Neutron Star Matter at Finite Temperatures

NASA Astrophysics Data System (ADS)

Szmaglinski, A.; Kubis, S.; Wójcik, W.

2014-02-01

We study properties of the proton component of neutron star matter for realistic nuclear models. Vanishing of the nuclear symmetry energy implies proton-neutron separation in dense nuclear matter. Protons which form admixture tend to be localized in potential wells. Here, we extend the description of proton localization to finite temperatures. It appears that the protons are still localized at temperatures typical for hot neutron stars. That fact has important astrophysical consequences. Moreover, the temperature inclusion leads to unexpected results for the behavior of the proton localized state.

Characterization of a nuclear localization signal in the foot-and-mouth disease virus polymerase

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sanchez-Aparicio, Maria Teresa; Rosas, Maria Flora; Sobrino, Francisco, E-mail: fsobrino@cbm.uam.es

2013-09-15

We have experimentally tested whether the MRKTKLAPT sequence in FMDV 3D protein (residues 16 to 24) can act as a nuclear localization signal (NLS). Mutants with substitutions in two basic residues within this sequence, K18E and K20E, were generated. A decreased nuclear localization was observed in transiently expressed 3D and its precursor 3CD, suggesting a role of K18 and K20 in nuclear targeting. Fusion of MRKTKLAPT to the green fluorescence protein (GFP) increased the nuclear localization of GFP, which was not observed when GFP was fused to the 3D mutated sequences. These results indicate that the sequence MRKTKLAPT can bemore » functionally considered as a NLS. When introduced in a FMDV full length RNA replacements K18E and K20E led to production of revertant viruses that replaced the acidic residues introduced (E) by K, suggesting that the presence of lysins at positions 18 and 20 of 3D is essential for virus multiplication. - Highlights: • The FMDV 3D polymerase contains a nuclear localization signal. • Replacements K18E and K20E decrease nuclear localization of 3D and its precursor 3CD. • Fusion of the MRKTKLAPT 3D motif to GFP increases the nuclear localization of GFP. • Replacements K18E and K20E abolish the ability of MRKTKLAPT to relocate GFP. • RNAs harboring replacements K18E and K20E lead to recovery of revertant FMDVs.« less

FAA (Federal Aviation Administration) Air Traffic Activity FY 1986.

DTIC Science & Technology

1986-09-30

TEXARKANA STEil N a%.. ITINER4AT OPERATIONS 37964 4 99?? Z5791 197 LOCAL OPERATIONS 14216 12190 z026 TOTAL OPERATIONS 52180 4 997Z 37qRI 47?3 h...ID N 359 53627 MJLOKAI HI 36D S3228 DUSUQUE IA N 361 53044 SALINA KS N 3&2 52426 TEXARKANA AR N 363 52180 5%MANSFIELD LAHM MUNICIPAL OH N 364 5168...N 340 33483 .% k3CIEStEk MN S 341 38238 A% TEXARKANA AR N 34? 37964 HILD GEN LYMAN FIELD HI N 343 31764 SANTA FE NH N 344 37735 MUNCIE DELAWAR= CNTY

Nuclear localization signal regulates porcine circovirus type 2 capsid protein nuclear export through phosphorylation.

PubMed

Hou, Qiang; Hou, Shaohua; Chen, Qing; Jia, Hong; Xin, Ting; Jiang, Yitong; Guo, Xiaoyu; Zhu, Hongfei

2018-02-15

The open reading frame 2 (ORF2) of Porcine circovirus type 2 (PCV2) encodes the major Capsid (Cap) protein, which self-assembles into virus-like particle (VLP) of similar morphology to the PCV2 virion and accumulates in the nucleus through the N-terminal arginine-rich nuclear localization signal (NLS). In this study, PCV2 Cap protein and its derivates were expressed via the baculovirus expression system, and the cellular localization of the recombinant proteins were investigated using anti-Cap mAb by imaging flow cytometry. Analysis of subcellular localization of Cap protein and its variants demonstrated that NLS mediated Cap protein nuclear export as well as nuclear import, and a phosphorylation site (S17) was identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in the NLS domain to regulate Cap protein nuclear export. Phosphorylation of NLS regulating the PCV2 Cap protein nuclear export was also demonstrated in PK15 cells by fluorescence microscopy. Moreover, the influence of Rep and Rep' protein on Cap protein subcellular localization was investigated in PK15 cells. Phosphorylation of NLS regulating Cap protein nuclear export provides more detailed knowledge of the PCV2 viral life cycle. Copyright © 2018 Elsevier B.V. All rights reserved.

