The N-CoR complex enables chromatin remodeler SNF2H to enhance repression by thyroid hormone receptor

PubMed Central

Alenghat, Theresa; Yu, Jiujiu; Lazar, Mitchell A

2006-01-01

Unliganded thyroid hormone receptor (TR) actively represses transcription via the nuclear receptor corepressor (N-CoR)/histone deacetylase 3 (HDAC3) complex. Although transcriptional activation by liganded receptors involves chromatin remodeling, the role of ATP-dependent remodeling in receptor-mediated repression is unknown. Here we report that SNF2H, the mammalian ISWI chromatin remodeling ATPase, is critical for repression of a genomically integrated, TR-regulated reporter gene. N-CoR and HDAC3 are both required for recruitment of SNF2H to the repressed gene. SNF2H does not interact directly with the N-CoR/HDAC3 complex, but binds to unacetylated histone H4 tails, suggesting that deacetylase activity of the corepressor complex is critical to SNF2H function. Indeed, HDAC3 as well as SNF2H are required for nucleosomal organization on the TR target gene. Consistent with these findings, reduction of SNF2H induces expression of an endogenous TR-regulated gene, dio1, in liver cells. Thus, although not apparent from studies of transiently transfected reporter genes, gene repression by TR involves the targeting of chromatin remodeling factors to repressed genes by the HDAC activity of nuclear receptor corepressors. PMID:16917504

Corepressors: custom tailoring and alterations while you wait

PubMed Central

Goodson, Michael; Jonas, Brian A.; Privalsky, Martin A.

2005-01-01

A diverse cadre of metazoan transcription factors mediate repression by recruiting protein complexes containing the SMRT (silencing mediator of retinoid and thyroid hormone receptor) or N-CoR (nuclear receptor corepressor) corepressors. SMRT and N-CoR nucleate the assembly of still larger corepressor complexes that perform the specific molecular incantations necessary to confer transcriptional repression. Although SMRT and N-CoR are paralogs and possess similar molecular architectures and mechanistic strategies, they nonetheless exhibit distinct molecular and biological properties. It is now clear that the functions of both SMRT and N-CoR are further diversified through alternative mRNA splicing, yielding a series of corepressor protein variants that participate in distinctive transcription factor partnerships and display distinguishable repression properties. This review will discuss what is known about the structure and actions of SMRT, N-CoR, and their splicing variants, and how alternative splicing may allow the functions of these corepressors to be adapted and tailored to different cells and to different developmental stages. PMID:16604171

dSAP18 and dHDAC1 contribute to the functional regulation of the Drosophila Fab-7 element.

PubMed

Canudas, Silvia; Pérez, Silvia; Fanti, Laura; Pimpinelli, Sergio; Singh, Navjot; Hanes, Steven D; Azorín, Fernando; Espinás, M Lluïsa

2005-01-01

It was described earlier that the Drosophila GAGA factor [Trithorax-like (Trl)] interacts with dSAP18, which, in mammals, was reported to be a component of the Sin3-HDAC co-repressor complex. GAGA-dSAP18 interaction was proposed to contribute to the functional regulation of the bithorax complex (BX-C). Here, we show that mutant alleles of Trl, dsap18 and drpd3/hdac1 enhance A6-to-A5 transformation indicating a contribution to the regulation of Abd-B expression at A6. In A6, expression of Abd-B is driven by the iab-6 enhancer, which is insulated from iab-7 by the Fab-7 element. Here, we report that GAGA, dSAP18 and dRPD3/HDAC1 co-localize to ectopic Fab-7 sites in polytene chromosomes and that mutant Trl, dsap18 and drpd3/hdac1 alleles affect Fab-7-dependent silencing. Consistent with these findings, chromatin immunoprecipitation analysis shows that, in Drosophila embryos, the endogenous Fab-7 element is hypoacetylated at histones H3 and H4. These results indicate a contribution of GAGA, dSAP18 and dRPD3/HDAC1 to the regulation of Fab-7 function.

Symmetric dimethylation of H3R2 is a newly identified histone mark that supports euchromatin maintenance.

PubMed

Migliori, Valentina; Müller, Julius; Phalke, Sameer; Low, Diana; Bezzi, Marco; Mok, Wei Chuen; Sahu, Sanjeeb Kumar; Gunaratne, Jayantha; Capasso, Paola; Bassi, Christian; Cecatiello, Valentina; De Marco, Ario; Blackstock, Walter; Kuznetsov, Vladimir; Amati, Bruno; Mapelli, Marina; Guccione, Ernesto

2012-01-08

The asymmetric dimethylation of histone H3 arginine 2 (H3R2me2a) acts as a repressive mark that antagonizes trimethylation of H3 lysine 4. Here we report that H3R2 is also symmetrically dimethylated (H3R2me2s) by PRMT5 and PRMT7 and present in euchromatic regions. Profiling of H3-tail interactors by SILAC MS revealed that H3R2me2s excludes binding of RBBP7, a central component of co-repressor complexes Sin3a, NURD and PRC2. Conversely H3R2me2s enhances binding of WDR5, a common component of the coactivator complexes MLL, SET1A, SET1B, NLS1 and ATAC. The interaction of histone H3 with WDR5 distinguishes H3R2me2s from H3R2me2a, which impedes the recruitment of WDR5 to chromatin. The crystallographic structure of WDR5 and the H3R2me2s peptide elucidates the molecular determinants of this high affinity interaction. Our findings identify H3R2me2s as a previously unknown mark that keeps genes poised in euchromatin for transcriptional activation upon cell-cycle withdrawal and differentiation in human cells.

Nuclear Matrix protein SMAR1 represses HIV-1 LTR mediated transcription through chromatin remodeling

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

Sreenath, Kadreppa; Pavithra, Lakshminarasimhan; Singh, Sandeep

2010-04-25

Nuclear Matrix and MARs have been implicated in the transcriptional regulation of host as well as viral genes but their precise role in HIV-1 transcription remains unclear. Here, we show that > 98% of HIV sequences contain consensus MAR element in their promoter. We show that SMAR1 binds to the LTR MAR and reinforces transcriptional silencing by tethering the LTR MAR to nuclear matrix. SMAR1 associated HDAC1-mSin3 corepressor complex is dislodged from the LTR upon cellular activation by PMA/TNFalpha leading to an increase in the acetylation and a reduction in the trimethylation of histones, associated with the recruitment of RNAmore » Polymerase II on the LTR. Overexpression of SMAR1 lead to reduction in LTR mediated transcription, both in a Tat dependent and independent manner, resulting in a decreased virion production. These results demonstrate the role of SMAR1 in regulating viral transcription by alternative compartmentalization of LTR between the nuclear matrix and chromatin.« less

Quantitative determination of conformational, dynamic, and kinetic parameters of a ligand-protein/DNA complex from a complete relaxation and conformational exchange matrix analysis of intermolecular transferred NOESY.

PubMed

Moseley, H N; Lee, W; Arrowsmith, C H; Krishna, N R

1997-05-06

We report a quantitative analysis of the 13C-edited intermolecular transferred NOESY (inter-TrNOESY) spectrum of the trp-repressor/operator complex (trp-rep/op) with [ul-13C/15N]-L-tryptophan corepressor using a computer program implementing complete relaxation and conformational exchange matrix (CORCEMA) methodology [Moseley et al. (1995) J. Magn. Reson. 108B, 243-261]. Using complete mixing time curves of three inter-TrNOESY peaks between the tryptophan and the Trp-rep/op, this self-consistent analysis determined the correlation time of the bound species (tauB = 13.5 ns) and the exchange off-rate (k(off) = 3.6 s(-1)) of the corepressor. In addition, the analysis estimated the correlation time of the free species (tauF approximately 0.15 ns). Also, we demonstrate the sensitivity of these inter-TrNOESY peaks to several factors including the k(off) and orientation of the tryptophan corepressor within the binding site. The analysis indicates that the crystal structure orientation for the corepressor is compatible with the solution NMR data.

The corepressor CtBP interacts with Evi-1 to repress transforming growth factor beta signaling.

PubMed

Izutsu, K; Kurokawa, M; Imai, Y; Maki, K; Mitani, K; Hirai, H

2001-05-01

Evi-1 is a zinc finger nuclear protein whose inappropriate expression leads to leukemic transformation of hematopoietic cells in mice and humans. This was previously shown to block the antiproliferative effect of transforming growth factor beta (TGF-beta). Evi-1 represses TGF-beta signaling by direct interaction with Smad3 through its first zinc finger motif. Here, it is demonstrated that Evi-1 represses Smad-induced transcription by recruiting C-terminal binding protein (CtBP) as a corepressor. Evi-1 associates with CtBP1 through one of the consensus binding motifs, and this association is required for efficient inhibition of TGF-beta signaling. A specific inhibitor for histone deacetylase (HDAc) alleviates Evi-1-mediated repression of TGF-beta signaling, suggesting that HDAc is involved in the transcriptional repression by Evi-1. This identifies a novel function of Evi-1 as a member of corepressor complexes and suggests that aberrant recruitment of corepressors is one of the mechanisms for Evi-1-induced leukemogenesis.

The MTA family proteins as novel histone H3 binding proteins.

PubMed

Wu, Meng; Wang, Lina; Li, Qian; Li, Jiwen; Qin, Jun; Wong, Jiemin

2013-01-03

The nucleosome remodeling and histone deacetylase complex (Mi2/NRD/NuRD/NURD) has a broad role in regulation of transcription, DNA repair and cell cycle. Previous studies have revealed a specific interaction between NURD and histone H3N-terminal tail in vitro that is not observed for another HDAC1/2-containing complex, Sin3A. However, the subunit(s) responsible for specific binding of H3 by NURD has not been defined. In this study, we show among several class I HDAC-containing corepressor complexes only NURD exhibits a substantial H3 tail-binding activity in vitro. We present the evidence that the MTA family proteins within the NURD complex interact directly with H3 tail. Extensive in vitro binding assays mapped the H3 tail-binding domain to the C-terminal region of MTA1 and MTA2. Significantly, although the MTA1 and MTA2 mutant proteins with deletion of the C-terminal H3 tail binding domain were assembled into the endogenous NURD complex when expressed in mammalian cells, the resulting NURD complexes were deficient in binding H3 tail in vitro, indicating that the MTA family proteins are required for the observed specific binding of H3 tail peptide by NURD in vitro. However, chromatin fractionation experiments show that the NURD complexes with impaired MTA1/2-H3 tail binding activity remained to be associated with chromatin in cells. Together our study reveals a novel histone H3-binding activity for the MTA family proteins and provides evidence that the MTA family proteins mediate the in vitro specific binding of H3 tail peptide by NURD complex. However, multiple mechanisms are likely to contribute to the chromatin association of NURD complex in cells. Our finding also raises the possibility that the MTA family proteins may exert their diverse biological functions at least in part through their direct interaction with H3 tail.

The MTA family proteins as novel histone H3 binding proteins

PubMed Central

2013-01-01

Background The nucleosome remodeling and histone deacetylase complex (Mi2/NRD/NuRD/NURD) has a broad role in regulation of transcription, DNA repair and cell cycle. Previous studies have revealed a specific interaction between NURD and histone H3N-terminal tail in vitro that is not observed for another HDAC1/2-containing complex, Sin3A. However, the subunit(s) responsible for specific binding of H3 by NURD has not been defined. Results In this study, we show among several class I HDAC-containing corepressor complexes only NURD exhibits a substantial H3 tail-binding activity in vitro. We present the evidence that the MTA family proteins within the NURD complex interact directly with H3 tail. Extensive in vitro binding assays mapped the H3 tail-binding domain to the C-terminal region of MTA1 and MTA2. Significantly, although the MTA1 and MTA2 mutant proteins with deletion of the C-terminal H3 tail binding domain were assembled into the endogenous NURD complex when expressed in mammalian cells, the resulting NURD complexes were deficient in binding H3 tail in vitro, indicating that the MTA family proteins are required for the observed specific binding of H3 tail peptide by NURD in vitro. However, chromatin fractionation experiments show that the NURD complexes with impaired MTA1/2-H3 tail binding activity remained to be associated with chromatin in cells. Conclusions Together our study reveals a novel histone H3-binding activity for the MTA family proteins and provides evidence that the MTA family proteins mediate the in vitro specific binding of H3 tail peptide by NURD complex. However, multiple mechanisms are likely to contribute to the chromatin association of NURD complex in cells. Our finding also raises the possibility that the MTA family proteins may exert their diverse biological functions at least in part through their direct interaction with H3 tail. PMID:23286669

Role of co-regulators in metabolic and transcriptional actions of thyroid hormone.

PubMed

Astapova, Inna

2016-04-01

Thyroid hormone (TH) controls a wide range of physiological processes through TH receptor (TR) isoforms. Classically, TRs are proposed to function as tri-iodothyronine (T3)-dependent transcription factors: on positively regulated target genes, unliganded TRs mediate transcriptional repression through recruitment of co-repressor complexes, while T3 binding leads to dismissal of co-repressors and recruitment of co-activators to activate transcription. Co-repressors and co-activators were proposed to play opposite roles in the regulation of negative T3 target genes and hypothalamic-pituitary-thyroid axis, but exact mechanisms of the negative regulation by TH have remained elusive. Important insights into the roles of co-repressors and co-activators in different physiological processes have been obtained using animal models with disrupted co-regulator function. At the same time, recent studies interrogating genome-wide TR binding have generated compelling new data regarding effects of T3, local chromatin structure, and specific response element configuration on TR recruitment and function leading to the proposal of new models of transcriptional regulation by TRs. This review discusses data obtained in various mouse models with manipulated function of nuclear receptor co-repressor (NCoR or NCOR1) and silencing mediator of retinoic acid receptor and thyroid hormone receptor (SMRT or NCOR2), and family of steroid receptor co-activators (SRCs also known as NCOAs) in the context of TH action, as well as insights into the function of co-regulators that may emerge from the genome-wide TR recruitment analysis. © 2016 Society for Endocrinology.

ING2 (inhibitor of growth protein-2) plays a crucial role in preimplantation development.

PubMed

Zhou, Lin; Wang, Pei; Zhang, Juanjuan; Heng, Boon Chin; Tong, Guo Qing

2016-02-01

ING2 (inhibitor of growth protein-2) is a member of the ING-gene family and participates in diverse cellular processes involving tumor suppression, DNA repair, cell cycle regulation, and cellular senescence. As a subunit of the Sin3 histone deacetylase complex co-repressor complex, ING2 binds to H3K4me3 to regulate chromatin modification and gene expression. Additionally, ING2 recruits histone methyltransferase (HMT) activity for gene repression, which is independent of the HDAC class I or II pathway. However, the physiological function of ING2 in mouse preimplantation embryo development has not yet been characterized previously. The expression, localization and function of ING2 during preimplantation development were investigated in this study. We showed increasing expression of ING2 within the nucleus from the 4-cell embryo stage onwards; and that down-regulation of ING2 expression by endoribonuclease-prepared small interfering RNA (esiRNA) microinjection results in developmental arrest during the morula to blastocyst transition. Embryonic cells microinjected with ING2-specific esiRNA exhibited decreased blastulation rate compared to the negative control. Further investigation of the underlying mechanism indicated that down-regulation of ING2 significantly increased expression of p21, whilst decreasing expression of HDAC1. These results suggest that ING2 may play a crucial role in the process of preimplantation embryo development through chromatin regulation.

A New Member of the Sin3 Family of Corepressors Is Essential for Cell Viability and Required for Retroelement Propagation in Fission Yeast

PubMed Central

Dang, Van Dinh; Benedik, Michael J.; Ekwall, Karl; Choi, Jeannie; Allshire, Robin C.; Levin, Henry L.

1999-01-01

Tf1 is a long terminal repeat (LTR)-containing retrotransposon that propagates within the fission yeast Schizosaccharomyces pombe. LTR-retrotransposons possess significant similarity to retroviruses and therefore serve as retrovirus models. To determine what features of the host cell are important for the proliferation of this class of retroelements, we screened for mutations in host genes that reduced the transposition activity of Tf1. We report here the isolation and characterization of pst1+, a gene required for Tf1 transposition. The predicted amino acid sequence of Pst1p possessed high sequence homology with the Sin3 family of proteins, known for their interaction with histone deacetylases. However, unlike the SIN3 gene of Saccharomyces cerevisiae, pst1+ is essential for cell viability. Immunofluorescence microscopy indicated that Pst1p was localized in the nucleus. Consistent with the critical role previously reported for Sin3 proteins in the histone acetylation process, we found that the growth of the strain with the pst1-1 allele was supersensitive to the specific histone deacetylase inhibitor trichostatin A. However, our analysis of strains with the pst1-1 mutation was unable to detect any changes in the acetylation of specific lysines of histones H3 and H4 as measured in bulk chromatin. Interestingly, the pst1-1 mutant strain produced wild-type levels of Tf1-encoded proteins and cDNA, indicating that the defect in transposition occurred after reverse transcription. The results of immunofluorescence microscopy showed that the nuclear localization of the Tf1 capsid protein was disrupted in the strain with the pst1-1 mutation, indicating an important role of pst1+ in modulating the nuclear import of Tf1 virus-like particles. PMID:10022921

Restoration of Tamoxifen Sensitivity in Estrogen Receptor–Negative Breast Cancer Cells: Tamoxifen-Bound Reactivated ER Recruits Distinctive Corepressor Complexes

PubMed Central

Sharma, Dipali; Saxena, Neeraj K.; Davidson, Nancy E.; Vertino, Paula M.

2010-01-01

Breast tumors expressing estrogen receptor-α (ER) respond well to therapeutic strategies using selective ER modulators, such as tamoxifen. However, ~ 30% of invasive breast cancers are hormone independent because they lack ER expression due to hypermethylation of ER promoter. Treatment of ER-negative breast cancer cells with demethylating agents [5-aza-2′-deoxycytidine (5-aza-dC)] and histone deacetylase (HDAC) inhibitors (trichostatin A) leads to expression of ER mRNA and functional protein. Here, we examined whether epigenetically reactivated ER is a target for tamoxifen therapy. Following treatment with trichostatin A and 5-aza-dC, the formerly unresponsive ER-negative MDA-MB-231 breast cancer cells became responsive to tamoxifen. Tamoxifen-mediated inhibition of cell growth in these cells is mediated at least in part by the tamoxifen-bound ER. Tamoxifen-bound reactivated ER induces transcriptional repression at estrogen-responsive genes by ordered recruitment of multiple distinct chromatin-modifying complexes. Using chromatin immunoprecipitation, we show recruitment of two different corepressor complexes to ER-responsive promoters in a mutually exclusive and sequential manner: the nuclear receptor corepressor-HDAC3 complex followed by nucleosome remodeling and histone deacetylation complex. The mechanistic insight provided by this study might help in designing therapeutic strategies directed toward epigenetic mechanisms in the prevention or treatment of breast cancer. PMID:16778215

Eukaryotic translation initiator protein 1A isoform, CCS-3, enhances the transcriptional repression of p21CIP1 by proto-oncogene FBI-1 (Pokemon/ZBTB7A).

PubMed

Choi, Won-Il; Kim, Youngsoo; Kim, Yuri; Yu, Mi-young; Park, Jungeun; Lee, Choong-Eun; Jeon, Bu-Nam; Koh, Dong-In; Hur, Man-Wook

2009-01-01

FBI-1, a member of the POK (POZ and Kruppel) family of transcription factors, plays a role in differentiation, oncogenesis, and adipogenesis. eEF1A is a eukaryotic translation elongation factor involved in several cellular processes including embryogenesis, oncogenic transformation, cell proliferation, and cytoskeletal organization. CCS-3, a potential cervical cancer suppressor, is an isoform of eEF1A. We found that eEF1A forms a complex with FBI-1 by co-immunoprecipitation, SDS-PAGE, and MALDI-TOF Mass analysis of the immunoprecipitate. GST fusion protein pull-downs showed that FBI-1 directly interacts with eEF1A and CCS-3 via the zinc finger and POZ-domain of FBI-1. FBI-1 co-localizes with either eEF1A or CCS-3 at the nuclear periplasm. CCS-3 enhances transcriptional repression of the p21CIP1 gene (hereafter referred to as p21) by FBI-1. The POZ-domain of FBI-1 interacts with the co-repressors, SMRT and BCoR. We found that CCS-3 also interacts with the co-repressors independently. The molecular interaction between the co-repressors and CCS-3 at the POZ-domain of FBI-1 appears to enhance FBI-1 mediated transcriptional repression. Our data suggest that CCS-3 may be important in cell differentiation, tumorigenesis, and oncogenesis by interacting with the proto-oncogene FBI-1 and transcriptional co-repressors. Copyright 2009 S. Karger AG, Basel.

Control of developmentally primed erythroid genes by combinatorial co-repressor actions

PubMed Central

Stadhouders, Ralph; Cico, Alba; Stephen, Tharshana; Thongjuea, Supat; Kolovos, Petros; Baymaz, H. Irem; Yu, Xiao; Demmers, Jeroen; Bezstarosti, Karel; Maas, Alex; Barroca, Vilma; Kockx, Christel; Ozgur, Zeliha; van Ijcken, Wilfred; Arcangeli, Marie-Laure; Andrieu-Soler, Charlotte; Lenhard, Boris; Grosveld, Frank; Soler, Eric

2015-01-01

How transcription factors (TFs) cooperate within large protein complexes to allow rapid modulation of gene expression during development is still largely unknown. Here we show that the key haematopoietic LIM-domain-binding protein-1 (LDB1) TF complex contains several activator and repressor components that together maintain an erythroid-specific gene expression programme primed for rapid activation until differentiation is induced. A combination of proteomics, functional genomics and in vivo studies presented here identifies known and novel co-repressors, most notably the ETO2 and IRF2BP2 proteins, involved in maintaining this primed state. The ETO2–IRF2BP2 axis, interacting with the NCOR1/SMRT co-repressor complex, suppresses the expression of the vast majority of archetypical erythroid genes and pathways until its decommissioning at the onset of terminal erythroid differentiation. Our experiments demonstrate that multimeric regulatory complexes feature a dynamic interplay between activating and repressing components that determines lineage-specific gene expression and cellular differentiation. PMID:26593974

NMR assignments of SPOC domain of the human transcriptional corepressor SHARP in complex with a C-terminal SMRT peptide.

PubMed

Mikami, Suzuka; Kanaba, Teppei; Ito, Yutaka; Mishima, Masaki

2013-10-01

The transcriptional corepressor SMRT/HDAC1-associated repressor protein (SHARP) recruits histone deacetylases. Human SHARP protein is thought to function in processes involving steroid hormone responses and the Notch signaling pathway. SHARP consists of RNA recognition motifs (RRMs) in the N-terminal region and the spen paralog and ortholog C-terminal (SPOC) domain in the C-terminal region. It is known that the SPOC domain binds the LSD motif in the C-terminal tail of corepressors silencing mediator for retinoid and thyroid receptor (SMRT)/nuclear receptor corepressor (NcoR). We are interested in delineating the mechanism by which the SPOC domain recognizes the LSD motif of the C-terminal tail of SMRT/NcoR. To this end, we are investigating the tertiary structure of the SPOC/SMRT peptide using NMR. Herein, we report on the (1)H, (13)C and (15)N resonance assignments of the SPOC domain in complex with a SMRT peptide, which contributes towards a structural understanding of the SPOC/SMRT peptide and its molecular recognition.

Transcription factor FBI-1 acts as a dual regulator in adipogenesis by coordinated regulation of cyclin-A and E2F-4.

PubMed

Laudes, Matthias; Bilkovski, Roman; Oberhauser, Frank; Droste, Andrea; Gomolka, Matthias; Leeser, Uschi; Udelhoven, Michael; Krone, Wilhelm

2008-05-01

Generation of new adipocytes plays a major role in the development of obesity. We previously have shown that transcriptional repressor factor that binds to IST (FBI)-1 exerts a dual effect in the process of adipogenesis by inhibiting proliferation and promoting differentiation of preadipocytes. The aim of the present study was to identify FBI-1 regulated molecular effectors that could account for these effects. Overexpressing FBI-1 in preadipocytes resulted in reduced expression of the cell cycle regulator cyclin A, which may explain FBI-1 induced inhibition of proliferation. Interestingly, FBI-1 repressed cyclin A promoter activity through an indirect mechanisms that did not involve direct binding of FBI-1 to the promoter sequence, but rather FBI-1 inhibition of transcriptional activator Sp1 binding to a regulatory element at -452 to -443. We also show that FBI-1 promotes terminal preadipocyte differentiation through a mechanism involving decreased levels of expression of the PPARgamma inhibitor E2F-4. FBI-1 significantly reduced E2F-4 promoter activity. Contrary to cyclin A, we found FBI-1-induced repression of E2F-4 is mediated by a direct mechanism via a FBI-1 regulatory element at -11 to -5. As function of transcriptional repressors normally depends on the presence of regulatory co-factors we also performed expression profiling of potential FBI-1 co-repressors throughout adipogenesis. In these experiments Sin3A and histon deacetylase (HDAC)-1 showed a similar expression pattern compared to FBI-1. Strikingly, co-immunoprecipitation studies revealed that FBI-1 binds Sin3A and HDAC-1 to form a repressor complex. Furthermore, by mutational analysis the amino terminal Poxvirus (POZ) domain of FBI-1 was found to be important for Sin3A and HDAC-1 binding. Taken together, FBI-1 is the first transcriptional repressor shown to act as a dual regulator in adipogenesis exerting repressor activities on target genes by both, direct and indirect mechanisms.

Complex Actions of Thyroid Hormone Receptor Antagonist NH-3 on Gene Promoters in Different Cell Lines

PubMed Central

Shah, Vanya; Nguyen, Phuong; Nguyen, Ngoc-Ha; Togashi, Marie; Scanlan, Thomas S.; Baxter, John D.; Webb, Paul

2014-01-01

It is desirable to obtain new antagonists for thyroid hormone (TRs) and other nuclear receptors (NRs). We previously used X-ray structural models of TR ligand binding domains (LBDs) to design compounds, such as NH-3, that impair coactivator binding to activation function 2 (AF-2) and block thyroid hormone (triiodothyronine, T3) actions. However, TRs bind DNA and are transcriptionally active without ligand. Thus, NH-3 could modulate TR activity via effects on other coregulator interaction surfaces, such as activation function (AF-1) and corepressor binding sites. Here, we find that NH-3 blocks TR-LBD interactions with coactivators and corepressors and also inhibits activities of AF-1 and AF-2 in transfections. While NH-3 lacks detectable agonist activity at T3-activated genes in GC pituitary cells it nevertheless activates spot 14 (S14) in HTC liver cells with the latter effect accompanied by enhanced histone H4 acetylation and coactivator recruitment at the S14 promoter. Surprisingly, T3 promotes corepressor recruitment to target promoters. NH-3 effects vary; we observe transient recruitment of N-CoR to S14 in GC cells and dismissal and rebinding of N-CoR to the same promoter in HTC cells. We propose that NH-3 will generally behave as an antagonist by blocking AF-1 and AF-2 but that complex effects on coregulator recruitment may result in partial/mixed agonist effects that are independent of blockade of T3 binding in some contexts. These properties could ultimately be utilized in drug design and development of new selective TR modulators. PMID:18930112

The structure of the core NuRD repression complex provides insights into its interaction with chromatin

PubMed Central

Millard, Christopher J; Varma, Niranjan; Saleh, Almutasem; Morris, Kyle; Watson, Peter J; Bottrill, Andrew R; Fairall, Louise; Smith, Corinne J; Schwabe, John WR

2016-01-01

The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities. The complex regulates the higher-order structure of chromatin, and has important roles in the regulation of gene expression, DNA damage repair and cell differentiation. HDACs 1 and 2 are recruited by the MTA1 corepressor to form the catalytic core of the complex. The histone chaperone protein RBBP4, has previously been shown to bind to the carboxy-terminal tail of MTA1. We show that MTA1 recruits a second copy of RBBP4. The crystal structure reveals an extensive interface between MTA1 and RBBP4. An EM structure, supported by SAXS and crosslinking, reveals the architecture of the dimeric HDAC1:MTA1:RBBP4 assembly which forms the core of the NuRD complex. We find evidence that in this complex RBBP4 mediates interaction with histone H3 tails, but not histone H4, suggesting a mechanism for recruitment of the NuRD complex to chromatin. DOI: http://dx.doi.org/10.7554/eLife.13941.001 PMID:27098840

Hydrophobic patches on SMAD2 and SMAD3 determine selective binding to cofactors.

PubMed

Miyazono, Ken-Ichi; Moriwaki, Saho; Ito, Tomoko; Kurisaki, Akira; Asashima, Makoto; Tanokura, Masaru

2018-03-27

The transforming growth factor-β (TGF-β) superfamily of cytokines regulates various biological processes, including cell proliferation, immune responses, autophagy, and senescence. Dysregulation of TGF-β signaling causes various diseases, such as cancer and fibrosis. SMAD2 and SMAD3 are core transcription factors involved in TGF-β signaling, and they form heterotrimeric complexes with SMAD4 (SMAD2-SMAD2-SMAD4, SMAD3-SMAD3-SMAD4, and SMAD2-SMAD3-SMAD4) in response to TGF-β signaling. These heterotrimeric complexes interact with cofactors to control the expression of TGF-β-dependent genes. SMAD2 and SMAD3 may promote or repress target genes depending on whether they form complexes with other transcription factors, coactivators, or corepressors; therefore, the selection of specific cofactors is critical for the appropriate activity of these transcription factors. To reveal the structural basis by which SMAD2 and SMAD3 select cofactors, we determined the crystal structures of SMAD3 in complex with the transcription factor FOXH1 and SMAD2 in complex with the transcriptional corepressor SKI. The structures of the complexes show that the MAD homology 2 (MH2) domains of SMAD2 and SMAD3 have multiple hydrophobic patches on their surfaces. The cofactors tether to various subsets of these patches to interact with SMAD2 and SMAD3 in a cooperative or competitive manner to control the output of TGF-β signaling. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Sin3b interacts with Myc and decreases Myc levels.

PubMed

Garcia-Sanz, Pablo; Quintanilla, Andrea; Lafita, M Carmen; Moreno-Bueno, Gema; García-Gutierrez, Lucia; Tabor, Vedrana; Varela, Ignacio; Shiio, Yuzuru; Larsson, Lars-Gunnar; Portillo, Francisco; Leon, Javier

2014-08-08

Myc expression is deregulated in many human cancers. A yeast two-hybrid screen has revealed that the transcriptional repressor Sin3b interacts with Myc protein. Endogenous Myc and Sin3b co-localize and interact in the nuclei of human and rat cells, as assessed by co-immunoprecipitation, immunofluorescence, and proximity ligation assay. The interaction is Max-independent. A conserved Myc region (amino acids 186-203) is required for the interaction with Sin3 proteins. Histone deacetylase 1 is recruited to Myc-Sin3b complexes, and its deacetylase activity is required for the effects of Sin3b on Myc. Myc and Sin3a/b co-occupied many sites on the chromatin of human leukemia cells, although the presence of Sin3 was not associated with gene down-regulation. In leukemia cells and fibroblasts, Sin3b silencing led to Myc up-regulation, whereas Sin3b overexpression induced Myc deacetylation and degradation. An analysis of Sin3b expression in breast tumors revealed an association between low Sin3b expression and disease progression. The data suggest that Sin3b decreases Myc protein levels upon Myc deacetylation. As Sin3b is also required for transcriptional repression by Mxd-Max complexes, our results suggest that, at least in some cell types, Sin3b limits Myc activity through two complementary activities: Mxd-dependent gene repression and reduction of Myc levels. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

MTA family of coregulators in nuclear receptor biology and pathology

PubMed Central

Manavathi, Bramanandam; Singh, Kamini; Kumar, Rakesh

2007-01-01

Nuclear receptors (NRs) rely on coregulators (coactivators and corepressors) to modulate the transcription of target genes. By interacting with nucleosome remodeling complexes, NR coactivators potentiate transcription, whereas corepressors inhibit transcription of the target genes. Metastasis-associated proteins (MTA) represent an emerging family of novel NR coregulators. In general, MTA family members form independent nucleosome remodeling and deacetylation (NuRD) complexes and repress the transcription of different genes by recruiting histone deacetylases onto their target genes. However, MTA1 also acts as a coactivator in a promoter-context dependent manner. Recent findings that repression of estrogen receptor transactivation functions by MTA1, MTA1s, and MTA2 and regulation of MTA3 by estrogen signaling have indicated the significance of these proteins in NR signaling. Here, we highlight the action of MTA proteins on NR signaling and their roles in pathophysiological conditions. PMID:18174918

Epigenetic involvement of Alien/ESET complex in thyroid hormone-mediated repression of E2F1 gene expression and cell proliferation

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

Hong, Wei, E-mail: hongwei@tijmu.edu.cn; College of Basic Medicine, Tianjin Medical University, 300070 Tianjin; Li, Jinru

Highlights: Black-Right-Pointing-Pointer Corepressor Alien interacts with histone methyltransferase ESET in vivo. Black-Right-Pointing-Pointer Alien/ESET complex is recruited to nTRE of T3-responsive gene by liganded TR{beta}1. Black-Right-Pointing-Pointer ESET-mediated H3K9 methylation is required for liganded TR{beta}1-repressed transcription. Black-Right-Pointing-Pointer ESET is involved in T3-repressed G1/S phase transition and proliferation. -- Abstract: The ligand-bound thyroid hormone receptor (TR) is known to repress via a negative TRE (nTRE) the expression of E2F1, a key transcription factor that controls the G1/S phase transition. Alien has been identified as a novel interacting factor of E2F1 and acts as a corepressor of E2F1. The detailed molecular mechanism by whichmore » Alien inhibits E2F1 gene expression remains unclear. Here, we report that the histone H3 lysine 9 (H3K9) methyltransferase (HMT) ESET is an integral component of the corepressor Alien complex and the Alien/ESET complex is recruited to both sites, the E2F1 and the nTRE site of the E2F1 gene while the recruitment to the negative thyroid hormone response element (nTRE) is induced by the ligand-bound TR{beta}1 within the E2F1 gene promoter. We show that, overexpression of ESET promotes, whereas knockdown of ESET releases, the inhibition of TR{beta}1-regulated gene transcription upon T3 stimulation; and H3K9 methylation is required for TR{beta}1-repressed transcription. Furthermore, depletion of ESET impairs thyroid hormone-repressed proliferation as well as the G1/S transition of the cell cycle. Taken together, our data indicate that ESET is involved in TR{beta}1-mediated transcription repression and provide a molecular basis of thyroid hormone-induced repression of proliferation.« less

Chromatin associated Sin3A is essential for male germ cell lineage in the mouse

PubMed Central

Pellegrino, Jessica; Castrillon, Diego H.; David, Gregory

2012-01-01

Spermatogenesis is a complex process that requires coordinated proliferation and differentiation of male germ cells. The molecular events that dictate this process are largely unknown, but are likely to involve highly regulated transcriptional control. In this study, we investigate the contribution of chromatin associated Sin3A in mouse germ cell lineage development. Genetic inactivation of Sin3A in the male germline leads to sterility that results from the early and penetrant apoptotic death observed in Sin3A-deleted germ cells, coincident with the reentry in mitosis. Sin3A-deleted testes exhibit a Sertoli-cell only phenotype, consistent with the absolute requirement for Sin3A in germ cells’ development and/or viability. Interestingly, transcripts analysis revealed that the expression program of Sertoli cells is altered upon inactivation of Sin3A in germ cells. These studies identified a central role for the mammalian Sin3-HDAC complex in the germ cell lineage, and point to an exquisite transcriptional crosstalk between germ cells and their niche to support fertility in mammals. PMID:22820070

Transcriptional repression mediated by the KRAB domain of the human C2H2 zinc finger protein Kox1/ZNF10 does not require histone deacetylation.

PubMed

Lorenz, P; Koczan, D; Thiesen, H J

2001-04-01

The KRAB domain of human Kox1, a member of the KRAB C2H2 zinc finger family, confers strong transcriptional repressor activities even to remote promoter positions. Here, HDAC inhibitors were used to demonstrate that histone deacetylation is not required for mediating transcriptional repression of KRAB zinc finger proteins. Two reporter systems with either stably integrated or transiently transfected templates, both under control of strong viral promoters, were analyzed. Under all circumstances, HDAC inhibition did not alter the repression potential of the KRAB domain. In case of the stably integrated luciferase reporter gene system, neither expression levels of the KRAB fusion protein nor complex formation with its putative co-repressor TIF1beta were significantly changed. Furthermore, the TIF1beta/KRAB complex was devoid of mSin3A and HDAC1. In the transient transfection system, the transcriptional repression induced by TIF1beta and HP1alpha was not diminished by HDAC inhibitors, whereas the repressory activity of TIF1alpha was significantly affected. Thus, KRAB, TIF1beta and HP1alpha are likely to be functionally linked. In conclusion, HDAC activity is not essential for the strong transcriptional repressor activity mediated by the KRAB domain of Kox1 in particular and, presumably, by KRAB domains in general. This feature might be helpful in identifying and characterizing target genes under the control of

Activation of p53 Transcriptional Activity by SMRT: a Histone Deacetylase 3-Independent Function of a Transcriptional Corepressor

PubMed Central

Adikesavan, Anbu Karani; Karmakar, Sudipan; Pardo, Patricia; Wang, Liguo; Liu, Shuang; Li, Wei

2014-01-01

The silencing mediator of retinoic acid and thyroid hormone receptors (SMRT) is an established histone deacetylase 3 (HDAC3)-dependent transcriptional corepressor. Microarray analyses of MCF-7 cells transfected with control or SMRT small interfering RNA revealed SMRT regulation of genes involved in DNA damage responses, and the levels of the DNA damage marker γH2AX as well as poly(ADP-ribose) polymerase cleavage were elevated in SMRT-depleted cells treated with doxorubicin. A number of these genes are established p53 targets. SMRT knockdown decreased the activity of two p53-dependent reporter genes as well as the expression of p53 target genes, such as CDKN1A (which encodes p21). SMRT bound directly to p53 and was recruited to p53 binding sites within the p21 promoter. Depletion of GPS2 and TBL1, components of the SMRT corepressor complex, but not histone deacetylase 3 (HDAC3) decreased p21-luciferase activity. p53 bound to the SMRT deacetylase activation domain (DAD), which mediates HDAC3 binding and activation, and HDAC3 could attenuate p53 binding to the DAD region of SMRT. Moreover, an HDAC3 binding-deficient SMRT DAD mutant coactivated p53 transcriptional activity. Collectively, these data highlight a biological role for SMRT in mediating DNA damage responses and suggest a model where p53 binding to the DAD limits HDAC3 interaction with this coregulator, thereby facilitating SMRT coactivation of p53-dependent gene expression. PMID:24449765

The Nuclear Receptor Corepressor Has Organizational Effects within the Developing Amygdala on Juvenile Social Play and Anxiety-Like Behavior

PubMed Central

Jessen, Heather M.; Kolodkin, Mira H.; Bychowski, Meaghan E.; Auger, Catherine J.; Auger, Anthony P.

2010-01-01

Nuclear receptor function on DNA is regulated by the balanced recruitment of coregulatory complexes. Recruited proteins that increase gene expression are called coactivators, and those that decrease gene expression are called corepressors. Little is known about the role of corepressors, such as nuclear receptor corepressor (NCoR), on the organization of behavior. We used real-time PCR to show that NCoR mRNA levels are sexually dimorphic, that females express higher levels of NCoR mRNA within the developing amygdala and hypothalamus, and that NCoR mRNA levels are reduced by estradiol treatment. To investigate the functional role of NCoR on juvenile social behavior, we infused small interfering RNA targeted against NCoR within the developing rat amygdala and assessed the enduring impact on juvenile social play behavior, sociability, and anxiety-like behavior. As expected, control males exhibited higher levels of juvenile social play than control females. Reducing NCoR expression during development further increased juvenile play in males only. Interestingly, decreased NCoR expression within the developing amygdala had lasting effects on increasing juvenile anxiety-like behavior in males and females. These data suggest that the corepressor NCoR functions to blunt sex differences in juvenile play behavior, a sexually dimorphic and hormone-dependent behavior, and appears critical for appropriate anxiety-like behavior in juvenile males and females. PMID:20051490

The nuclear receptor corepressor has organizational effects within the developing amygdala on juvenile social play and anxiety-like behavior.

PubMed

Jessen, Heather M; Kolodkin, Mira H; Bychowski, Meaghan E; Auger, Catherine J; Auger, Anthony P

2010-03-01

Nuclear receptor function on DNA is regulated by the balanced recruitment of coregulatory complexes. Recruited proteins that increase gene expression are called coactivators, and those that decrease gene expression are called corepressors. Little is known about the role of corepressors, such as nuclear receptor corepressor (NCoR), on the organization of behavior. We used real-time PCR to show that NCoR mRNA levels are sexually dimorphic, that females express higher levels of NCoR mRNA within the developing amygdala and hypothalamus, and that NCoR mRNA levels are reduced by estradiol treatment. To investigate the functional role of NCoR on juvenile social behavior, we infused small interfering RNA targeted against NCoR within the developing rat amygdala and assessed the enduring impact on juvenile social play behavior, sociability, and anxiety-like behavior. As expected, control males exhibited higher levels of juvenile social play than control females. Reducing NCoR expression during development further increased juvenile play in males only. Interestingly, decreased NCoR expression within the developing amygdala had lasting effects on increasing juvenile anxiety-like behavior in males and females. These data suggest that the corepressor NCoR functions to blunt sex differences in juvenile play behavior, a sexually dimorphic and hormone-dependent behavior, and appears critical for appropriate anxiety-like behavior in juvenile males and females.