Protein Sub-Nuclear Localization Prediction Using SVM and Pfam Domain Information

PubMed Central

Kumar, Ravindra; Jain, Sohni; Kumari, Bandana; Kumar, Manish

2014-01-01

The nucleus is the largest and the highly organized organelle of eukaryotic cells. Within nucleus exist a number of pseudo-compartments, which are not separated by any membrane, yet each of them contains only a specific set of proteins. Understanding protein sub-nuclear localization can hence be an important step towards understanding biological functions of the nucleus. Here we have described a method, SubNucPred developed by us for predicting the sub-nuclear localization of proteins. This method predicts protein localization for 10 different sub-nuclear locations sequentially by combining presence or absence of unique Pfam domain and amino acid composition based SVM model. The prediction accuracy during leave-one-out cross-validation for centromeric proteins was 85.05%, for chromosomal proteins 76.85%, for nuclear speckle proteins 81.27%, for nucleolar proteins 81.79%, for nuclear envelope proteins 79.37%, for nuclear matrix proteins 77.78%, for nucleoplasm proteins 76.98%, for nuclear pore complex proteins 88.89%, for PML body proteins 75.40% and for telomeric proteins it was 83.33%. Comparison with other reported methods showed that SubNucPred performs better than existing methods. A web-server for predicting protein sub-nuclear localization named SubNucPred has been established at http://14.139.227.92/mkumar/subnucpred/. Standalone version of SubNucPred can also be downloaded from the web-server. PMID:24897370

Androgen Receptor (AR) Suppresses Normal Human Prostate Epithelial Cell Proliferation via AR/β-catenin/TCF-4 Complex Inhibition of c-MYC Transcription

PubMed Central

Antony, Lizamma; van der Schoor, Freek; Dalrymple, Susan L.; Isaacs, John T.

2016-01-01

INTRODUCTION Physiologic testosterone continuously stimulates prostate stromal cell secretion of paracrine growth factors (PGFs), which if unopposed would induce hyperplastic overgrowth of normal prostate epithelial cells (PrECs). METHODS Lentiviral shRNA stable knock down of c-MYC, β-catenin, or TCF-4 completely inhibits normal (i.e., non-transformed) human PrECs growth. c-MYC enhancer driven reporter expression and growth is inhibited by two chemically distinct molecules, which prevent β-catenin signaling either by blocking TCF-4 binding (i.e., toxoflavin) or by stimulating degradation (i.e., AVX939). Recombinant DKK1 protein at a dose, which inhibits activation of canonical Wnt signaling does not inhibit PrEC growth. Nuclear β-catenin translocation and PrEC growth is prevented by both lack of PGFs or Akt inhibitor-I. Growth inhibition induced by lack of PGFs, toxoflavin, or Akt inhibitor-I is overcome by constitutive c-MYC transcription. RESULTS In the presence of continuous PGF signaling, PrEC hyperplasia is prevented by androgen binding to AR suppressing c-MYC transcription, resulting in G0 arrest/terminal differentiation independent of Rb, p21, p27, FoxP3, or down regulation of growth factors receptors and instead involves androgen-induced formation of AR/β-catenin/TCF-4 complexes, which suppress c-MYC transcription. Such suppression does not occur when AR is mutated in its zinc-finger binding domain. DISCUSSION Proliferation of non-transformed human PrECs is dependent upon c-MYC transcription via formation/binding of β-catenin/TCF-4 complexes at both 5′ and 3′ c-MYC enhancers stimulated by Wnt-independent, PGF induced Akt signaling. In the presence of continuous PGF signaling, PrEC hyperplasia is prevented by androgen-induced formation of AR/β-catenin/TCF-4 complexes, which retains binding to 3′ c-MYC enhancer, but now suppresses c-MYC transcription. PMID:24913829