HDAC3 and the Molecular Brake Pad Hypothesis

PubMed Central

McQuown, Susan C.; Wood, Marcelo A.

2011-01-01

Successful transcription of specific genes required for long-term memory processes involves the orchestrated effort of not only transcription factors, but also very specific enzymatic protein complexes that modify chromatin structure. Chromatin modification has been identified as a pivotal molecular mechanism underlying certain forms of synaptic plasticity and memory. The best-studied form of chromatin modification in the learning and memory field is histone acetylation, which is regulated by histone acetyltransferases and histone deacetylases (HDACs). HDAC inhibitors have been shown to strongly enhance long-term memory processes, and recent work has aimed to identify contributions of individual HDACs. In this review, we focus on HDAC3 and discuss its recently defined role as a negative regulator of long-term memory formation. HDAC3 is part of a corepressor complex and has direct interactions with class II HDACs that may be important for its molecular and behavioral consequences. And last, we propose the “molecular brake pad” hypothesis of HDAC function. The HDACs and associated corepressor complexes may function in neurons, in part, as “molecular brake pads.” HDACs are localized to promoters of active genes and act as a persistent clamp that requires strong activity-dependent signaling to temporarily release these complexes (or brake pads) to activate gene expression required for long-term memory formation. Thus, HDAC inhibition removes the “molecular brake pads” constraining the processes necessary for long-term memory and results in strong, persistent memory formation. PMID:21521655

Structural and functional characterization of a cell cycle associated HDAC1/2 complex reveals the structural basis for complex assembly and nucleosome targeting

PubMed Central

Itoh, Toshimasa; Fairall, Louise; Muskett, Frederick W.; Milano, Charles P.; Watson, Peter J.; Arnaudo, Nadia; Saleh, Almutasem; Millard, Christopher J.; El-Mezgueldi, Mohammed; Martino, Fabrizio; Schwabe, John W.R.

2015-01-01

Recent proteomic studies have identified a novel histone deacetylase complex that is upregulated during mitosis and is associated with cyclin A. This complex is conserved from nematodes to man and contains histone deacetylases 1 and 2, the MIDEAS corepressor protein and a protein called DNTTIP1 whose function was hitherto poorly understood. Here, we report the structures of two domains from DNTTIP1. The amino-terminal region forms a tight dimerization domain with a novel structural fold that interacts with and mediates assembly of the HDAC1:MIDEAS complex. The carboxy-terminal domain of DNTTIP1 has a structure related to the SKI/SNO/DAC domain, despite lacking obvious sequence homology. We show that this domain in DNTTIP1 mediates interaction with both DNA and nucleosomes. Thus, DNTTIP1 acts as a dimeric chromatin binding module in the HDAC1:MIDEAS corepressor complex. PMID:25653165

Opi1 mediates repression of phospholipid biosynthesis by phosphate limitation in the yeast Saccharomyces cerevisiae.

PubMed

Kliewe, Felix; Kumme, Jacqueline; Grigat, Mathias; Hintze, Stefan; Schüller, Hans-Joachim

2017-02-01

Structural genes of phospholipid biosynthesis in the yeast Saccharomyces cerevisiae are transcribed when precursor molecules inositol and choline (IC) are limiting. Gene expression is stimulated by the heterodimeric activator Ino2/Ino4, which binds to ICRE (inositol/choline-responsive element) promoter sequences. Activation is prevented by repressor Opi1, counteracting Ino2 when high concentrations of IC are available. Here we show that ICRE-dependent gene activation is repressed not only by an excess of IC but also under conditions of phosphate starvation. While PHO5 is activated by phosphate limitation, INO1 expression is repressed about 10-fold. Repression of ICRE-dependent genes by low phosphate is no longer observed in an opi1 mutant while repression is still effective in mutants of the PHO regulon (pho4, pho80, pho81 and pho85). In contrast, gene expression with high phosphate is reduced in the absence of pleiotropic sensor protein kinase Pho85. We could demonstrate that Pho85 binds to Opi1 in vitro and in vivo and that this interaction is increased in the presence of high concentrations of phosphate. Interestingly, Pho85 binds to two separate domains of Opi1 which have been previously shown to recruit pleiotropic corepressor Sin3 and activator Ino2, respectively. We postulate that Pho85 positively influences ICRE-dependent gene expression by phosphorylation-dependent weakening of Opi1 repressor, affecting its functional domains required for promoter recruitment and corepressor interaction. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Superrepression through Altered Corepressor-Activated Protein:Protein Interactions.

PubMed

He, Chenlu; Custer, Gregory; Wang, Jingheng; Matysiak, Silvina; Beckett, Dorothy

2018-02-20

Small molecules regulate transcription in both eukaryotes and prokaryotes by either enhancing or repressing assembly of transcription regulatory complexes. For allosteric transcription repressors, superrepressor mutants can exhibit increased sensitivity to small molecule corepressors. However, because many transcription regulatory complexes assemble in multiple steps, the superrepressor phenotype can reflect changes in any or all of the individual assembly steps. Escherichia coli biotin operon repression complex assembly, which responds to input biotin concentration, occurs via three coupled equilibria, including corepressor binding, holorepressor dimerization, and binding of the dimer to DNA. A genetic screen has yielded superrepressor mutants that repress biotin operon transcription in vivo at biotin concentrations much lower than those required by the wild type repressor. In this work, isothermal titration calorimetry and sedimentation measurements were used to determine the superrepressor biotin binding and homodimerization properties. The results indicate that, although all variants exhibit biotin binding affinities similar to that measured for BirA wt , five of the six superrepressors show altered homodimerization energetics. Molecular dynamics simulations suggest that the altered dimerization results from perturbation of an electrostatic network that contributes to allosteric activation of BirA for dimerization. Modeling of the multistep repression complex assembly for these proteins reveals that the altered sensitivity of the transcription response to biotin concentration is readily explained solely by the altered superrepressor homodimerization energetics. These results highlight how coupled equilibria enable alterations in a transcription regulatory response to input signal through an indirect mechanism.

Ski acts as a co-repressor with Smad2 and Smad3 to regulate the response to type β transforming growth factor

PubMed Central

Xu, Weidong; Angelis, Konstantina; Danielpour, David; Haddad, Maher M.; Bischof, Oliver; Campisi, Judith; Stavnezer, Ed; Medrano, Estela E.

2000-01-01

The c-ski protooncogene encodes a transcription factor that binds DNA only in association with other proteins. To identify co-binding proteins, we performed a yeast two-hybrid screen. The results of the screen and subsequent co-immunoprecipitation studies identified Smad2 and Smad3, two transcriptional activators that mediate the type β transforming growth factor (TGF-β) response, as Ski-interacting proteins. In Ski-transformed cells, all of the Ski protein was found in Smad3-containing complexes that accumulated in the nucleus in the absence of added TGF-β. DNA binding assays showed that Ski, Smad2, Smad3, and Smad4 form a complex with the Smad/Ski binding element GTCTAGAC (SBE). Ski repressed TGF-β-induced expression of 3TP-Lux, the natural plasminogen activator inhibitor 1 promoter and of reporter genes driven by the SBE and the related CAGA element. In addition, Ski repressed a TGF-β-inducible promoter containing AP-1 (TRE) elements activated by a combination of Smads, Fos, and/or Jun proteins. Ski also repressed synergistic activation of promoters by combinations of Smad proteins but failed to repress in the absence of Smad4. Thus, Ski acts in opposition to TGF-β-induced transcriptional activation by functioning as a Smad-dependent co-repressor. The biological relevance of this transcriptional repression was established by showing that overexpression of Ski abolished TGF-β-mediated growth inhibition in a prostate-derived epithelial cell line. PMID:10811875

Ski acts as a co-repressor with Smad2 and Smad3 to regulate the response to type beta transforming growth factor.

PubMed

Xu, W; Angelis, K; Danielpour, D; Haddad, M M; Bischof, O; Campisi, J; Stavnezer, E; Medrano, E E

2000-05-23

The c-ski protooncogene encodes a transcription factor that binds DNA only in association with other proteins. To identify co-binding proteins, we performed a yeast two-hybrid screen. The results of the screen and subsequent co-immunoprecipitation studies identified Smad2 and Smad3, two transcriptional activators that mediate the type beta transforming growth factor (TGF-beta) response, as Ski-interacting proteins. In Ski-transformed cells, all of the Ski protein was found in Smad3-containing complexes that accumulated in the nucleus in the absence of added TGF-beta. DNA binding assays showed that Ski, Smad2, Smad3, and Smad4 form a complex with the Smad/Ski binding element GTCTAGAC (SBE). Ski repressed TGF-beta-induced expression of 3TP-Lux, the natural plasminogen activator inhibitor 1 promoter and of reporter genes driven by the SBE and the related CAGA element. In addition, Ski repressed a TGF-beta-inducible promoter containing AP-1 (TRE) elements activated by a combination of Smads, Fos, and/or Jun proteins. Ski also repressed synergistic activation of promoters by combinations of Smad proteins but failed to repress in the absence of Smad4. Thus, Ski acts in opposition to TGF-beta-induced transcriptional activation by functioning as a Smad-dependent co-repressor. The biological relevance of this transcriptional repression was established by showing that overexpression of Ski abolished TGF-beta-mediated growth inhibition in a prostate-derived epithelial cell line.

Molecular brake pad hypothesis: pulling off the brakes for emotional memory

PubMed Central

Vogel-Ciernia, Annie

2015-01-01

Under basal conditions histone deacetylases (HDACs) and their associated co-repressor complexes serve as molecular ‘brake pads’ to prevent the gene expression required for long-term memory formation. Following a learning event, HDACs and their co-repressor complexes are removed from a subset of specific gene promoters, allowing the histone acetylation and active gene expression required for long-term memory formation. Inhibition of HDACs increases histone acetylation, extends gene expression profiles, and allows for the formation of persistent long-term memories for training events that are otherwise forgotten. We propose that emotionally salient experiences have utilized this system to form strong and persistent memories for behaviorally significant events. Consequently, the presence or absence of HDACs at a selection of specific gene promoters could serve as a critical barrier for permitting the formation of long-term memories. PMID:23096102

Transcriptional activation by the thyroid hormone receptor through ligand-dependent receptor recruitment and chromatin remodelling.

PubMed

Grøntved, Lars; Waterfall, Joshua J; Kim, Dong Wook; Baek, Songjoon; Sung, Myong-Hee; Zhao, Li; Park, Jeong Won; Nielsen, Ronni; Walker, Robert L; Zhu, Yuelin J; Meltzer, Paul S; Hager, Gordon L; Cheng, Sheue-yann

2015-04-28

A bimodal switch model is widely used to describe transcriptional regulation by the thyroid hormone receptor (TR). In this model, the unliganded TR forms stable, chromatin-bound complexes with transcriptional co-repressors to repress transcription. Binding of hormone dissociates co-repressors and facilitates recruitment of co-activators to activate transcription. Here we show that in addition to hormone-independent TR occupancy, ChIP-seq against endogenous TR in mouse liver tissue demonstrates considerable hormone-induced TR recruitment to chromatin associated with chromatin remodelling and activated gene transcription. Genome-wide footprinting analysis using DNase-seq provides little evidence for TR footprints both in the absence and presence of hormone, suggesting that unliganded TR engagement with repressive complexes on chromatin is, similar to activating receptor complexes, a highly dynamic process. This dynamic and ligand-dependent interaction with chromatin is likely shared by all steroid hormone receptors regardless of their capacity to repress transcription in the absence of ligand.

The biotin repressor: modulation of allostery by corepressor analogs.

PubMed

Brown, Patrick H; Cronan, John E; Grøtli, Morten; Beckett, Dorothy

2004-04-02

The Escherichia coli biotin repressor functions in biotin retention and regulation of biotin biosynthesis. Biotin retention is accomplished via the two-step biotinylation of the biotin-dependent enzyme, acetyl-CoA carboxylase. In the first step of this reaction the substrates biotin and ATP are utilized in synthesis of the activated biotin, biotinyl-5'-AMP, while in the second step this activated biotin is transferred to a unique lysine residue of the biotin carboxyl carrier protein subunit of the carboxylase. Regulation of biotin biosynthesis is accomplished through binding of the repressor to the transcription control region of the biotin biosynthetic operon. The adenylated or activated biotin functions as the corepressor in this DNA binding process. The activated biotin is a mixed anhydride and thus labile. In efforts to develop tools for structural and thermodynamic studies of the biotin regulatory interactions, two analogs of the adenylate, a sulfamoyl derivative and an ester derivative, have been synthesized and functionally characterized. Results of fluorescence measurements indicate that both analogs bind with high affinity to the repressor and that both are inactive in biotin transfer to the acceptor protein. Functional studies of their corepressor properties indicate that while the sulfamoyl is a weak allosteric activator, the ester closely mimics the physiological corepressor in activation of assembly of the transcription repression complex. Results of these studies also provide further insight into the allosteric mechanism of the biotin repressor.

Integrated RNA- and protein profiling of fermentation and respiration in diploid budding yeast provides insight into nutrient control of cell growth and development.

PubMed

Becker, Emmanuelle; Liu, Yuchen; Lardenois, Aurélie; Walther, Thomas; Horecka, Joe; Stuparevic, Igor; Law, Michael J; Lavigne, Régis; Evrard, Bertrand; Demougin, Philippe; Riffle, Michael; Strich, Randy; Davis, Ronald W; Pineau, Charles; Primig, Michael

2015-04-24

Diploid budding yeast undergoes rapid mitosis when it ferments glucose, and in the presence of a non-fermentable carbon source and the absence of a nitrogen source it triggers sporulation. Rich medium with acetate is a commonly used pre-sporulation medium, but our understanding of the molecular events underlying the acetate-driven transition from mitosis to meiosis is still incomplete. We identified 263 proteins for which mRNA and protein synthesis are linked or uncoupled in fermenting and respiring cells. Using motif predictions, interaction data and RNA profiling we find among them 28 likely targets for Ume6, a subunit of the conserved Rpd3/Sin3 histone deacetylase-complex regulating genes involved in metabolism, stress response and meiosis. Finally, we identify 14 genes for which both RNA and proteins are detected exclusively in respiring cells but not in fermenting cells in our sample set, including CSM4, SPR1, SPS4 and RIM4, which were thought to be meiosis-specific. Our work reveals intertwined transcriptional and post-transcriptional control mechanisms acting when a MATa/α strain responds to nutritional signals, and provides molecular clues how the carbon source primes yeast cells for entering meiosis. Our integrated genomics study provides insight into the interplay between the transcriptome and the proteome in diploid yeast cells undergoing vegetative growth in the presence of glucose (fermentation) or acetate (respiration). Furthermore, it reveals novel target genes involved in these processes for Ume6, the DNA binding subunit of the conserved histone deacetylase Rpd3 and the co-repressor Sin3. We have combined data from an RNA profiling experiment using tiling arrays that cover the entire yeast genome, and a large-scale protein detection analysis based on mass spectrometry in diploid MATa/α cells. This distinguishes our study from most others in the field-which investigate haploid yeast strains-because only diploid cells can undergo meiotic development in the simultaneous absence of a non-fermentable carbon source and nitrogen. Indeed, we report molecular clues how respiration of acetate might prime diploid cells for efficient spore formation, a phenomenon that is well known but poorly understood. Copyright © 2015 Elsevier B.V. All rights reserved.

Integrated RNA- and protein profiling of fermentation and respiration in diploid budding yeast provides insight into nutrient control of cell growth and development

PubMed Central

Becker, Emmanuelle; Liu, Yuchen; Lardenois, Aurélie; Walther, Thomas; Horecka, Joe; Stuparevic, Igor; Law, Michael J.; Lavigne, Régis; Evrard, Bertrand; Demougin, Philippe; Riffle, Michael; Strich, Randy; Davis, Ronald W.; Pineau, Charles; Primig, Michael

2017-01-01

Diploid budding yeast undergoes rapid mitosis when it ferments glucose, and in the presence of a non-fermentable carbon source and the absence of a nitrogen source it triggers sporulation. Rich medium with acetate is a commonly used pre-sporulation medium, but our understanding of the molecular events underlying the acetate-driven transition from mitosis to meiosis is still incomplete. We identified 263 proteins for which mRNA and protein synthesis are linked or uncoupled in fermenting and respiring cells. Using motif predictions, interaction data and RNA profiling we find among them 28 likely targets for Ume6, a subunit of the conserved Rpd3/Sin3 histone deacetylase-complex regulating genes involved in metabolism, stress response and meiosis. Finally, we identify 14 genes for which both RNA and proteins are detected exclusively in respiring cells but not in fermenting cells in our sample set, including CSM4, SPR1, SPS4 and RIM4, which were thought to be meiosis-specific. Our work reveals intertwined transcriptional and post-transcriptional control mechanisms acting when a MATa/α strain responds to nutritional signals, and provides molecular clues how the carbon source primes yeast cells for entering meiosis. Biological significance Our integrated genomics study provides insight into the interplay between the transcriptome and the proteome in diploid yeast cells undergoing vegetative growth in the presence of glucose (fermentation) or acetate (respiration). Furthermore, it reveals novel target genes involved in these processes for Ume6, the DNA binding subunit of the conserved histone deacetylase Rpd3 and the co-repressor Sin3. We have combined data from an RNA profiling experiment using tiling arrays that cover the entire yeast genome, and a large-scale protein detection analysis based on mass spectrometry in diploid MATa/α cells. This distinguishes our study from most others in the field—which investigate haploid yeast strains—because only diploid cells can undergo meiotic development in the simultaneous absence of a non-fermentable carbon source and nitrogen. Indeed, we report molecular clues how respiration of acetate might prime diploid cells for efficient spore formation, a phenomenon that is well known but poorly understood. PMID:25662576

[Control levels of Sin3 histone deacetylase for spontaneous and UV-induced mutagenesis in yeasts Saccharomyces cerevisiae].

PubMed

Lebovka, I Iu; Kozhina, T N; Fedorova, I V; Peshekhonov, V T; Evstiukhina, T A; Chernenkov, A Iu; Korolev, V G

2014-01-01

SIN3 gene product operates as a repressor for a huge amount of genes in Saccharomyces cerevisiae. Sin3 protein with a mass of about 175 kDa is a member of the RPD3 protein complex with an assessed mass of greater than 2 million Da. It was previously shownthat RPD3 gene mutations influence recombination and repair processes in S. cerevisiae yeasts. We studied the impacts of the sin3 mutation on UV-light sensitivity and UV-induced mutagenesis in budding yeast cells. The deletion ofthe SIN3 gene causes weak UV-sensitivity of mutant budding cells as compared to the wild-type strain. These results show that the sin3 mutation decreases both spontaneous and UV-induced levels of levels. This fact is hypothetically related to themalfunction of ribonucleotide reductase activity regulation, which leads to a decrease in the dNTP pool and the inaccurate error-prone damage bypass postreplication repair pathway, which in turn provokes a reduction in the incidence of mutations.

Loss of the co-repressor GPS2 sensitizes macrophage activation upon metabolic stress induced by obesity and type 2 diabetes.

PubMed

Fan, Rongrong; Toubal, Amine; Goñi, Saioa; Drareni, Karima; Huang, Zhiqiang; Alzaid, Fawaz; Ballaire, Raphaelle; Ancel, Patricia; Liang, Ning; Damdimopoulos, Anastasios; Hainault, Isabelle; Soprani, Antoine; Aron-Wisnewsky, Judith; Foufelle, Fabienne; Lawrence, Toby; Gautier, Jean-Francois; Venteclef, Nicolas; Treuter, Eckardt

2016-07-01

Humans with obesity differ in their susceptibility to developing insulin resistance and type 2 diabetes (T2D). This variation may relate to the extent of adipose tissue (AT) inflammation that develops as their obesity progresses. The state of macrophage activation has a central role in determining the degree of AT inflammation and thus its dysfunction, and these states are driven by epigenomic alterations linked to gene expression. The underlying mechanisms that regulate these alterations, however, are poorly defined. Here we demonstrate that a co-repressor complex containing G protein pathway suppressor 2 (GPS2) crucially controls the macrophage epigenome during activation by metabolic stress. The study of AT from humans with and without obesity revealed correlations between reduced GPS2 expression in macrophages, elevated systemic and AT inflammation, and diabetic status. The causality of this relationship was confirmed by using macrophage-specific Gps2-knockout (KO) mice, in which inappropriate co-repressor complex function caused enhancer activation, pro-inflammatory gene expression and hypersensitivity toward metabolic-stress signals. By contrast, transplantation of GPS2-overexpressing bone marrow into two mouse models of obesity (ob/ob and diet-induced obesity) reduced inflammation and improved insulin sensitivity. Thus, our data reveal a potentially reversible disease mechanism that links co-repressor-dependent epigenomic alterations in macrophages to AT inflammation and the development of T2D.

The TIE1 Transcriptional Repressor Links TCP Transcription Factors with TOPLESS/TOPLESS-RELATED Corepressors and Modulates Leaf Development in Arabidopsis[W

PubMed Central

Tao, Qing; Guo, Dongshu; Wei, Baoye; Zhang, Fan; Pang, Changxu; Jiang, Hao; Zhang, Jinzhe; Wei, Tong; Gu, Hongya; Qu, Li-Jia; Qin, Genji

2013-01-01

Leaf size and shape are mainly determined by coordinated cell division and differentiation in lamina. The CINCINNATA (CIN)-like TEOSINTE BRANCHED1/CYCLOIDEA/PCF (TCP) transcription factors are key regulators of leaf development. However, the mechanisms that control TCP activities during leaf development are largely unknown. We identified the TCP Interactor containing EAR motif protein1 (TIE1), a novel transcriptional repressor, as a major modulator of TCP activities during leaf development. Overexpression of TIE1 leads to hyponastic and serrated leaves, whereas disruption of TIE1 causes epinastic leaves. TIE1 is expressed in young leaves and encodes a transcriptional repressor containing a C-terminal EAR motif, which mediates interactions with the TOPLESS (TPL)/TOPLESS-RELATED (TPR) corepressors. In addition, TIE1 physically interacts with CIN-like TCPs. We propose that TIE1 regulates leaf size and morphology by inhibiting the activities of TCPs through recruiting the TPL/TPR corepressors to form a tertiary complex at early stages of leaf development. PMID:23444332

Oncogenic mechanisms of Evi-1 protein.

PubMed

Hirai, H; Izutsu, K; Kurokawa, M; Mitani, K

2001-08-01

Although Evi-1 is thought to promote growth or block differentiation in some cell types, its biological functions have not been elucidated. To explore the mechanisms underlying Evi-1-induced oncogenesis, we investigated whether Evi-1 affects the signaling of transforming growth factor beta (TGF-beta), which inhibits proliferation of a wide range of cell types and is one of the most studied growth regulatory factors. We demonstrated that Evi-1 represses TGF-beta signaling and antagonizes its growth-inhibitory effects. Two separate regions of Evi-1 are responsible for this repression, one of which is the first zinc-finger domain. Through this domain, Evi-1 physically interacts with Smad3, an intracellular mediator of TGF-beta signaling, thereby suppressing the transcriptional activity of Smad3. These results define a novel function of Evi-1 as a repressor of signaling components of TGF-beta. We also demonstrated that Evi-1 represses Smad-induced transcriptional activation by recruiting CtBP as a corepressor. Evi-1 associates with CtBP1 through one of the CtBP-binding consensus motifs within the region from amino acid 544 to 607, and this association is required for the efficient inhibition of TGF-beta signaling. A specific histone deacetylase (HDAc) inhibitor, trichostatin A (TSA), alleviates Evi-1-mediated repression of TGF-beta signaling, suggesting that HDAc is involved in transcriptional repression by Evi-1. This identifies a novel function of Evi-1 as a member of corepressor complexes and suggests that aberrant recruitment of corepressors is one of the mechanisms involved in Evi-1-induced leukemogenesis. These results indicate that specific HDAc inhibitors may be useful in the treatment of Evi-1-induced neoplastic tumors, including myeloid leukemias.

Transrepressive function of TLX requires the histone demethylase LSD1.

PubMed

Yokoyama, Atsushi; Takezawa, Shinichiro; Schüle, Roland; Kitagawa, Hirochika; Kato, Shigeaki

2008-06-01

TLX is an orphan nuclear receptor (also called NR2E1) that regulates the expression of target genes by functioning as a constitutive transrepressor. The physiological significance of TLX in the cytodifferentiation of neural cells in the brain is known. However, the corepressors supporting the transrepressive function of TLX have yet to be identified. In this report, Y79 retinoblastoma cells were subjected to biochemical techniques to purify proteins that interact with TLX, and we identified LSD1 (also called KDM1), which appears to form a complex with CoREST and histone deacetylase 1. LSD1 interacted with TLX directly through its SWIRM and amine oxidase domains. LSD1 potentiated the transrepressive function of TLX through its histone demethylase activity as determined by a luciferase assay using a genomically integrated reporter gene. LSD1 and TLX were recruited to a TLX-binding site in the PTEN gene promoter, accompanied by the demethylation of H3K4me2 and deacetylation of H3. Knockdown of either TLX or LSD1 derepressed expression of the endogenous PTEN gene and inhibited cell proliferation of Y79 cells. Thus, the present study suggests that LSD1 is a prime corepressor for TLX.

Probing Dominant Negative Behavior of Glucocorticoid Receptor β through a Hybrid Structural and Biochemical Approach

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

Min, Jungki; Perera, Lalith; Krahn, Juno M.

ABSTRACT Glucocorticoid receptor β (GRβ) is associated with glucocorticoid resistance via dominant negative regulation of GRα. To better understand how GRβ functions as a dominant negative inhibitor of GRα at a molecular level, we determined the crystal structure of the ligand binding domain of GRβ complexed with the antagonist RU-486. The structure reveals that GRβ binds RU-486 in the same ligand binding pocket as GRα, and the unique C-terminal amino acids of GRβ are mostly disordered. Binding energy analysis suggests that these C-terminal residues of GRβ do not contribute to RU-486 binding. Intriguingly, the GRβ/RU-486 complex binds corepressor peptide withmore » affinity similar to that of a GRα/RU-486 complex, despite the lack of helix 12. Our biophysical and biochemical analyses reveal that in the presence of RU-486, GRβ is found in a conformation that favors corepressor binding, potentially antagonizing GRα function. This study thus presents an unexpected molecular mechanism by which GRβ could repress transcription.« less

The orphan nuclear receptor DAX-1 acts as a novel transcriptional corepressor of PPAR{gamma}

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

Kim, Gwang Sik; Lee, Gha Young; Nedumaran, Balachandar

2008-05-30

DAX-1 is an atypical nuclear receptor (NR) which functions primarily as a transcriptional corepressor of other NRs via heterodimerization. Peroxisome proliferator-activated receptor (PPAR) {gamma} is a ligand-dependent NR which performs a key function in adipogenesis. In this study, we evaluated a novel cross-talk mechanism between DAX-1 and PPAR{gamma}. Transient transfection assays demonstrated that DAX-1 inhibits the transactivity of PPAR{gamma} in a dose-dependent manner. DAX-1 directly competed with the PPAR{gamma} coactivator (PGC)-1{alpha} for binding to PPAR{gamma}. Endogenous levels of DAX-1 were significantly lower in differentiated 3T3-L1 adipocytes as compared to preadipocytes. Using a retroviral expression system, we demonstrated that DAX-1 overexpressionmore » downregulates the expression of PPAR{gamma} target genes, resulting in an attenuation of adipogenesis in 3T3-L1 cells. Our results suggest that DAX-1 acts as a corepressor of PPAR{gamma} and performs a potential function in the regulation of PPAR{gamma}-mediated cellular differentiation.« less

Acetylation of Histone Deacetylase 1 Regulates NuRD Corepressor Complex Activity*

PubMed Central

Yang, Tao; Jian, Wei; Luo, Yi; Fu, Xueqi; Noguchi, Constance; Bungert, Jörg; Huang, Suming; Qiu, Yi

2012-01-01

Histone deacetylases (HDACs) play important roles in regulating cell proliferation and differentiation. The HDAC1-containing NuRD complex is generally considered as a corepressor complex and is required for GATA-1-mediated repression. However, recent studies also show that the NuRD complex is involved in GATA-1-mediated gene activation. We tested whether the GATA-1-associated NuRD complex loses its deacetylase activity and commits the GATA-1 complex to become an activator during erythropoiesis. We found that GATA-1-associated deacetylase activity gradually decreased upon induction of erythroid differentiation. GATA-1-associated HDAC1 is increasingly acetylated after differentiation. It has been demonstrated earlier that acetylated HDAC1 has no deacetylase activity. Indeed, overexpression of an HDAC1 mutant, which mimics acetylated HDAC1, promotes GATA-1-mediated transcription and erythroid differentiation. Furthermore, during erythroid differentiation, acetylated HDAC1 recruitment is increased at GATA-1-activated genes, whereas it is significantly decreased at GATA-1-repressed genes. Interestingly, deacetylase activity is not required for Mi2 remodeling activity, suggesting that remodeling activity may be required for both activation and repression. Thus, our data suggest that NuRD can function as a coactivator or repressor and that acetylated HDAC1 converts the NuRD complex from a repressor to an activator during GATA-1-directed erythroid differentiation. PMID:23014989

LINE-1 silencing by retinoblastoma proteins is effected through the nucleosomal and remodeling deacetylase multiprotein complex.

PubMed

Montoya-Durango, Diego E; Ramos, Kenneth A; Bojang, Pasano; Ruiz, Lorell; Ramos, Irma N; Ramos, Kenneth S

2016-01-25

Long Interspersed Nuclear Element-1 (L1) is an oncogenic mammalian retroelement silenced early in development via tightly controlled epigenetic mechanisms. We have previously shown that the regulatory region of human and murine L1s interact with retinoblastoma (RB) proteins to effect retroelement silencing. The present studies were conducted to identify the corepressor complex responsible for RB-mediated silencing of L1. Chromatin immunoprecipitation and silencing RNA technology were used to identify the repressor complex that silences L1 in human and murine cells. Components of the Nucleosomal and Remodeling Deacetylase (NuRD) multiprotein complex specifically enriched the L1 5'-untranslated DNA sequence in human and murine cells. Genetic ablation of RB proteins in murine cells destabilized interactions within the NuRD macromolecular complex and mediated nuclear rearrangement of Mi2-β, an ATP-dependent helicase subunit with nucleosome remodeling activity. Depletion of Mi2-β, RbAP46 and HDAC2 reduced the repressor activity of the NuRD complex and reactivated a synthetic L1 reporter in human cells. Epigenetic reactivation of L1 in RB-null cells by DNA damage was markedly enhanced compared to wild type cells. RB proteins stabilize interactions of the NuRD corepressor complex within the L1 promoter to effect L1 silencing. L1 retroelements may serve as a scaffold on which RB builds heterochromatic regions that regulate chromatin function.

Glucocorticoid-induced tethered transrepression requires SUMOylation of GR and formation of a SUMO-SMRT/NCoR1-HDAC3 repressing complex

PubMed Central

Hua, Guoqiang; Ganti, Krishna Priya; Chambon, Pierre

2016-01-01

Upon binding of a glucocorticoid (GC), the GC receptor (GR) can exert one of three transcriptional regulatory functions. We recently reported that SUMOylation of the GR at position K293 in humans (K310 in mice) within the N-terminal domain is indispensable for GC-induced evolutionary conserved inverted repeated negative GC response element (IR nGRE)-mediated direct transrepression. We now demonstrate that the integrity of this GR SUMOylation site is mandatory for the formation of a GR-small ubiquitin-related modifiers (SUMOs)-SMRT/NCoR1-HDAC3 repressing complex, which is indispensable for NF-κB/AP1-mediated GC-induced tethered indirect transrepression in vitro. Using GR K310R mutant mice or mice containing the N-terminal truncated GR isoform GRα-D3 lacking the K310 SUMOylation site, revealed a more severe skin inflammation than in WT mice. Importantly, cotreatment with dexamethasone (Dex) could not efficiently suppress a 12-O-tetradecanoylphorbol-13-acetate (TPA)–induced skin inflammation in these mutant mice, whereas it was clearly decreased in WT mice. In addition, in mice selectively ablated in skin keratinocytes for either nuclear receptor corepressor 1 (NCoR1)/silencing mediator for retinoid or thyroid-hormone receptors (SMRT) corepressors or histone deacetylase 3 (HDAC3), Dex-induced tethered transrepression and the formation of a repressing complex on DNA-bound NF-κB/AP1 were impaired. We previously suggested that GR ligands that would lack both (+)GRE-mediated transactivation and IR nGRE-mediated direct transrepression activities of GCs may preferentially exert the therapeutically beneficial GC antiinflammatory properties. Interestingly, we now identified a nonsteroidal antiinflammatory selective GR agonist (SEGRA) that selectively lacks both Dex-induced (+)GRE-mediated transactivation and IR nGRE-mediated direct transrepression functions, while still exerting a tethered indirect transrepression activity and could therefore be clinically lesser debilitating on long-term GC therapy. PMID:26712006

Problem-Solving Test: Attenuation--A Mechanism to Regulate Bacterial Tryptophan Biosynthesis

ERIC Educational Resources Information Center

Szeberenyi, Jozsef

2010-01-01

Terms to be familiar with before you start to solve the test: tryptophan, transcription unit, operon, "trp" repressor, corepressor, operator, promoter, palindrome, initiation, elongation, and termination of transcription, open reading frame, coupled transcription/translation, chromosome-polysome complex. (Contains 2 figures and 1 footnote.)

A Small-Molecule Inhibitor of BCL6 Kills DLBCL Cells In Vitro and In Vivo

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

Cerchietti, L.C.; Ghetu, A.F.; Zhu, X.

2010-09-22

The BCL6 transcriptional repressor is the most frequently involved oncogene in diffuse large B cell lymphoma (DLBCL). We combined computer-aided drug design with functional assays to identify low-molecular-weight compounds that bind to the corepressor binding groove of the BCL6 BTB domain. One such compound disrupted BCL6/corepressor complexes in vitro and in vivo, and was observed by X-ray crystallography and NMR to bind the critical site within the BTB groove. This compound could induce expression of BCL6 target genes and kill BCL6-positive DLBCL cell lines. In xenotransplantation experiments, the compound was nontoxic and potently suppressed DLBCL tumors in vivo. The compoundmore » also killed primary DLBCLs from human patients.« less

HSP70 and heat shock factor 1 cooperate to repress Ras-induced transcriptional activation of the c-fos gene.

PubMed

He, H; Chen, C; Xie, Y; Asea, A; Calderwood, S K

2000-11-01

Heat shock protein 70 (HSP70) is a molecular chaperone involved in protein folding and resistance to the deleterious effects of stress. Here we show that HSP70 suppresses transcription of c-fos, an early response gene that is a key component of the ubiquitous AP-1 transcription factor complex. HSP70 repressed Ras-induced c-fos transcription only in the presence of functional heat shock factor1 (HSF1). This suggests that HSP70 functions as a corepressor with HSF1 to inhibit c-fos gene transcription. Therefore, besides its known function in the stress response, HSP70 also has the property of a corepressor and combines with HSF1 to antagonize Fos expression and may thus impact multiple aspects of cell regulation.

Modification of tRNALys UUU by Elongator Is Essential for Efficient Translation of Stress mRNAs

PubMed Central

Sansó, Miriam; Buhne, Karin; Carmona, Mercè; Paulo, Esther; Hermand, Damien; Rodríguez-Gabriel, Miguel; Ayté, José; Leidel, Sebastian; Hidalgo, Elena

2013-01-01

The Elongator complex, including the histone acetyl transferase Sin3/Elp3, was isolated as an RNA polymerase II-interacting complex, and cells deficient in Elongator subunits display transcriptional defects. However, it has also been shown that Elongator mediates the modification of some tRNAs, modulating translation efficiency. We show here that the fission yeast Sin3/Elp3 is important for oxidative stress survival. The stress transcriptional program, governed by the Sty1-Atf1-Pcr1 pathway, is affected in mutant cells, but not severely. On the contrary, cells lacking Sin3/Elp3 cannot modify the uridine wobble nucleoside of certain tRNAs, and other tRNA modifying activities such as Ctu1-Ctu2 are also essential for normal tolerance to H2O2. In particular, a plasmid over-expressing the tRNALys UUU complements the stress-related phenotypes of Sin3/Elp3 mutant cells. We have determined that the main H2O2-dependent genes, including those coding for the transcription factors Atf1 and Pcr1, are highly expressed mRNAs containing a biased number of lysine-coding codons AAA versus AAG. Thus, their mRNAs are poorly translated after stress in cells lacking Sin3/Elp3 or Ctu2, whereas a mutated atf1 transcript with AAA-to-AAG lysine codons is efficiently translated in all strain backgrounds. Our study demonstrates that the lack of a functional Elongator complex results in stress phenotypes due to its contribution to tRNA modification and subsequent translation inefficiency of certain stress-induced, highly expressed mRNAs. These results suggest that the transcriptional defects of these strain backgrounds may be a secondary consequence of the deficient expression of a transcription factor, Atf1-Pcr1, and other components of the transcriptional machinery. PMID:23874237

Modification of tRNA(Lys) UUU by elongator is essential for efficient translation of stress mRNAs.

PubMed

Fernández-Vázquez, Jorge; Vargas-Pérez, Itzel; Sansó, Miriam; Buhne, Karin; Carmona, Mercè; Paulo, Esther; Hermand, Damien; Rodríguez-Gabriel, Miguel; Ayté, José; Leidel, Sebastian; Hidalgo, Elena

2013-01-01

The Elongator complex, including the histone acetyl transferase Sin3/Elp3, was isolated as an RNA polymerase II-interacting complex, and cells deficient in Elongator subunits display transcriptional defects. However, it has also been shown that Elongator mediates the modification of some tRNAs, modulating translation efficiency. We show here that the fission yeast Sin3/Elp3 is important for oxidative stress survival. The stress transcriptional program, governed by the Sty1-Atf1-Pcr1 pathway, is affected in mutant cells, but not severely. On the contrary, cells lacking Sin3/Elp3 cannot modify the uridine wobble nucleoside of certain tRNAs, and other tRNA modifying activities such as Ctu1-Ctu2 are also essential for normal tolerance to H2O2. In particular, a plasmid over-expressing the tRNA(Lys) UUU complements the stress-related phenotypes of Sin3/Elp3 mutant cells. We have determined that the main H2O2-dependent genes, including those coding for the transcription factors Atf1 and Pcr1, are highly expressed mRNAs containing a biased number of lysine-coding codons AAA versus AAG. Thus, their mRNAs are poorly translated after stress in cells lacking Sin3/Elp3 or Ctu2, whereas a mutated atf1 transcript with AAA-to-AAG lysine codons is efficiently translated in all strain backgrounds. Our study demonstrates that the lack of a functional Elongator complex results in stress phenotypes due to its contribution to tRNA modification and subsequent translation inefficiency of certain stress-induced, highly expressed mRNAs. These results suggest that the transcriptional defects of these strain backgrounds may be a secondary consequence of the deficient expression of a transcription factor, Atf1-Pcr1, and other components of the transcriptional machinery.

The oncoprotein Ski acts as an antagonist of transforming growth factor-beta signaling by suppressing Smad2 phosphorylation.

PubMed

Prunier, Celine; Pessah, Marcia; Ferrand, Nathalie; Seo, Su Ryeon; Howe, Philip; Atfi, Azeddine

2003-07-11

The phosphorylation of Smad2 and Smad3 by the transforming growth factor (TGF)-beta-activated receptor kinases and their subsequent heterodimerization with Smad4 and translocation to the nucleus form the basis for a model how Smad proteins work to transmit TGF-beta signals. The transcriptional activity of Smad2-Smad4 or Smad3-Smad4 complexes can be limited by the corepressor Ski, which is believed to interact with Smad complexes on TGF-beta-responsive promoters and represses their ability to activate TGF-beta target genes by assembling on DNA a repressor complex containing histone deacetylase. Here we show that Ski can block TGF-beta signaling by interfering with the phosphorylation of Smad2 and Smad3 by the activated TGF-beta type I receptor. Furthermore, we demonstrate that overexpression of Ski induces the assembly of Smad2-Smad4 and Smad3-Smad4 complexes independent of TGF-beta signaling. The ability of Ski to engage Smad proteins in nonproductive complexes provides new insights into the molecular mechanism used by Ski for disabling TGF-beta signaling.