In Vivo Effects Of Traditional Ayurvedic Formulations in Drosophila melanogaster Model Relate with Therapeutic Applications

PubMed Central

Dwivedi, Vibha; Anandan, E. M.; Mony, Rajesh S.; Muraleedharan, T. S.; Valiathan, M. S.; Mutsuddi, Mousumi; Lakhotia, Subhash C.

2012-01-01

Background Ayurveda represents the traditional medicine system of India. Since mechanistic details of therapy in terms of current biology are not available in Ayurvedic literature, modern scientific studies are necessary to understand its major concepts and procedures. It is necessary to examine effects of the whole Ayurvedic formulations rather than their “active” components as is done in most current studies. Methods We tested two different categories of formulations, a Rasayana (Amalaki Rasayana or AR, an herbal derivative) and a Bhasma (Rasa-Sindoor or RS, an organo-metallic derivative of mercury), for effects on longevity, development, fecundity, stress-tolerance, and heterogeneous nuclear ribonucleoprotein (hnRNP) levels of Drosophila melanogaster using at least 200 larvae or flies for each assay. Results A 0.5% (weight/volume) supplement of AR or RS affected life-history and other physiological traits in distinct ways. While the size of salivary glands, hnRNP levels in larval tissues, and thermotolerance of larvae/adult flies improved significantly following feeding either of the two formulations, the median life span and starvation resistance improved only with AR. Feeding on AR or RS supplemented food improved fecundity differently. Feeding of larvae and adults with AR increased the fecundity while the same with RS had opposite effect. On the contrary, feeding larvae on normal food and adults on AR supplement had no effect on fecundity but a comparable regime of feeding on RS-supplemented food improved fecundity. RS feeding did not cause heavy metal toxicity. Conclusions The present study with two Ayurvedic formulations reveals formulation-specific effects on several parameters of the fly's life, which seem to generally agree with their recommended human usages in Ayurvedic practices. Thus, Drosophila, with its very rich genetic tools and well-worked-out developmental pathways promises to be a very good model for examining the cellular and molecular bases of the effects of different Ayurvedic formulations. PMID:22606337

A Comparative Study of Standardized Infinity Reference and Average Reference for EEG of Three Typical Brain States

PubMed Central

Zheng, Gaoxing; Qi, Xiaoying; Li, Yuzhu; Zhang, Wei; Yu, Yuguo

2018-01-01

The choice of different reference electrodes plays an important role in deciphering the functional meaning of electroencephalography (EEG) signals. In recent years, the infinity zero reference using the reference electrode standard technique (REST) has been increasingly applied, while the average reference (AR) was generally advocated as the best available reference option in previous classical EEG studies. Here, we designed EEG experiments and performed a direct comparison between the influences of REST and AR on EEG-revealed brain activity features for three typical brain behavior states (eyes-closed, eyes-open and music-listening). The analysis results revealed the following observations: (1) there is no significant difference in the alpha-wave-blocking effect during the eyes-open state compared with the eyes-closed state for both REST and AR references; (2) there was clear frontal EEG asymmetry during the resting state, and the degree of lateralization under REST was higher than that under AR; (3) the global brain functional connectivity density (FCD) and local FCD have higher values for REST than for AR under different behavior states; and (4) the value of the small-world network characteristic in the eyes-closed state is significantly (in full, alpha, beta and gamma frequency bands) higher than that in the eyes-open state, and the small-world effect under the REST reference is higher than that under AR. In addition, the music-listening state has a higher small-world network effect than the eyes-closed state. The above results suggest that typical EEG features might be more clearly presented by applying the REST reference than by applying AR when using a 64-channel recording. PMID:29593490

Crosstalk Between Adrenergic and Toll-Like Receptors in Human Mesenchymal Stem Cells and Keratinocytes: A Recipe for Impaired Wound Healing

PubMed Central

Ramirez, Sandra R.; La, Thi Dinh; Gorouhi, Farzam; Nguyen, Chuong; Lin, Benjamin R.; Mashburn, Chelcy; Stewart, Heather; Peavy, Thomas R.; Nolta, Jan A.