Unliganded Thyroid Hormone Receptor Regulates Metamorphic Timing via the Recruitment of Histone Deacetylase Complexes

PubMed Central

2014-01-01

Anuran metamorphosis involves a complex series of tissue transformations that change an aquatic tadpole to a terrestrial frog and resembles the postembryonic perinatal period in mammals. Thyroid hormone (TH) plays a causative role in amphibian metamorphosis and its effect is mediated by TH receptors (TRs). Molecular analyses during Xenopus development have shown that unliganded TR recruits histone deacetylase (HDAC)-containing N-CoR/SMRT complexes and causes histone deacetylation at target genes while liganded TR leads to increased histone acetylations and altered histone methylations at target genes. Transgenic studies involving mutant TR-cofactors have shown that corepressor recruitment by unliganded TR is required to ensure proper timing of the onset of metamorphosis while coactivator levels influence the rate of metamorphic progression. In addition, a number of factors that can influence cellular free TH levels appear to contribute the timing of metamorphic transformations of different organs by regulating the levels of unliganded vs. liganded TR in an organ-specific manner. Thus, the recruitment of HDAC-containing corepressor complexes by unliganded TR likely controls both the timing of the initiation of metamorphosis and the temporal regulation of organ-specific transformations. Similar mechanisms likely mediate TR function in mammals as the maturation of many organs during postembryonic development is dependent upon TH and resembles organ metamorphosis in amphibians. PMID:23962846

Transrepressive Function of TLX Requires the Histone Demethylase LSD1 ▿ †

PubMed Central

Yokoyama, Atsushi; Takezawa, Shinichiro; Schüle, Roland; Kitagawa, Hirochika; Kato, Shigeaki

2008-01-01

TLX is an orphan nuclear receptor (also called NR2E1) that regulates the expression of target genes by functioning as a constitutive transrepressor. The physiological significance of TLX in the cytodifferentiation of neural cells in the brain is known. However, the corepressors supporting the transrepressive function of TLX have yet to be identified. In this report, Y79 retinoblastoma cells were subjected to biochemical techniques to purify proteins that interact with TLX, and we identified LSD1 (also called KDM1), which appears to form a complex with CoREST and histone deacetylase 1. LSD1 interacted with TLX directly through its SWIRM and amine oxidase domains. LSD1 potentiated the transrepressive function of TLX through its histone demethylase activity as determined by a luciferase assay using a genomically integrated reporter gene. LSD1 and TLX were recruited to a TLX-binding site in the PTEN gene promoter, accompanied by the demethylation of H3K4me2 and deacetylation of H3. Knockdown of either TLX or LSD1 derepressed expression of the endogenous PTEN gene and inhibited cell proliferation of Y79 cells. Thus, the present study suggests that LSD1 is a prime corepressor for TLX. PMID:18391013

The Role of Retinal Determination Gene Network (RDGN) in Hormone Signaling Transduction and Prostate Tumorigenesis

DTIC Science & Technology

2012-10-01

support with our hypothesis, expressions of AR co-repressors (48-50), HDAC1, HDAC3 or SirT1 inhibit the ligand-induced AR activation at different...signaling and androgen-dependent growth. We hypothesis that DACH1/Six1/Eya pathway is an endogenous regulator of AR trans- activation and contributes to...mechanism. Inhibitory function of Eya1 on AR transactivation required a phosphates activity and could be enhanced by ectopic expression of co-repressors

HSP70 and heat shock factor 1 cooperate to repress Ras-induced transcriptional activation of the c-fos gene

PubMed Central

He, Haiying; Chen, Changmin; Xie, Yue; Asea, Alexzander; Calderwood, Stuart K.

2000-01-01

Heat shock protein 70 (HSP70) is a molecular chaperone involved in protein folding and resistance to the deleterious effects of stress. Here we show that HSP70 suppresses transcription of c-fos, an early response gene that is a key component of the ubiquitous AP-1 transcription factor complex. HSP70 repressed Ras-induced c-fos transcription only in the presence of functional heat shock factor1 (HSF1). This suggests that HSP70 functions as a corepressor with HSF1 to inhibit c-fos gene transcription. Therefore, besides its known function in the stress response, HSP70 also has the property of a corepressor and combines with HSF1 to antagonize Fos expression and may thus impact multiple aspects of cell regulation. PMID:11189444

Structural basis for corepressor assembly by the orphan nuclear receptor TLX

PubMed Central

Zhou, X. Edward; He, Yuanzheng; Searose-Xu, Kelvin; Zhang, Chun-Li; Tsai, Chih-Cheng; Melcher, Karsten

2015-01-01

The orphan nuclear receptor TLX regulates neural stem cell self-renewal in the adult brain and functions primarily as a transcription repressor through recruitment of Atrophin corepressors, which bind to TLX via a conserved peptide motif termed the Atro box. Here we report crystal structures of the human and insect TLX ligand-binding domain in complex with Atro box peptides. In these structures, TLX adopts an autorepressed conformation in which its helix H12 occupies the coactivator-binding groove. Unexpectedly, H12 in this autorepressed conformation forms a novel binding pocket with residues from helix H3 that accommodates a short helix formed by the conserved ALXXLXXY motif of the Atro box. Mutations that weaken the TLX–Atrophin interaction compromise the repressive activity of TLX, demonstrating that this interaction is required for Atrophin to confer repressor activity to TLX. Moreover, the autorepressed conformation is conserved in the repressor class of orphan nuclear receptors, and mutations of corresponding residues in other members of this class of receptors diminish their repressor activities. Together, our results establish the functional conservation of the autorepressed conformation and define a key sequence motif in the Atro box that is essential for TLX-mediated repression. PMID:25691470

Structural basis for corepressor assembly by the orphan nuclear receptor TLX

DOE PAGES

Zhi, Xiaoyong; Zhou, X. Edward; He, Yuanzheng; ...

2015-02-15

The orphan nuclear receptor TLX regulates neural stem cell self-renewal in the adult brain and functions primarily as a transcription repressor through recruitment of Atrophin corepressors, which bind to TLX via a conserved peptide motif termed the Atro box. Here we report crystal structures of the human and insect TLX ligand-binding domain in complex with Atro box peptides. In these structures, TLX adopts an autorepressed conformation in which its helix H12 occupies the coactivator-binding groove. Unexpectedly, H12 in this autorepressed conformation forms a novel binding pocket with residues from helix H3 that accommodates a short helix formed by the conservedmore » ALXXLXXY motif of the Atro box. Mutations that weaken the TLX–Atrophin interaction compromise the repressive activity of TLX, demonstrating that this interaction is required for Atrophin to confer repressor activity to TLX. Moreover, the autorepressed conformation is conserved in the repressor class of orphan nuclear receptors, and mutations of corresponding residues in other members of this class of receptors diminish their repressor activities. Together, our results establish the functional conservation of the autorepressed conformation and define a key sequence motif in the Atro box that is essential for TLX-mediated repression.« less

Mediator subunit MED1 is a T3-dependent and T3-independent coactivator on the thyrotropin β gene promoter

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

Matsui, Keiji; Oda, Kasumi; Mizuta, Shumpei

2013-10-11

Highlights: •MED1 is a bona fide T3-dependent coactivator on TSHB promoter. •Mice with LxxLL-mutant MED1 have attenuated TSHβ mRNA and thyroid hormone levels. •MED1 activates TSHB promoter T3-dependently in cultured cells. •T3-dependent MED1 action is enhanced when SRC1/SRC2 or HDAC2 is downregulated. •MED1 is also a T3-independent GATA2/Pit1 coactivator on TSHB promoter. -- Abstract: The MED1 subunit of the Mediator transcriptional coregulator complex is a nuclear receptor-specific coactivator. A negative feedback mechanism of thyroid-stimulating hormone (TSH, or thyrotropin) expression in the thyrotroph in the presence of triiodothyronine (T3) is employed by liganded thyroid hormone receptor β (TRβ) on the TSHβmore » gene promoter, where conventional histone-modifying coactivators act as corepressors. We now provide evidence that MED1 is a ligand-dependent positive cofactor on this promoter. TSHβ gene transcription was attenuated in MED1 mutant mice in which the nuclear receptor-binding ability of MED1 was specifically disrupted. MED1 stimulated GATA2- and Pit1-mediated TSHβ gene promoter activity in a ligand-independent manner in cultured cells. MED1 also stimulated transcription from the TSHβ gene promoter in a T3-dependent manner. The transcription was further enhanced when the T3-dependent corepressors SRC1, SRC2, and HDAC2 were downregulated. Hence, MED1 is a T3-dependent and -independent coactivator on the TSHβ gene promoter.« less

Zinc Finger Protein 451 Is a Novel Smad Corepressor in Transforming Growth Factor-β Signaling*

PubMed Central

Feng, Yili; Wu, Hongxing; Xu, Yongxian; Zhang, Zhengmao; Liu, Ting; Lin, Xia; Feng, Xin-Hua

2014-01-01

ZNF451 is a transcriptional cofactor localized to promyelocytic leukemia bodies. Here, we present evidence demonstrating that ZNF451 physically interacts with Smad3/4 and functionally inhibits TGF-β signaling. Increased expression of ZNF451 attenuates TGF-β-induced growth inhibitory and gene transcriptional responses, whereas depletion of ZNF451 enhances TGF-β responses. Mechanistically, ZNF451 blocks the ability of Smad3/4 to recruit p300 in response to TGF-β, which causes reduction of histone H3K9 acetylation on the promoters of TGF-β target genes. Taken together, ZNF451 acts as a transcriptional corepressor for Smad3/4 and negatively regulates TGF-β signaling. PMID:24324267

Acetylation of histone deacetylase 1 regulates NuRD corepressor complex activity.

PubMed

Yang, Tao; Jian, Wei; Luo, Yi; Fu, Xueqi; Noguchi, Constance; Bungert, Jörg; Huang, Suming; Qiu, Yi

2012-11-23

HDAC1-containing NuRD complex is required for GATA-1-mediated repression and activation. GATA-1 associated with acetylated HDAC1-containing NuRD complex, which has no deacetylase activity, for gene activation. Acetylated HDAC1 converts NuRD complex from a repressor to an activator during GATA-1-directed erythroid differentiation program. HDAC1 acetylation may function as a master regulator for the activity of HDAC1 containing complexes. Histone deacetylases (HDACs) play important roles in regulating cell proliferation and differentiation. The HDAC1-containing NuRD complex is generally considered as a corepressor complex and is required for GATA-1-mediated repression. However, recent studies also show that the NuRD complex is involved in GATA-1-mediated gene activation. We tested whether the GATA-1-associated NuRD complex loses its deacetylase activity and commits the GATA-1 complex to become an activator during erythropoiesis. We found that GATA-1-associated deacetylase activity gradually decreased upon induction of erythroid differentiation. GATA-1-associated HDAC1 is increasingly acetylated after differentiation. It has been demonstrated earlier that acetylated HDAC1 has no deacetylase activity. Indeed, overexpression of an HDAC1 mutant, which mimics acetylated HDAC1, promotes GATA-1-mediated transcription and erythroid differentiation. Furthermore, during erythroid differentiation, acetylated HDAC1 recruitment is increased at GATA-1-activated genes, whereas it is significantly decreased at GATA-1-repressed genes. Interestingly, deacetylase activity is not required for Mi2 remodeling activity, suggesting that remodeling activity may be required for both activation and repression. Thus, our data suggest that NuRD can function as a coactivator or repressor and that acetylated HDAC1 converts the NuRD complex from a repressor to an activator during GATA-1-directed erythroid differentiation.

DWARF 53 acts as a repressor of strigolactone signalling in rice

NASA Astrophysics Data System (ADS)

Jiang, Liang; Liu, Xue; Xiong, Guosheng; Liu, Huihui; Chen, Fulu; Wang, Lei; Meng, Xiangbing; Liu, Guifu; Yu, Hong; Yuan, Yundong; Yi, Wei; Zhao, Lihua; Ma, Honglei; He, Yuanzheng; Wu, Zhongshan; Melcher, Karsten; Qian, Qian; Xu, H. Eric; Wang, Yonghong; Li, Jiayang

2013-12-01

Strigolactones (SLs) are a group of newly identified plant hormones that control plant shoot branching. SL signalling requires the hormone-dependent interaction of DWARF 14 (D14), a probable candidate SL receptor, with DWARF 3 (D3), an F-box component of the Skp-Cullin-F-box (SCF) E3 ubiquitin ligase complex. Here we report the characterization of a dominant SL-insensitive rice (Oryza sativa) mutant dwarf 53 (d53) and the cloning of D53, which encodes a substrate of the SCFD3 ubiquitination complex and functions as a repressor of SL signalling. Treatments with GR24, a synthetic SL analogue, cause D53 degradation via the proteasome in a manner that requires D14 and the SCFD3 ubiquitin ligase, whereas the dominant form of D53 is resistant to SL-mediated degradation. Moreover, D53 can interact with transcriptional co-repressors known as TOPLESS-RELATED PROTEINS. Our results suggest a model of SL signalling that involves SL-dependent degradation of the D53 repressor mediated by the D14-D3 complex.

Structure of the apo form of the catabolite control protein A (CcpA) from Bacillus megaterium with a DNA-binding domain

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

Singh, Rajesh Kumar; Palm, Gottfried J.; Panjikar, Santosh

2007-04-01

Crystal structure analysis of the apo form of catabolite control protein A reveals the three-helix bundle of the DNA-binding domain. In the crystal packing, this domain interacts with the binding site for the corepressor protein. Crystal structure determination of catabolite control protein A (CcpA) at 2.6 Å resolution reveals for the first time the structure of a full-length apo-form LacI-GalR family repressor protein. In the crystal structures of these transcription regulators, the three-helix bundle of the DNA-binding domain has only been observed in cognate DNA complexes; it has not been observed in other crystal structures owing to its mobility. Inmore » the crystal packing of apo-CcpA, the protein–protein contacts between the N-terminal three-helix bundle and the core domain consisted of interactions between the homodimers that were similar to those between the corepressor protein HPr and the CcpA N-subdomain in the ternary DNA complex. In contrast to the DNA complex, the apo-CcpA structure reveals large subdomain movements in the core, resulting in a complete loss of contacts between the N-subdomains of the homodimer.« less

Adipose and muscle tissue expression of two genes (NCAPG and LCORL) located in a chromosomal region associated with cattle feed intake and gain

USDA-ARS?s Scientific Manuscript database

A region on bovine chromosome 6 has been implicated in cattle birth weight, growth, and length. Non-SMC conodensin I complex subunit G (NCAPG) and ligand dependent nuclear receptor corepressor-like protein (LCORL) are positional candidate genes within this region. We previously identified genetic ...

A mutation-led search for novel functional domains in MeCP2.

PubMed

Guy, Jacky; Alexander-Howden, Beatrice; FitzPatrick, Laura; DeSousa, Dina; Koerner, Martha V; Selfridge, Jim; Bird, Adrian

2018-04-27

Most missense mutations causing Rett syndrome affect domains of MeCP2 that have been shown to either bind methylated DNA or interact with a transcriptional co-repressor complex. Several mutations, however, including the C-terminal truncations that account for ∼10% of cases, fall outside these characterised domains. We studied the molecular consequences of four of these "non-canonical" mutations in cultured neurons and mice to see if they reveal additional essential domains without affecting known properties of MeCP2. The results show that the mutations partially or strongly deplete the protein and also in some cases interfere with co-repressor recruitment. These mutations therefore impact the activity of known functional domains and do not invoke new molecular causes of Rett syndrome. The finding that a stable C-terminal truncation does not compromise MeCP2 function raises the possibility that small molecules which stabilise these mutant proteins may be of therapeutic value.

Adipose and muscle tissue gene expression of two genes (NCAPG and LCORL) located in a chromosomal region associated with cattle feed intake and gain

USDA-ARS?s Scientific Manuscript database

A region on bovine chromosome 6 has been implicated in cattle birth weight, growth, and length. Non-SMC conodensin I complex subunit G (NCAPG) and ligand dependent nuclear receptor corepressor-like protein (LCORL) are positional candidate genes within this region. Previously identified genetic mark...

Dynamic Sumoylation of a Conserved Transcription Corepressor Prevents Persistent Inclusion Formation during Hyperosmotic Stress

PubMed Central

Oeser, Michelle L.; Amen, Triana; Nadel, Cory M.; Bradley, Amanda I.; Reed, Benjamin J.; Jones, Ramon D.; Gopalan, Janani; Kaganovich, Daniel; Gardner, Richard G.

2016-01-01

Cells are often exposed to physical or chemical stresses that can damage the structures of essential biomolecules. Stress-induced cellular damage can become deleterious if not managed appropriately. Rapid and adaptive responses to stresses are therefore crucial for cell survival. In eukaryotic cells, different stresses trigger post-translational modification of proteins with the small ubiquitin-like modifier SUMO. However, the specific regulatory roles of sumoylation in each stress response are not well understood. Here, we examined the sumoylation events that occur in budding yeast after exposure to hyperosmotic stress. We discovered by proteomic and biochemical analyses that hyperosmotic stress incurs the rapid and transient sumoylation of Cyc8 and Tup1, which together form a conserved transcription corepressor complex that regulates hundreds of genes. Gene expression and cell biological analyses revealed that sumoylation of each protein directs distinct outcomes. In particular, we discovered that Cyc8 sumoylation prevents the persistence of hyperosmotic stress-induced Cyc8-Tup1 inclusions, which involves a glutamine-rich prion domain in Cyc8. We propose that sumoylation protects against persistent inclusion formation during hyperosmotic stress, allowing optimal transcriptional function of the Cyc8-Tup1 complex. PMID:26800527

Global alterations of the transcriptional landscape during yeast growth and development in the absence of Ume6-dependent chromatin modification

PubMed Central

Lardenois, Aurélie; Becker, Emmanuelle; Walther, Thomas; Law, Michael J.; Xie, Bingning; Demougin, Philippe; Strich, Randy

2017-01-01

Chromatin modification enzymes are important regulators of gene expression and some are evolutionarily conserved from yeast to human. Saccharomyces cerevisiae is a major model organism for genome-wide studies that aim at the identification of target genes under the control of conserved epigenetic regulators. Ume6 interacts with the upstream repressor site 1 (URS1) and represses transcription by recruiting both the conserved histone deacetylase Rpd3 (through the co-repressor Sin3) and the chromatin-remodeling factor Isw2. Cells lacking Ume6 are defective in growth, stress response, and meiotic development. RNA profiling studies and in vivo protein-DNA binding assays identified mRNAs or transcript isoforms that are directly repressed by Ume6 in mitosis. However, a comprehensive understanding of the transcriptional alterations, which underlie the complex ume6Δ mutant phenotype during fermentation, respiration, or sporulation, is lacking. We report the protein-coding transcriptome of a diploid MATa/α wild-type and ume6/ume6 mutant strains cultured in rich media with glucose or acetate as a carbon source, or sporulation-inducing medium. We distinguished direct from indirect effects on mRNA levels by combining GeneChip data with URS1 motif predictions and published high-throughput in vivo Ume6-DNA binding data. To gain insight into the molecular interactions between successive waves of Ume6-dependent meiotic genes, we integrated expression data with information on protein networks. Our work identifies novel Ume6 repressed genes during growth and development and reveals a strong effect of the carbon source on the derepression pattern of transcripts in growing and developmentally arrested ume6/ume6 mutant cells. Since yeast is a useful model organism for chromatin-mediated effects on gene expression, our results provide a rich source for further genetic and molecular biological work on the regulation of cell growth and cell differentiation in eukaryotes. PMID:25957495

Global alterations of the transcriptional landscape during yeast growth and development in the absence of Ume6-dependent chromatin modification.

PubMed

Lardenois, Aurélie; Becker, Emmanuelle; Walther, Thomas; Law, Michael J; Xie, Bingning; Demougin, Philippe; Strich, Randy; Primig, Michael

2015-10-01

Chromatin modification enzymes are important regulators of gene expression and some are evolutionarily conserved from yeast to human. Saccharomyces cerevisiae is a major model organism for genome-wide studies that aim at the identification of target genes under the control of conserved epigenetic regulators. Ume6 interacts with the upstream repressor site 1 (URS1) and represses transcription by recruiting both the conserved histone deacetylase Rpd3 (through the co-repressor Sin3) and the chromatin-remodeling factor Isw2. Cells lacking Ume6 are defective in growth, stress response, and meiotic development. RNA profiling studies and in vivo protein-DNA binding assays identified mRNAs or transcript isoforms that are directly repressed by Ume6 in mitosis. However, a comprehensive understanding of the transcriptional alterations, which underlie the complex ume6Δ mutant phenotype during fermentation, respiration, or sporulation, is lacking. We report the protein-coding transcriptome of a diploid MAT a/α wild-type and ume6/ume6 mutant strains cultured in rich media with glucose or acetate as a carbon source, or sporulation-inducing medium. We distinguished direct from indirect effects on mRNA levels by combining GeneChip data with URS1 motif predictions and published high-throughput in vivo Ume6-DNA binding data. To gain insight into the molecular interactions between successive waves of Ume6-dependent meiotic genes, we integrated expression data with information on protein networks. Our work identifies novel Ume6 repressed genes during growth and development and reveals a strong effect of the carbon source on the derepression pattern of transcripts in growing and developmentally arrested ume6/ume6 mutant cells. Since yeast is a useful model organism for chromatin-mediated effects on gene expression, our results provide a rich source for further genetic and molecular biological work on the regulation of cell growth and cell differentiation in eukaryotes.

Structural basis for corepressor assembly by the orphan nuclear receptor TLX.

PubMed

Zhi, Xiaoyong; Zhou, X Edward; He, Yuanzheng; Searose-Xu, Kelvin; Zhang, Chun-Li; Tsai, Chih-Cheng; Melcher, Karsten; Xu, H Eric

2015-02-15

The orphan nuclear receptor TLX regulates neural stem cell self-renewal in the adult brain and functions primarily as a transcription repressor through recruitment of Atrophin corepressors, which bind to TLX via a conserved peptide motif termed the Atro box. Here we report crystal structures of the human and insect TLX ligand-binding domain in complex with Atro box peptides. In these structures, TLX adopts an autorepressed conformation in which its helix H12 occupies the coactivator-binding groove. Unexpectedly, H12 in this autorepressed conformation forms a novel binding pocket with residues from helix H3 that accommodates a short helix formed by the conserved ALXXLXXY motif of the Atro box. Mutations that weaken the TLX-Atrophin interaction compromise the repressive activity of TLX, demonstrating that this interaction is required for Atrophin to confer repressor activity to TLX. Moreover, the autorepressed conformation is conserved in the repressor class of orphan nuclear receptors, and mutations of corresponding residues in other members of this class of receptors diminish their repressor activities. Together, our results establish the functional conservation of the autorepressed conformation and define a key sequence motif in the Atro box that is essential for TLX-mediated repression. © 2015 Zhi et al.; Published by Cold Spring Harbor Laboratory Press.

Reversal of an Epigenetic Switch Governing Cell Chaining in Bacillus subtilis by Protein Instability

PubMed Central

Chai, Yunrong; Kolter, Roberto; Losick, Richard

2010-01-01

Bacillus subtilis forms long chains of cells during growth and biofilm formation. Cell separation is mediated by autolysins, whose genes are under the negative control of a heteromeric complex composed of the proteins SinR and SlrR. Formation of the SinR•SlrR complex is governed by a self-reinforcing, double-negative feedback loop in which SinR represses the gene for SlrR and SlrR, by forming the SinR•SlrR complex, titrates SinR and prevents it from repressing slrR. The loop is a bistable switch and exists in a SlrRLOW state in which autolysin genes are on, and a SlrRHIGH state in which autolysin genes are repressed by SinR•SlrR. Cells in the SlrRLOW state are driven into the SlrRHIGH state by SinI, an antirepressor that binds to and inhibits SinR. However, the mechanism by which cells in the SlrRHIGH state revert back to the SlrRLOW state is unknown. We report that SlrR is proteolytically unstable and present evidence that self-cleavage via a LexA-like autopeptidase and ClpC contribute to its degradation. Cells producing a self-cleavage-resistant mutant of SlrR exhibited more persistent chaining during growth and yielded biofilms with enhanced structural complexity. We propose that degradation of SlrR allows cells to switch from the SlrRHIGH to the SlrRLOW state. PMID:20923420

LSD1 Neurospecific Alternative Splicing Controls Neuronal Excitability in Mouse Models of Epilepsy.

PubMed

Rusconi, Francesco; Paganini, Leda; Braida, Daniela; Ponzoni, Luisa; Toffolo, Emanuela; Maroli, Annalisa; Landsberger, Nicoletta; Bedogni, Francesco; Turco, Emilia; Pattini, Linda; Altruda, Fiorella; De Biasi, Silvia; Sala, Mariaelvina; Battaglioli, Elena

2015-09-01

Alternative splicing in the brain is dynamic and instrumental to adaptive changes in response to stimuli. Lysine-specific demethylase 1 (LSD1/KDM1A) is a ubiquitously expressed histone H3Lys4 demethylase that acts as a transcriptional co-repressor in complex with its molecular partners CoREST and HDAC1/2. In mammalian brain, alternative splicing of LSD1 mini-exon E8a gives rise to neuroLSD1, a neurospecific isoform that, upon phosphorylation, acts as a dominant-negative causing disassembly of the co-repressor complex and de-repression of target genes. Here we show that the LSD1/neuroLSD1 ratio changes in response to neuronal activation and such effect is mediated by neurospecific splicing factors NOVA1 and nSR100/SRRM4 together with a novel cis-silencer. Indeed, we found that, in response to epileptogenic stimuli, downregulation of NOVA1 reduces exon E8a splicing and expression of neuroLSD1. Using behavioral and EEG analyses we observed that neuroLSD1-specific null mice are hypoexcitable and display decreased seizure susceptibility. Conversely, in a mouse model of Rett syndrome characterized by hyperexcitability, we measured higher levels of NOVA1 protein and upregulation of neuroLSD1. In conclusion, we propose that, in the brain, correct ratio between LSD1 and neuroLSD1 contributes to excitability and, when altered, could represent a pathogenic event associated with neurological disorders involving altered E/I. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Loss of c-myc repression coincides with ovarian cancer resistance to transforming growth factor beta growth arrest independent of transforming growth factor beta/Smad signaling.

PubMed

Baldwin, Rae Lynn; Tran, Hang; Karlan, Beth Y

2003-03-15

Many epithelial carcinomas, including ovarian, are refractory to the antiproliferative effects of transforming growth factor (TGF) beta. In some cancers, TGF-beta resistance has been linked to TGF-beta receptor II (TbetaR-II) and Smad4 mutations; however, in ovarian cancer, the mechanism of resistance remains unclear. Primary ovarian epithelial cell cultures were used as a model system to determine the mechanisms of TGF-beta resistance. To simulate in vivo responses to TGF-beta, primary cultures derived from normal human ovarian surface epithelium (HOSE) and from ovarian carcinomas (CSOC) were grown on collagen I gel, the predominant matrix molecule in the ovarian tumor milieu. When treated with 5 ng/ml TGF-beta for 72 h, HOSE (n = 11) proliferation was inhibited by 20 +/- 21% on average. In contrast, CSOC (n = 10) proliferation was stimulated 5 +/- 10% in response to TGF-beta (a statistically significant difference in response when compared with HOSE; P = 0.001). To dissect the TGF-beta/Smad signaling pathway we used a quantitative RNase protection assay (RPA) for measuring mRNA levels of TGF-beta pathway components in 20 HOSE and 20 CSOC cultures. Basal mRNA levels of TGF-beta receptors I and II, downstream signaling components Smad2, 3, 4, 6, 7, and the transcriptional corepressors Ski and SnoN did not show a statistically significant difference between HOSE and CSOC, and cannot explain their differential susceptibility to TGF-beta-induced cell cycle arrest. To assess functional differences of the TGF-beta pathway in TGF-beta-sensitive HOSE and TGF-beta-resistant CSOC, we measured Smad2/4 and 3/4 complex induction after TGF-beta treatment. HOSE and CSOC showed equivalent Smad2/4 and 3/4 complex induction after TGF-beta exposure for 0, 0.5, 2, and 4 h. It has been proposed that SnoN and Ski are corepressors of the TGF-beta/Smad pathway and undergo TGF-beta-induced degradation followed by reinduction of SnoN mRNA. However, our data show equivalent SnoN degradation in HOSE and CSOC, and equivalent SnoN mRNA induction after TGF-beta treatment. Surprising, TGF-beta-induced Ski degradation was not observed in HOSE or CSOC, suggesting that Ski may not function as a TGF-beta/Smad corepressor in ovarian epithelial cells. These data implied that the TGF-beta/Smad pathway remains functional in CSOC, although CSOC cells are resistant to antimitogenic TGF-beta effects. CSOC resistance to TGF-beta coincided with the loss of c-myc down-regulation. These data suggest that TGF-beta/Smad signaling is blocked downstream of Smad complex formation or that an alternate signaling pathway other than TGF-beta/Smad may transmit TGF-beta-induced cell cycle arrest in the ovarian epithelium.

Regulated Ubiquitinylation-Dependent Corepressor and Coactivator Complex Exchange as a Potential Target in Estrogen-Dependent Breast Cancer

DTIC Science & Technology

2006-09-01

Appendices B) References Miller, L. D., Smeds , J., George, J., Vega, V. B., Vergara, L., Ploner, A., Pawitan, Y., Hall, P., Klaar, S., Liu, E. T...Liyanarachchi S, Yan PS, Leu YW, Chan MW, Plass C, Nephew KP, et al. (2006) Mol Cell 21:393–404. 40. Miller LD, Smeds J, George J, Vega VB, Vergara L

Acquisition of the Ability To Assimilate Mannitol by Saccharomyces cerevisiae through Dysfunction of the General Corepressor Tup1-Cyc8

PubMed Central

Chujo, Moeko; Yoshida, Shiori; Ota, Anri; Murata, Kousaku

2014-01-01

Saccharomyces cerevisiae normally cannot assimilate mannitol, a promising brown macroalgal carbon source for bioethanol production. The molecular basis of this inability remains unknown. We found that cells capable of assimilating mannitol arose spontaneously from wild-type S. cerevisiae during prolonged culture in mannitol-containing medium. Based on microarray data, complementation analysis, and cell growth data, we demonstrated that acquisition of mannitol-assimilating ability was due to spontaneous mutations in the genes encoding Tup1 or Cyc8, which constitute a general corepressor complex that regulates many kinds of genes. We also showed that an S. cerevisiae strain carrying a mutant allele of CYC8 exhibited superior salt tolerance relative to other ethanologenic microorganisms; this characteristic would be highly beneficial for the production of bioethanol from marine biomass. Thus, we succeeded in conferring the ability to assimilate mannitol on S. cerevisiae through dysfunction of Tup1-Cyc8, facilitating production of ethanol from mannitol. PMID:25304510

A novel corepressor, BCoR-L1, represses transcription through an interaction with CtBP.

PubMed

Pagan, Julia K; Arnold, Jeremy; Hanchard, Kim J; Kumar, Raman; Bruno, Tiziana; Jones, Mathew J K; Richard, Derek J; Forrest, Alistair; Spurdle, Amanda; Verdin, Eric; Crossley, Merlin; Fanciulli, Maurizio; Chenevix-Trench, Georgia; Young, David B; Khanna, Kum Kum

2007-05-18

Corepressors play a crucial role in negative gene regulation and are defective in several diseases. BCoR is a corepressor for the BCL6 repressor protein. Here we describe and functionally characterize BCoR-L1, a homolog of BCoR. When tethered to a heterologous promoter, BCoR-L1 is capable of strong repression. Like other corepressors, BCoR-L1 associates with histone deacetylase (HDAC) activity. Specifically, BCoR-L1 coprecipitates with the Class II HDACs, HDAC4, HDAC5, and HDAC7, suggesting that they are involved in its role as a transcriptional repressor. BCoR-L1 also interacts with the CtBP corepressor through a CtBP-interacting motif in its amino terminus. Abrogation of the CtBP binding site within BCoR-L1 partially relieves BCoR-L1-mediated transcriptional repression. Furthermore, BCoR-L1 is located on the E-cadherin promoter, a known CtBP-regulated promoter, and represses the E-cadherin promoter activity in a reporter assay. The inhibition of BCoR-L1 expression by RNA-mediated interference results in derepression of E-cadherin in cells that do not normally express E-cadherin, indicating that BCoR-L1 contributes to the repression of an authentic endogenous CtBP target.

The Phosphatidylinositol 3,5-Bisphosphate (PI(3,5)P2)-dependent Tup1 Conversion (PIPTC) Regulates Metabolic Reprogramming from Glycolysis to Gluconeogenesis*

PubMed Central

Han, Bong-Kwan; Emr, Scott D.

2013-01-01

Glucose/carbon metabolism is a fundamental cellular process in living cells. In response to varying environments, eukaryotic cells reprogram their glucose/carbon metabolism between aerobic or anaerobic glycolysis, oxidative phosphorylation, and/or gluconeogenesis. The distinct type of glucose/carbon metabolism that a cell carries out has significant effects on the cell's proliferation and differentiation. However, it is poorly understood how the reprogramming of glucose/carbon metabolism is regulated. Here, we report a novel endosomal PI(3,5)P2 lipid-dependent regulatory mechanism that is required for metabolic reprogramming from glycolysis to gluconeogenesis in Saccharomyces cerevisiae. Certain gluconeogenesis genes, such as FBP1 (encoding fructose-1,6-bisphosphatase 1) and ICL1 (encoding isocitrate lyase 1) are under control of the Mig1 repressor and Cyc8-Tup1 corepressor complex. We previously identified the PI(3,5)P2-dependent Tup1 conversion (PIPTC), a mechanism to convert Cyc8-Tup1 corepressor to Cti6-Cyc8-Tup1 coactivator. We demonstrate that the PIPTC plays a critical role for transcriptional activation of FBP1 and ICL1. Furthermore, without the PIPTC, the Cat8 and Sip4 transcriptional activators cannot be efficiently recruited to the promoters of FBP1 and ICL1, suggesting a key role for the PIPTC in remodulating the chromatin architecture at the promoters. Our findings expand our understanding of the regulatory mechanisms for metabolic reprogramming in eukaryotes to include key regulation steps outside the nucleus. Given that Tup1 and the metabolic enzymes that control PI(3,5)P2 are highly conserved among eukaryotes, our findings may provide important insights toward understanding glucose/carbon metabolic reprogramming in other eukaryotes, including humans. PMID:23733183

The phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2)-dependent Tup1 conversion (PIPTC) regulates metabolic reprogramming from glycolysis to gluconeogenesis.

PubMed

Han, Bong-Kwan; Emr, Scott D

2013-07-12

Glucose/carbon metabolism is a fundamental cellular process in living cells. In response to varying environments, eukaryotic cells reprogram their glucose/carbon metabolism between aerobic or anaerobic glycolysis, oxidative phosphorylation, and/or gluconeogenesis. The distinct type of glucose/carbon metabolism that a cell carries out has significant effects on the cell's proliferation and differentiation. However, it is poorly understood how the reprogramming of glucose/carbon metabolism is regulated. Here, we report a novel endosomal PI(3,5)P2 lipid-dependent regulatory mechanism that is required for metabolic reprogramming from glycolysis to gluconeogenesis in Saccharomyces cerevisiae. Certain gluconeogenesis genes, such as FBP1 (encoding fructose-1,6-bisphosphatase 1) and ICL1 (encoding isocitrate lyase 1) are under control of the Mig1 repressor and Cyc8-Tup1 corepressor complex. We previously identified the PI(3,5)P2-dependent Tup1 conversion (PIPTC), a mechanism to convert Cyc8-Tup1 corepressor to Cti6-Cyc8-Tup1 coactivator. We demonstrate that the PIPTC plays a critical role for transcriptional activation of FBP1 and ICL1. Furthermore, without the PIPTC, the Cat8 and Sip4 transcriptional activators cannot be efficiently recruited to the promoters of FBP1 and ICL1, suggesting a key role for the PIPTC in remodulating the chromatin architecture at the promoters. Our findings expand our understanding of the regulatory mechanisms for metabolic reprogramming in eukaryotes to include key regulation steps outside the nucleus. Given that Tup1 and the metabolic enzymes that control PI(3,5)P2 are highly conserved among eukaryotes, our findings may provide important insights toward understanding glucose/carbon metabolic reprogramming in other eukaryotes, including humans.

Structure of the Polycomb Group protein PCGF1 (NSPC1) in complex with BCOR reveals basis for binding selectivity of PCGF homologs

PubMed Central

Junco, Sarah E.; Wang, Renjing; Gaipa, John C.; Taylor, Alexander B.; Schirf, Virgil; Gearhart, Micah D.; Bardwell, Vivian J.; Demeler, Borries; Hart, P. John; Kim, Chongwoo A.

2014-01-01

Summary Polycomb Group RING finger homologs (PCGF1, 2, 3, 4, 5 and 6) are critical components in the assembly of distinct Polycomb Repression Complex 1 (PRC1) related complexes. Here we identify a protein interaction domain in BCL6 co-repressor, BCOR, which binds the ubiquitin-like RAWUL domain of PCGF1 (NSPC1) and PCGF3 but not of PCGF2 (MEL18) or PCGF4 (BMI1). Because of the selective binding, we have named this domain PCGF Ub-like fold Discriminator (PUFD). The structure of BCOR PUFD bound to PCGF1 reveals 1. that PUFD binds to the same surfaces as observed for a different Polycomb Group RAWUL domain and 2. the ability of PUFD to discriminate among RAWULs stems from the identity of specific residues within these interaction surfaces. These data are the first to show the molecular basis for determining the binding preference for a PCGF homolog, which ultimately helps determine the identity of the larger PRC1-like assembly. PMID:23523425

DNA–PKcs–SIN1 complexation mediates low-dose X-ray irradiation (LDI)-induced Akt activation and osteoblast differentiation

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

Xu, Yong; Fang, Shi-ji; Zhu, Li-juan

Highlights: • LDI increases ALP activity, promotes type I collagen (Col I)/Runx2 mRNA expression. • LDI induces DNA–PKcs activation, which is required for osteoblast differentiation. • Akt activation mediates LDI-induced ALP activity and Col I/Runx2 mRNA increase. • DNA–PKcs–SIN1 complexation mediates LDI-induced Akt Ser-473 phosphorylation. • DNA–PKcs–SIN1 complexation is important for osteoblast differentiation. - Abstract: Low-dose irradiation (LDI) induces osteoblast differentiation, however the underlying mechanisms are not fully understood. In this study, we explored the potential role of DNA-dependent protein kinase catalytic subunit (DNA–PKcs)–Akt signaling in LDI-induced osteoblast differentiation. We confirmed that LDI promoted mouse calvarial osteoblast differentiation, which wasmore » detected by increased alkaline phosphatase (ALP) activity as well as mRNA expression of type I collagen (Col I) and runt-related transcription factor 2 (Runx2). In mouse osteoblasts, LDI (1 Gy) induced phosphorylation of DNA–PKcs and Akt (mainly at Ser-473). The kinase inhibitors against DNA–PKcs (NU-7026 and NU-7441) or Akt (LY294002, perifosine and MK-2206), as well as partial depletion of DNA–PKcs or Akt1 by targeted-shRNA, dramatically inhibited LDI-induced Akt activation and mouse osteoblast differentiation. Further, siRNA-knockdown of SIN1, a key component of mTOR complex 2 (mTORC2), also inhibited LDI-induced Akt Ser-473 phosphorylation as well as ALP activity increase and Col I/Runx2 expression in mouse osteoblasts. Co-immunoprecipitation (Co-IP) assay results demonstrated that LDI-induced DNA–PKcs–SIN1 complexation, which was inhibited by NU-7441 or SIN1 siRNA-knockdown in mouse osteoblasts. In summary, our data suggest that DNA–PKcs–SIN1 complexation-mediated Akt activation (Ser-473 phosphorylation) is required for mouse osteoblast differentiation.« less

c-Ski inhibits the TGF-beta signaling pathway through stabilization of inactive Smad complexes on Smad-binding elements.

PubMed

Suzuki, Hiroyuki; Yagi, Ken; Kondo, Miki; Kato, Mitsuyasu; Miyazono, Kohei; Miyazawa, Keiji

2004-06-24

c-Ski inhibits transforming growth factor-beta (TGF-beta) signaling through interaction with Smad proteins. c-Ski represses Smad-mediated transcriptional activation, probably through its action as a transcriptional co-repressor. c-Ski also inhibits TGF-beta-induced downregulation of genes such as c-myc. However, mechanisms for transcriptional regulation of target genes by c-Ski have not been fully determined. In this study, we examined how c-Ski inhibits both TGF-beta-induced transcriptional activation and repression. DNA-affinity precipitation analysis revealed that c-Ski enhances the binding of Smad2 and 4, and to a lesser extent Smad3, to both CAGA and TGF-beta1 inhibitory element probes. A c-Ski mutant, which is unable to interact with Smad4, failed to enhance the binding of Smad complex on these probes and to inhibit the Smad-responsive promoter. These results suggest that stabilization of inactive Smad complexes on DNA is a critical event in c-Ski-mediated inhibition of TGF-beta signaling.

Modification of Light Emission in Si-Rich Silicon Nitride Films Versus Stoichiometry and Excitation Light Energy

NASA Astrophysics Data System (ADS)

Torchynska, T.; Khomenkova, L.; Slaoui, A.

2018-04-01

Si-rich SiN x films with different stoichiometry were grown on Si substrate by plasma-enhanced chemical vapor deposition. The Si content was varied by changing the NH3/SiH4 gas flow ratio from 0.45 up to 1.0. Conventional furnace annealing at 1100°C for 30 min was applied to produce the Si quantum dots (QDs) in the SiN x films. Spectroscopic ellipsometry was used to determine the refractive index of the SiN x films that allowed estimating the film's stoichiometry. Fourier transform infrared spectroscopy has been also used to confirm the stoichiometry and microstructure. Photoluminescence (PL) spectra of Si-rich SiN x films are complex. A non-monotonous variation of the different PL peaks versus Si excess contents testifies to the competition of different radiative channels. The analysis of PL spectra, measured at the different excitation light energies and variable temperatures, has revealed that the PL bands with the peaks within the range 2.1-3.0 eV are related to the carrier recombination via radiative native defects in the SiN x host. Simultaneously, the PL bands with the peaks at 1.5-2.0 eV are caused by the exciton recombination in the Si QDs of different sizes. The way to control the SiN x emission is discussed.