2014-01-01

Previous studies demonstrate that skin wounds generate epinephrine (EPI) that can activate local adrenergic receptors (ARs), impairing healing. Bacterially derived activators of Toll-like receptors (TLRs) within the wound initiate inflammatory responses and can also impair healing. In this study, we examined the hypothesis that these two pathways crosstalk to one another, using EPI and macrophage-activating lipopeptide-2 (MALP2) to activate ARs and TLR2, respectively, in human bone marrow-derived mesenchymal stem cells (BM-MSCs) and neonatal keratinocytes (NHKs). BM-MSCs exposed to EPI significantly (p < .05) increased TLR2 message (sevenfold BM-MSCs), TLR2 protein (twofold), and myeloid differentiation factor 88 (MyD88) (fourfold). Conversely, activation of TLR2 by MALP2 in these cells increased β2-AR message (twofold in BM-MSCs, 2.7-fold in NHKs), β2-AR protein (2.5-fold), phosphorylation of β-AR-activated kinase (p-BARK, twofold), and induced release of EPI from both cell types (twofold). Treating cells with EPI and MALP2 together, as would be encountered in a wound, increased β2-AR and p-BARK protein expression (sixfold), impaired cell migration (BM-MSCs- 21%↓ and NHKs- 60%↓, p < .002), and resulted in a 10-fold (BM-MSCs) and 51-fold (NHKs) increase in release of IL-6 (p < .001) responses that were remarkably reduced by pretreatment with β2-AR antagonists. In vivo, EPI-stressed animals exhibited impaired healing, with elevated levels of TLR2, MyD88, and IL-6 in the wounds (p < .05) relative to nonstressed controls. Thus, our data describe a recipe for decreasing cell migration and exacerbating inflammation via novel crosstalk between the adrenergic and Toll-like receptor pathways in BM-MSCs and NHKs. PMID:24760207

Ralstonia solanacearum novel E3 ubiquitin ligase (NEL) effectors RipAW and RipAR suppress pattern-triggered immunity in plants.

PubMed

Nakano, Masahito; Oda, Kenji; Mukaihara, Takafumi

2017-07-01

Ralstonia solanacearum is the causal agent of bacterial wilt in solanaceous crops. This pathogen injects more than 70 effector proteins into host plant cells via the Hrp type III secretion system to cause a successful infection. However, the function of these effectors in plant cells, especially in the suppression of plant immunity, remains largely unknown. In this study, we characterized two Ralstonia solanacearum effectors, RipAW and RipAR, which share homology with the IpaH family of effectors from animal and plant pathogenic bacteria, that have a novel E3 ubiquitin ligase (NEL) domain. Recombinant RipAW and RipAR show E3 ubiquitin ligase activity in vitro. RipAW and RipAR localized to the cytoplasm of plant cells and significantly suppressed pattern-triggered immunity (PTI) responses such as the production of reactive oxygen species and the expression of defence-related genes when expressed in leaves of Nicotiana benthamiana. Mutation in the conserved cysteine residue in the NEL domain of RipAW completely abolished the E3 ubiquitin ligase activity in vitro and the ability to suppress PTI responses in plant leaves. These results indicate that RipAW suppresses plant PTI responses through the E3 ubiquitin ligase activity. Unlike other members of the IpaH family of effectors, RipAW and RipAR had no leucine-rich repeat motifs in their amino acid sequences. A conserved C-terminal region of RipAW is indispensable for PTI suppression. Transgenic Arabidopsis plants expressing RipAW and RipAR showed increased disease susceptibility, suggesting that RipAW and RipAR contribute to bacterial virulence in plants.