Modification of Light Emission in Si-Rich Silicon Nitride Films Versus Stoichiometry and Excitation Light Energy

NASA Astrophysics Data System (ADS)

Torchynska, T.; Khomenkova, L.; Slaoui, A.

2018-07-01

Si-rich SiN x films with different stoichiometry were grown on Si substrate by plasma-enhanced chemical vapor deposition. The Si content was varied by changing the NH3/SiH4 gas flow ratio from 0.45 up to 1.0. Conventional furnace annealing at 1100°C for 30 min was applied to produce the Si quantum dots (QDs) in the SiN x films. Spectroscopic ellipsometry was used to determine the refractive index of the SiN x films that allowed estimating the film's stoichiometry. Fourier transform infrared spectroscopy has been also used to confirm the stoichiometry and microstructure. Photoluminescence (PL) spectra of Si-rich SiN x films are complex. A non-monotonous variation of the different PL peaks versus Si excess contents testifies to the competition of different radiative channels. The analysis of PL spectra, measured at the different excitation light energies and variable temperatures, has revealed that the PL bands with the peaks within the range 2.1-3.0 eV are related to the carrier recombination via radiative native defects in the SiN x host. Simultaneously, the PL bands with the peaks at 1.5-2.0 eV are caused by the exciton recombination in the Si QDs of different sizes. The way to control the SiN x emission is discussed.

Cutting edge: A transcriptional repressor and corepressor induced by the STAT3-regulated anti-inflammatory signaling pathway.

PubMed

El Kasmi, Karim C; Smith, Amber M; Williams, Lynn; Neale, Geoffrey; Panopoulos, Athanasia D; Panopolous, Athanasia; Watowich, Stephanie S; Häcker, Hans; Foxwell, Brian M J; Murray, Peter J

2007-12-01

IL-10 regulates anti-inflammatory signaling via the activation of STAT3, which in turn controls the induction of a gene expression program whose products execute inhibitory effects on proinflammatory mediator production. In this study we show that IL-10 induces the expression of an ETS family transcriptional repressor, ETV3, and a helicase family corepressor, Strawberry notch homologue 2 (SBNO2), in mouse and human macrophages. IL-10-mediated induction of ETV3 and SBNO2 expression was dependent upon both STAT3 and a stimulus through the TLR pathway. We also observed that ETV3 expression was strongly induced by the STAT3 pathway regulated by IL-10 but not by STAT3 signaling activated by IL-6, which cannot activate the anti-inflammatory signaling pathway. ETV3 and SBNO2 repressed NF-kappaB- but not IFN regulatory factor 7 (IRF7)-activated transcriptional reporters. Collectively our data suggest that ETV3 and SBNO2 are components of the pathways that contribute to the downstream anti-inflammatory effects of IL-10.

Smad ubiquitination regulatory factor-2 in the fibrotic kidney: regulation, target specificity, and functional implication.

PubMed

Tan, Ruoyun; He, Weichun; Lin, Xia; Kiss, Lawrence P; Liu, Youhua

2008-05-01

Smad ubiquitination regulatory factor-2 (Smurf2) is an E3 ubiqutin ligase that plays a pivotal role in regulating TGF-beta signaling via selectively targeting key components of the Smad pathway for degradation. In this study, we have investigated the regulation of Smurf2 expression, its target specificity, and the functional implication of its induction in the fibrotic kidney. Immunohistochemical staining revealed that Smurf2 was upregulated specifically in renal tubules of kidney biopsies from patients with various nephropathies. In vitro, Smurf2 mRNA and protein were induced in human proximal tubular epithelial cells (HKC-8) upon TGF-beta1 stimulation. Ectopic expression of Smurf2 was sufficient to reduce the steady-state levels of Smad2, but not Smad1, Smad3, Smad4, and Smad7, in HKC-8 cells. Interestingly, Smurf2 was also able to downregulate the Smad transcriptional corepressors Ski, SnoN, and TG-interacting factor. Inhibition of the proteasomal pathway prevented Smurf2-mediated downregulation of Smad2 and Smad corepressors. Functionally, overexpression of Smurf2 enhanced the transcription of the TGF-beta-responsive promoter and augmented TGF-beta1-mediated E-cadherin suppression, as well as fibronectin and type I collagen induction in HKC-8 cells. These results indicate that Smurf2 specifically targets both positive and negative Smad regulators for destruction in tubular epithelial cells, thereby providing a complex fine-tuning of TGF-beta signaling. It appears that dysregulation of Smurf2 could contribute to an aberrant TGF-beta/Smad signaling in the pathogenesis of kidney fibrosis.

The WD40 Domain Protein MSI1 Functions in a Histone Deacetylase Complex to Fine-Tune Abscisic Acid Signaling.

PubMed

Mehdi, Saher; Derkacheva, Maria; Ramström, Margareta; Kralemann, Lejon; Bergquist, Jonas; Hennig, Lars

2016-01-01

MSI1 belongs to a family of histone binding WD40-repeat proteins. Arabidopsis thaliana contains five genes encoding MSI1-like proteins, but their functions in diverse chromatin-associated complexes are poorly understood. Here, we show that MSI1 is part of a histone deacetylase complex. We copurified HISTONE DEACETYLASE19 (HDA19) with MSI1 and transcriptional regulatory SIN3-like proteins and provide evidence that MSI1 and HDA19 associate into the same complex in vivo. These data suggest that MSI1, HDA19, and HISTONE DEACETYLATION COMPLEX1 protein form a core complex that can integrate various SIN3-like proteins. We found that reduction of MSI1 or HDA19 causes upregulation of abscisic acid (ABA) receptor genes and hypersensitivity of ABA-responsive genes. The MSI1-HDA19 complex fine-tunes ABA signaling by binding to the chromatin of ABA receptor genes and by maintaining low levels of acetylation of histone H3 at lysine 9, thereby affecting the expression levels of ABA receptor genes. Reduced MSI1 or HDA19 levels led to increased tolerance to salt stress corresponding to the increased ABA sensitivity of gene expression. Together, our results reveal the presence of an MSI1-HDA19 complex that fine-tunes ABA signaling in Arabidopsis. © 2016 American Society of Plant Biologists. All rights reserved.

The metazoan Mediator co-activator complex as an integrative hub for transcriptional regulation.

PubMed

Malik, Sohail; Roeder, Robert G

2010-11-01

The Mediator is an evolutionarily conserved, multiprotein complex that is a key regulator of protein-coding genes. In metazoan cells, multiple pathways that are responsible for homeostasis, cell growth and differentiation converge on the Mediator through transcriptional activators and repressors that target one or more of the almost 30 subunits of this complex. Besides interacting directly with RNA polymerase II, Mediator has multiple functions and can interact with and coordinate the action of numerous other co-activators and co-repressors, including those acting at the level of chromatin. These interactions ultimately allow the Mediator to deliver outputs that range from maximal activation of genes to modulation of basal transcription to long-term epigenetic silencing.

Prostate Cell Specific Regulation of Androgen Receptor Phosphorylation in Vivo

DTIC Science & Technology

2009-11-01

includes both Rpb5, a subunit shared by RNA polymerase (Pol) I, II , and III, and the corepressor, Unconventional prefoldin Rpb5-Interactor (URI/C19orf2...complex that contains RNA polymerase II subunit 5, a subunit shared by all three RNA polymerases; unconventional prefoldin RPB5-in- teractor (URI), which...sequence of ART-27 is conserved throughout evolution from worms to humans and its predicted protein structure is homologous to the prefoldin -a family of

Pterostilbene, a Potent Analog of Resveratrol, a Therapeutic Agent in Prostate Cancer: Epigenetic Mechanisms of Action

DTIC Science & Technology

2015-10-01

protein was loaded in 10-15% SDS-PAGE and transferred onto polyvinylidene difluoride (PVDF) membranes. Membranes were incubated in 5% nonfat dry milk ...epigenetic reader, metastasis-associated protein 1 (MTA1) which is a part of nucleosome remodeling and deacetylation (NuRD) co-repressor complex. MTA1...inhibitor cocktail (ThermoFisher Scientific). Samples containing 70 μg of protein were loaded in 10-12% SDS-PAGE and transferred onto polyvinylidene

Structural insights into selective agonist actions of tamoxifen on human estrogen receptor alpha.

PubMed

Chakraborty, Sandipan; Biswas, Pradip Kumar

2014-08-01

Tamoxifen-an anti-estrogenic ligand in breast tissues used as a first-line treatment in estrogen receptor (ER)-positive breast cancers-is associated with the development of resistance followed by resumption of tumor growth in about 30 % of cases. Whether tamoxifen assists in proliferation in such cases or whether any ligand-independent pathway to transcription exists is not fully understood; also, no ERα mutants have been detected so far that could lead to tamoxifen resistance. Using in silico conformational analysis of the ERα ligand binding domain (LBD), in the absence and presence of selective agonist (diethylstilbestrol; DES), antagonist (Faslodex; ICI), and selective estrogen receptor modulator (SERM; 4-hydroxy tamoxifen; 4-OHT) ligands, we have elucidated ligand-responsive structural modulations of the ERα-LBD dimer in its agonist and antagonist complexes to address the issue of "tamoxifen resistance". DES and ICI were found to stabilize the dimer in their agonist and antagonist conformations, respectively. The ERα-LBD dimer without the presence of any bound ligand also led to a stable structure in agonist conformation. However, binding of 4-OHT to the antagonist structure led to a flexible conformation allowing the protein to visit conformations populated by agonists as was evident from principal component analysis and radius of gyration plots. Further, the relaxed conformations of the 4-OHT bound protein exhibited a diminished size of the co-repressor binding pocket in the LBD, thus signaling a partial blockage of the co-repressor binding motif. Thus, the ability of 4-OHT-bound ERα-LBD to assume flexible conformations visited by agonists and reduced co-repressor binding surface at the LBD provide crucial structural insights into tamoxifen-resistance that complement our existing understanding.

Short linear motif acquisition, exon formation and alternative splicing determine a pathway to diversity for NCoR-family co-repressors

PubMed Central

Short, Stephen; Peterkin, Tessa; Guille, Matthew; Patient, Roger; Sharpe, Colin

2015-01-01

Vertebrate NCoR-family co-repressors play central roles in the timing of embryo and stem cell differentiation by repressing the activity of a range of transcription factors. They interact with nuclear receptors using short linear motifs (SLiMs) termed co-repressor for nuclear receptor (CoRNR) boxes. Here, we identify the pathway leading to increasing co-repressor diversity across the deuterostomes. The final complement of CoRNR boxes arose in an ancestral cephalochordate, and was encoded in one large exon; the urochordates and vertebrates then split this region between 10 and 12 exons. In Xenopus, alternative splicing is prevalent in NCoR2, but absent in NCoR1. We show for one NCoR1 exon that alternative splicing can be recovered by a single point mutation, suggesting NCoR1 lost the capacity for alternative splicing. Analyses in Xenopus and zebrafish identify that cellular context, rather than gene sequence, predominantly determines species differences in alternative splicing. We identify a pathway to diversity for the NCoR family beginning with the addition of a SLiM, followed by gene duplication, the generation of alternatively spliced isoforms and their differential deployment. PMID:26289800

Antagonism of Taxol Cytotoxicity by Prolactin: Implication for Patient Resistance to Chemotherapy

DTIC Science & Technology

2008-03-01

Perspectives I. Introduction SINCE ITS DISCOVERY in the 1930s as a distinct pituitaryhormone that stimulates milk production in rabbits, prolactin...vitellogenin ERE sequence (GGTCAnnn TGACC), is located at the distal rPRL enhancer next to the 1d Pit-1 site (Fig. 1), enabling physical association between Pit...1 and ER via the AF-2 domain of ER (19). Complex formation between Pit-1 and ER involves coactivators/corepressors, with SRC-1 and GRIP1 stimulating

Identification of sinensetin metabolites in rat urine by an isotope-labeling method and ultrahigh-performance liquid chromatography-electrospray ionization mass spectrometry.

PubMed

Wei, Guor-Jien; Sheen, Jenn-Feng; Lu, Wen-Chien; Hwang, Lucy Sun; Ho, Chi-Tang; Lin, Ching-I

2013-05-29

Sinensetin (SIN), one of the major polymethoxyflavones (PMFs) contained mainly in the citrus peels, has been reported to possess various bioactivities, including antifungal, antimutagenic, anticancer, and anti-inflammatory activities. Although the biotransformation of SIN in fungi and insects has been reported, the information about the metabolism of SIN in mammals is still unclear. In this study, formation of SIN metabolites in rats was investigated. Four isotope-labeled SINs ([4'-D3]SIN, [3'-D3]SIN, [5-D3]SIN, and [6-D3]SIN) were synthesized and administered to rat. The urine samples were collected and main metabolites were monitored by ultrahigh-performance liquid chromatography-electrospray ionization mass spectrometry. The administered compound and four SIN metabolites were detected in rat urine. These metabolites were identified as 4'-hydroxy-5,6,7,3'-tetramethoxyflavone, 5-hydroxy-6,7,3',4'-tetramethoxyflavone, 6-hydroxy-5,7,3',4'-tetramethoxyflavone, and 7-hydroxy-5,6,3',4'-tetramethoxyflavone sulfate.

Quaternary re-arrangement analysed by spectral enhancement: the interaction of a sporulation repressor with its antagonist.

PubMed

Scott, D J; Leejeerajumnean, S; Brannigan, J A; Lewis, R J; Wilkinson, A J; Hoggett, J G

1999-11-12

The protein/protein interaction between SinI and SinR has been studied by analytical ultracentrifugation and gel electrophoresis in an attempt to understand how these proteins contribute to developmental control of sporulation in Bacillus subtilis. SinR was found to be tetrameric, while SinI was found to exist as monomers and dimers in a rapidly reversible equilibrium. Labelling of SinR by incorporating the tryptophan analogue 7-azatryptophan (7AW) into the protein in place of tryptophan shifts the UV absorbance spectrum, thus allowing selective monitoring of 7AWSinR at 315 nm using the UV absorption optics of the analytical ultracentrifuge. Selective monitoring of SinR in mixtures of SinR and SinI enables the binding and stoichiometry of the interaction to be investigated quantitatively and unambiguously. We demonstrate that the oligomeric forms of SinR and SinI re-arrange to form a tight 1:1 SinR:SinI complex, with no stable intermediate species. A fragment of SinR, SinR(1-69), which contains only the DNA-binding domain, was found to be monomeric, showing that the protein appears not to oligomerise in a similar manner to the Cro repressor, a protein with which it shares a marked structural similarity. Copyright 1999 Academic Press.

Gonadotropin-Releasing Hormone Pulse Sensitivity of Follicle-Stimulating Hormone-β Gene Is Mediated by Differential Expression of Positive Regulatory Activator Protein 1 Factors and Corepressors SKIL and TGIF1

PubMed Central

Mistry, Devendra S.; Tsutsumi, Rie; Fernandez, Marina; Sharma, Shweta; Cardenas, Steven A.; Lawson, Mark A.

2011-01-01

Gonadotropin synthesis and release is dependent on pulsatile stimulation by the hypothalamic neuropeptide GnRH. Generally, slow GnRH pulses promote FSH production, whereas rapid pulses favor LH, but the molecular mechanism underlying this pulse sensitivity is poorly understood. In this study, we developed and tested a model for FSHβ regulation in mouse LβT2 gonadotropes. By mining a previous microarray data set, we found that mRNA for positive regulators of Fshb expression, such as Fos and Jun, were up-regulated at slower pulse frequencies than a number of potential negative regulators, such as the corepressors Skil, Crem, and Tgif1. These latter corepressors reduced Fshb promoter activity whether driven by transfection of individual transcription factors or by treatment with GnRH and activin. Overexpression of binding or phosphorylation-defective ski-oncogene-like protein (SKIL) and TG interacting factor (TGIF1) mutants, however, failed to repress Fshb promoter activity. Knockdown of the endogenous repressors SKIL and TGIF1, but not cAMP response element-modulator, increased Fshb promoter activity driven by constant GnRH or activin. Chromatin immunoprecipitation analysis showed that FOS, SKIL, and TGIF1 occupy the FSHβ promoter in a cyclical manner after GnRH stimulation. Overexpression of corepressors SKIL or TGIF1 repressed induction of the Fshb promoter at the slow GnRH pulse frequency but had little effect at the fast pulse frequency. In contrast, knockdown of endogenous SKIL or TGIF1 selectively increased Fshb mRNA at the fast GnRH pulse frequency. Therefore, we propose a potential mechanism by which production of gonadotropin Fshb is modulated by positive transcription factors and negative corepressors with different pulse sensitivities. PMID:21659477

The Ski oncoprotein interacts with the Smad proteins to repress TGFbeta signaling.

PubMed

Luo, K; Stroschein, S L; Wang, W; Chen, D; Martens, E; Zhou, S; Zhou, Q

1999-09-01

Smad proteins are critical signal transducers downstream of the receptors of the transforming growth factor-beta (TGFbeta) superfamily. On phosphorylation and activation by the active TGFbeta receptor complex, Smad2 and Smad3 form hetero-oligomers with Smad4 and translocate into the nucleus, where they interact with different cellular partners, bind to DNA, regulate transcription of various downstream response genes, and cross-talk with other signaling pathways. Here we show that a nuclear oncoprotein, Ski, can interact directly with Smad2, Smad3, and Smad4 on a TGFbeta-responsive promoter element and repress their abilities to activate transcription through recruitment of the nuclear transcriptional corepressor N-CoR and possibly its associated histone deacetylase complex. Overexpression of Ski in a TGFbeta-responsive cell line renders it resistant to TGFbeta-induced growth inhibition and defective in activation of JunB expression. This ability to overcome TGFbeta-induced growth arrest may be responsible for the transforming activity of Ski in human and avian cancer cells. Our studies suggest a new paradigm for inactivation of the Smad proteins by an oncoprotein through transcriptional repression.

The Ski oncoprotein interacts with the Smad proteins to repress TGFβ signaling

PubMed Central

Luo, Kunxin; Stroschein, Shannon L.; Wang, Wei; Chen, Dan; Martens, Eric; Zhou, Sharleen; Zhou, Qiang

1999-01-01

Smad proteins are critical signal transducers downstream of the receptors of the transforming growth factor-β (TGFβ) superfamily. On phosphorylation and activation by the active TGFβ receptor complex, Smad2 and Smad3 form hetero-oligomers with Smad4 and translocate into the nucleus, where they interact with different cellular partners, bind to DNA, regulate transcription of various downstream response genes, and cross-talk with other signaling pathways. Here we show that a nuclear oncoprotein, Ski, can interact directly with Smad2, Smad3, and Smad4 on a TGFβ-responsive promoter element and repress their abilities to activate transcription through recruitment of the nuclear transcriptional corepressor N-CoR and possibly its associated histone deacetylase complex. Overexpression of Ski in a TGFβ-responsive cell line renders it resistant to TGFβ-induced growth inhibition and defective in activation of JunB expression. This ability to overcome TGFβ-induced growth arrest may be responsible for the transforming activity of Ski in human and avian cancer cells. Our studies suggest a new paradigm for inactivation of the Smad proteins by an oncoprotein through transcriptional repression. PMID:10485843

Efficient replication, and evolution of Sindbis virus genomes with non-canonical 3'A/U-rich elements (NC3ARE) in neonatal mice.

PubMed

James, Frederick D; Hietala, Katie A; Eldar, Dganit; Guess, Tiffany E; Cone, Cecil; Mundell, Nathan A; Mundall, Nathan; Barnett, Joey V; Raju, Ramaswamy

2007-12-01

Sindbis virus (SIN) is a mosquito-transmitted animal RNA virus. We previously reported that SIN genomes lacking a canonical 19 nt 3'CSE undergo novel repair processes in BHK cells to generate a library of stable atypical SIN genomes with non-canonical 3'A/U-rich elements (NC3AREs) adjacent to the 3' poly(A) tail [1]. To determine the stability and evolutionary pressures on the SIN genomes with NC3AREs to regain a 3'CSE, five representative SIN isolates and a wild type SIN were tested in newborn mice. The key findings of this study are: (a) all six SIN isolates, including those that have extensive NC3AREs in the 3'NTRs, replicate well and produce high titer viremia in newborn mice; (b) 7-9 successive passages of these isolates in newborn mice produced comparable levels of viremia; (c) while all isolates produced only small-sized plaques during primary infection in animals, both small- and large-sized plaques were generated in all other passages; (d) polymerase stuttering occurs on select 3' oligo(U) motifs to add more U residues within the NC3AREs; (e) the S3-8 isolate with an internal UAUUU motif in the 3'poly(A) tail maintains this element even after 9 passages in animals; (f) despite differences in 3'NTRs and variable tissue distribution, all SIN isolates appear to produce similar tissue pathology in infected animals. Competition experiments with wt SIN and atypical SIN isolates in BHK cells show dominance of wt SIN. As shown for BHK cells in culture, the 3'CSE of the SIN genome is not required for virus replication and genome stability in live animals. Since the NC3AREs of atypical SIN genomes are not specific to SIN replicases, alternate RNA motifs of alphavirus genome must confer specificity in template selection. These studies fulfill the need to confirm the long-term viability of atypical SIN genomes in newborn mice and offer a basis for exploring the use of atypical SIN genomes in biotechnology.

Epigenetic silencing of the DNA mismatch repair gene, MLH1, induced by hypoxic stress in a pathway dependent on the histone demethylase, LSD1

PubMed Central

Lu, Yuhong; Wajapeyee, Narendra; Turker, Mitchell S.; Glazer, Peter M.

2014-01-01

SUMMARY Silencing of the MLH1 gene is frequently seen in sporadic cancers. We report that hypoxia causes decreased H3K4 methylation at the MLH1 promoter via the H3K4 demethylases, LSD1 and PLU-1, and promotes long-term silencing of the promoter in a pathway that requires LSD1. Knockdown of LSD1 or its co-repressor, CoREST, also prevents the re-silencing (and cytosine DNA methylation) of the endogenous MLH1 promoter in RKO colon cancer cells following transient reactivation by the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine (5-aza-dC). The results demonstrate that hypoxia is a critical driving force for silencing of MLH1 through chromatin modification and indicate that the LSD1/CoREST complex is essential for MLH1 silencing. PMID:25043185

Loss of corepressor PER2 under hypoxia up-regulates OCT1-mediated EMT gene expression and enhances tumor malignancy

PubMed Central

Hwang-Verslues, Wendy W.; Chang, Po-Hao; Jeng, Yung-Ming; Kuo, Wen-Hung; Chiang, Pei-Hsun; Chang, Yi-Cheng; Hsieh, Tsung-Han; Su, Fang-Yi; Lin, Liu-Chen; Abbondante, Serena; Yang, Cheng-Yuan; Hsu, Huan-Ming; Yu, Jyh-Cherng; Chang, King-Jen; Shew, Jin-Yuh; Lee, Eva Y.-H. P.; Lee, Wen-Hwa

2013-01-01

The circadian clock gene Period2 (PER2) has been suggested to be a tumor suppressor. However, detailed mechanistic evidence has not been provided to support this hypothesis. We found that loss of PER2 enhanced invasion and activated expression of epithelial-mesenchymal transition (EMT) genes including TWIST1, SLUG, and SNAIL. This finding was corroborated by clinical observation that PER2 down-regulation was associated with poor prognosis in breast cancer patients. We further demonstrated that PER2 served as a transcriptional corepressor, which recruited polycomb proteins EZH2 and SUZ12 as well as HDAC2 to octamer transcription factor 1 (OCT1) (POU2F1) binding sites of the TWIST1 and SLUG promoters to repress expression of these EMT genes. Hypoxia, a condition commonly observed in tumors, caused PER2 degradation and disrupted the PER2 repressor complex, leading to activation of EMT gene expression. This result was further supported by clinical data showing a significant negative correlation between hypoxia and PER2. Thus, our findings clearly demonstrate the tumor suppression function of PER2 and elucidate a pathway by which hypoxia promotes EMT via degradation of PER2. PMID:23836662

STERILE APETALA modulates the stability of a repressor protein complex to control organ size in Arabidopsis thaliana

PubMed Central

Wang, Zhibiao; Ru, Licong; Baekelandt, Alexandra; Goossens, Alain; Xu, Ran; Zhu, Zhengge; Inzé, Dirk; Li, Yunhai

2018-01-01

Organ size control is of particular importance for developmental biology and agriculture, but the mechanisms underlying organ size regulation remain elusive in plants. Meristemoids, which possess stem cell-like properties, have been recognized to play important roles in leaf growth. We have recently reported that the Arabidopsis F-box protein STERILE APETALA (SAP)/SUPPRESSOR OF DA1 (SOD3) promotes meristemoid proliferation and regulates organ size by influencing the stability of the transcriptional regulators PEAPODs (PPDs). Here we demonstrate that KIX8 and KIX9, which function as adaptors for the corepressor TOPLESS and PPD, are novel substrates of SAP. SAP interacts with KIX8/9 and modulates their protein stability. Further results show that SAP acts in a common pathway with KIX8/9 and PPD to control organ growth by regulating meristemoid cell proliferation. Thus, these findings reveal a molecular mechanism by which SAP targets the KIX-PPD repressor complex for degradation to regulate meristemoid cell proliferation and organ size. PMID:29401459

Elevated nuclear expression of the SMRT corepressor in breast cancer is associated with earlier tumor recurrence

PubMed Central

Migliaccio, Ilenia; Chaubal, Vaishali; Wu, Meng-Fen; Pace, Margaret C.; Hartmaier, Ryan; Jiang, Shiming; Edwards, Dean P.; Gutiérrez, M. Carolina; Hilsenbeck, Susan G.; Oesterreich, Steffi

2012-01-01

Silencing mediator of retinoic acid and thyroid hormone receptor (SMRT), also known as nuclear corepressor 2 (NCOR2) is a transcriptional corepressor for multiple members of the nuclear receptor superfamily of transcription factors, including estrogen receptor-α (ERα). In the classical model of corepressor action, SMRT binds to antiestrogen-bound ERα at target promoters and represses ERα transcriptional activity and gene expression. Herein SMRT mRNA and protein expression was examined in a panel of 30 breast cancer cell lines. Expression of both parameters was found to vary considerably amongst lines and the correlation between protein and mRNA expression was very poor (R2 = 0.0775). Therefore, SMRT protein levels were examined by immunohistochemical staining of a tissue microarray of 866 patients with stage I–II breast cancer. Nuclear and cytoplasmic SMRT were scored separately according to the Allred score. The majority of tumors (67 %) were negative for cytoplasmic SMRT, which when detected was found at very low levels. In contrast, nuclear SMRT was broadly detected. There was no significant difference in time to recurrence (TTR) according to SMRT expression levels in the ERα-positive tamoxifen-treated patients (P = 0.297) but the difference was significant in the untreated patients (P = 0.01). In multivariate analysis, ERα-positive tamoxifen-untreated patients with high nuclear SMRT expression (SMRT 5-8, i.e., 2nd to 4th quartile) had a shorter TTR (HR = 1.94, 95 % CI, 1.24–3.04; P = 0.004) while there was no association with SMRT expression for ERα-positive tamoxifen-treated patients. There was no association between SMRT expression and overall survival for patients, regardless of whether they received tamoxifen. Thus while SMRT protein expression was not predictive of outcome after antiestrogen therapy, it may have value in predicting tumor recurrence in patients not receiving adjuvant tamoxifen therapy. PMID:23015261

PHD domain-mediated E3 ligase activity directs intramolecular sumoylation of an adjacent bromodomain required for gene silencing.

PubMed

Ivanov, Alexey V; Peng, Hongzhuang; Yurchenko, Vyacheslav; Yap, Kyoko L; Negorev, Dmitri G; Schultz, David C; Psulkowski, Elyse; Fredericks, William J; White, David E; Maul, Gerd G; Sadofsky, Moshe J; Zhou, Ming-Ming; Rauscher, Frank J

2007-12-14

Tandem PHD and bromodomains are often found in chromatin-associated proteins and have been shown to cooperate in gene silencing. Each domain can bind specifically modified histones: the mechanisms of cooperation between these domains are unknown. We show that the PHD domain of the KAP1 corepressor functions as an intramolecular E3 ligase for sumoylation of the adjacent bromodomain. The RING finger-like structure of the PHD domain is required for both Ubc9 binding and sumoylation and directs modification to specific lysine residues in the bromodomain. Sumoylation is required for KAP1-mediated gene silencing and functions by directly recruiting the SETDB1 histone methyltransferase and the CHD3/Mi2 component of the NuRD complex via SUMO-interacting motifs. Sumoylated KAP1 stimulates the histone methyltransferase activity of SETDB1. These data provide a mechanistic explanation for the cooperation of PHD and bromodomains in gene regulation and describe a function of the PHD domain as an intramolecular E3 SUMO ligase.

CRISPR-mediated HDAC2 disruption identifies two distinct classes of target genes in human cells.

PubMed

Somanath, Priyanka; Herndon Klein, Rachel; Knoepfler, Paul S

2017-01-01

The transcriptional functions of the class I histone deacetylases (HDACs) HDAC1 and HDAC2 are mainly viewed as both repressive and redundant based on murine knockout studies, but they may have additional independent roles and their physiological functions in human cells are not as clearly defined. To address the individual epigenomic functions of HDAC2, here we utilized CRISPR-Cas9 to disrupt HDAC2 in human cells. We find that while HDAC2 null cells exhibited signs of cross-regulation between HDAC1 and HDAC2, specific epigenomic phenotypes were still apparent using RNA-seq and ChIP assays. We identified specific targets of HDAC2 repression, and defined a novel class of genes that are actively expressed in a partially HDAC2-dependent manner. While HDAC2 was required for the recruitment of HDAC1 to repressed HDAC2-gene targets, HDAC2 was dispensable for HDAC1 binding to HDAC2-activated targets, supporting the notion of distinct classes of targets. Both active and repressed classes of gene targets demonstrated enhanced histone acetylation and methylation in HDAC2-null cells. Binding of the HDAC1/2-associated SIN3A corepressor was altered at most HDAC2-targets, but without a clear pattern. Overall, our study defines two classes of HDAC2 targets in human cells, with a dependence of HDAC1 on HDAC2 at one class of targets, and distinguishes unique functions for HDAC2.

Drosophila arginine methyltransferase 1 (DART1) is an ecdysone receptor co-repressor

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

Kimura, Shuhei; Department of Obstetrics and Gynecology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574; Sawatsubashi, Shun

2008-07-11

Histone arginine methylation is an epigenetic marker that regulates gene expression by defining the chromatin state. Arginine methyltransferases, therefore, serve as transcriptional co-regulators. However, unlike other transcriptional co-regulators, the physiological roles of arginine methyltransferases are poorly understood. Drosophila arginine methyltransferase 1 (DART1), the mammalian PRMT1 homologue, methylates the arginine residue of histone H4 (H4R3me2). Disruption of DART1 in Drosophila by imprecise P-element excision resulted in low viability during metamorphosis in the pupal stages. In the pupal stage, an ecdysone hormone signal is critical for developmental progression. DART1 interacted with the nuclear ecdysone receptor (EcR) in a ligand-dependent manner, and co-repressedmore » EcR in intact flies. These findings suggest that DART1, a histone arginine methyltransferase, is a co-repressor of EcR that is indispensable for normal pupal development in the intact fly.« less

Prostate Cancer Aggressiveness Gene in Hereditary Prostate Cancer

DTIC Science & Technology

2007-03-01

with REA, and estrogen receptor corepressor. Breast Canc Res Treat., in press (2007). This grant provided research support for Dr Veda Giri while...an estrogen receptor corepressor Clara Hwang Æ Veda N. Giri Æ John C. Wilkinson Æ Casey W. Wright Æ Amanda S. Wilkinson Æ Kathleen A. Cooney Æ Colin S...histone deacetylases (HDAC), and members of the polycomb group (PcG) of proteins. Clara Hwang and Veda N. Giri contributed equally to this work. C

Expression of nuclear receptor interacting proteins TIF-1, SUG-1, receptor interacting protein 140, and corepressor SMRT in tamoxifen-resistant breast cancer.

PubMed

Chan, C M; Lykkesfeldt, A E; Parker, M G; Dowsett, M

1999-11-01

Regulation of gene transcription as a consequence of steroid receptor-DNA interaction is mediated via nuclear receptor interacting proteins (RIPs), including coactivator or corepressor proteins, which interact with both the receptor and components of the basic transcriptional unit and vary between cell types. The aim of this study was to test the hypothesis that resistance of some breast carcinomas to tamoxifen was associated with inappropriate expression of some of these RIPs. Using Northern analysis, we observed no significant difference between the amount of either TIF-1 or SUG-1 mRNA expressed in parental MCF-7 and MCF-7 tamoxifen-resistant cell lines. However, the expression of RIP140 mRNA was lower in the resistant cell line and in the presence of estradiol, the level of RIP140 mRNA was higher in the resistant cells but not in the parental cells. In a cohort of 19 tamoxifen-resistant breast tumor samples, there was no significant difference in the level of the RIP140 and TIF-1 and corepressor SMRT mRNA compared with tamoxifen-treated tumors (n = 6) or untreated tumors (n = 21). However, SUG-1 mRNA was lower in resistant breast tumors. These data provide no support for increased expression of these RIPs or decreased expression of corepressor SMRT for being a mechanism for resistance of breast tumors to tamoxifen.

FBI-1 functions as a novel AR co-repressor in prostate cancer cells.

PubMed

Cui, Jiajun; Yang, Yutao; Zhang, Chuanfu; Hu, Pinliang; Kan, Wei; Bai, Xianhong; Liu, Xuelin; Song, Hongbin

2011-03-01

The pro-oncogene FBI-1, encoded by Zbtb7a, is a transcriptional repressor that belongs to the POK (POZ/BTB and Krüppel) protein family. In this study, we investigated a potential interaction between androgen receptor (AR) signaling and FBI-1 and demonstrated that overexpression of FBI-1 inhibited ligand-dependent AR activation. A protein-protein interaction was identified between FBI-1 and AR in a ligand-dependent manner. Furthermore, FBI-1, AR and SMRT formed a ternary complex and FBI-1 enhanced the recruitment of NCoR and SMRT to endogenous PSA upstream sequences. Our data also indicated that the FBI-1-mediated inhibition of AR transcriptional activity is partially dependent on HDAC. Interestingly, FBI-1 plays distinct roles in regulating LNCaP (androgen-dependent) and PC-3 cell (androgen-independent) proliferation.

An emerging link between LIM domain proteins and nuclear receptors.

PubMed

Sala, Stefano; Ampe, Christophe

2018-06-01

Nuclear receptors are ligand-activated transcription factors that partake in several biological processes including development, reproduction and metabolism. Over the last decade, evidence has accumulated that group 2, 3 and 4 LIM domain proteins, primarily known for their roles in actin cytoskeleton organization, also partake in gene transcription regulation. They shuttle between the cytoplasm and the nucleus, amongst other as a consequence of triggering cells with ligands of nuclear receptors. LIM domain proteins act as important coregulators of nuclear receptor-mediated gene transcription, in which they can either function as coactivators or corepressors. In establishing interactions with nuclear receptors, the LIM domains are important, yet pleiotropy of LIM domain proteins and nuclear receptors frequently occurs. LIM domain protein-nuclear receptor complexes function in diverse physiological processes. Their association is, however, often linked to diseases including cancer.

Sin(x)**2 + cos(x)**2 = 1. [programming identities using comparative combinatorial substitutions

NASA Technical Reports Server (NTRS)

Stoutemyer, D. R.

1977-01-01

Attempts to achieve tasteful automatic employment of the identities sin sq x + cos sq x = 1 and cos sq h x -sin sq h x = 1 in a manner which truly minimizes the complexity of the resulting expression are described. The disappointments of trigonometric reduction, trigonometric expansion, pattern matching, Poisson series, and Demoivre's theorem are related. The advantages of using the method of comparative combinatorial substitutions are illustrated.

Transforming Growth Factor β Suppresses Peroxisome Proliferator–Activated Receptor γ Expression via Both SMAD Binding and Novel TGF-β Inhibitory Elements

PubMed Central

Lakshmi, Sowmya P.; Reddy, Aravind T.; Reddy, Raju C.

2017-01-01

Transforming growth factor β (TGF-β) contributes to wound healing and, when dysregulated, to pathological fibrosis. TGF-β and the anti-fibrotic nuclear hormone receptor peroxisome proliferator-activated receptor γ (PPARγ) repress each other’s expression, and such PPARγ downregulation is prominent in fibrosis and mediated, via previously unknown SMAD-signaling mechanisms. Here we show that TGF-β induces association of SMAD3 with both SMAD4, needed for translocation of the complex into the nucleus, and the essential context-sensitive corepressors E2F4 and p107. The complex mediates TGF-β-induced repression by binding to regulatory elements in the target promoter. In the PPARG promoter, we found that the SMAD3-SMAD4 complex binds both to a previously unknown consensus TGF-β inhibitory element (TIE) and also to canonical SMAD-binding elements (SBEs). Furthermore, the TIE and SBEs independently mediated partial repression of PPARG transcription, the first demonstration of a TIE and SBEs functioning within the same promoter. Also, TGF-β-treated fibroblasts contained SMAD complexes that activated a SMAD target gene in addition to those repressing PPARG transcription, the first finding of such dual activity within the same cell. These findings describe in detail novel mechanisms by which TGF-β represses PPARG transcription, thereby facilitating its own pro-fibrotic activity. PMID:28100650

Abstract Interface Specifications for the A-7E Device Interface Module.

DTIC Science & Technology

1980-11-20

Undesired events +GSINSAGE+ pl:time;O !+SINS attitude age +! %SINS not enabled% p2 :time:O !+SINS position age +! p3:time:O !+SINS velocity age +! +G SINS...attitude age +! The elapsed time since new valid attitude data was provided by the SINS hardware. !+SINS attitude valid+! True iff SINS attitude data is valid...horizontal plane. !+SINS position age +! The elapsed time since new valid position data was provided by the SINS hardware. !+SINS position valid+! True iff

Interaction with Smad4 is indispensable for suppression of BMP signaling by c-Ski.

PubMed

Takeda, Masafumi; Mizuide, Masafumi; Oka, Masako; Watabe, Tetsuro; Inoue, Hirofumi; Suzuki, Hiroyuki; Fujita, Toshiro; Imamura, Takeshi; Miyazono, Kohei; Miyazawa, Keiji

2004-03-01

c-Ski is a transcriptional corepressor that interacts strongly with Smad2, Smad3, and Smad4 but only weakly with Smad1 and Smad5. Through binding to Smad proteins, c-Ski suppresses signaling of transforming growth factor-beta (TGF-beta) as well as bone morphogenetic proteins (BMPs). In the present study, we found that a mutant of c-Ski, termed c-Ski (ARPG) inhibited TGF-beta/activin signaling but not BMP signaling. Selectivity was confirmed in luciferase reporter assays and by determination of cellular responses in mammalian cells (BMP-induced osteoblastic differentiation of C2C12 cells and TGF-beta-induced epithelial-to-mesenchymal transdifferentiation of NMuMG cells) and Xenopus embryos. The ARPG mutant recruited histone deacetylases 1 (HDAC1) to the Smad3-Smad4 complex but not to the Smad1/5-Smad4 complex. c-Ski (ARPG) was unable to interact with Smad4, and the selective loss of suppression of BMP signaling by c-Ski (ARPG) was attributed to the lack of Smad4 binding. We also found that c-Ski interacted with Smad3 or Smad4 without disrupting Smad3-Smad4 heteromer formation. c-Ski (ARPG) would be useful for selectively suppressing TGF-beta/activin signaling.

Interaction with Smad4 Is Indispensable for Suppression of BMP Signaling by c-Ski

PubMed Central

Takeda, Masafumi; Mizuide, Masafumi; Oka, Masako; Watabe, Tetsuro; Inoue, Hirofumi; Suzuki, Hiroyuki; Fujita, Toshiro; Imamura, Takeshi; Miyazono, Kohei; Miyazawa, Keiji

2004-01-01

c-Ski is a transcriptional corepressor that interacts strongly with Smad2, Smad3, and Smad4 but only weakly with Smad1 and Smad5. Through binding to Smad proteins, c-Ski suppresses signaling of transforming growth factor-β (TGF-β) as well as bone morphogenetic proteins (BMPs). In the present study, we found that a mutant of c-Ski, termed c-Ski (ARPG) inhibited TGF-β/activin signaling but not BMP signaling. Selectivity was confirmed in luciferase reporter assays and by determination of cellular responses in mammalian cells (BMP-induced osteoblastic differentiation of C2C12 cells and TGF-β–induced epithelial-to-mesenchymal transdifferentiation of NMuMG cells) and Xenopus embryos. The ARPG mutant recruited histone deacetylases 1 (HDAC1) to the Smad3-Smad4 complex but not to the Smad1/5-Smad4 complex. c-Ski (ARPG) was unable to interact with Smad4, and the selective loss of suppression of BMP signaling by c-Ski (ARPG) was attributed to the lack of Smad4 binding. We also found that c-Ski interacted with Smad3 or Smad4 without disrupting Smad3-Smad4 heteromer formation. c-Ski (ARPG) would be useful for selectively suppressing TGF-β/activin signaling. PMID:14699069

Roles of mono-ubiquitinated Smad4 in the formation of Smad transcriptional complexes

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

Wang Bei; Suzuki, Hiroyuki; Kato, Mitsuyasu

2008-11-14

TGF-{beta} activates receptor-regulated Smad (R-Smad) through phosphorylation by type I receptors. Activated R-Smad binds to Smad4 and the complex translocates into the nucleus and stimulates the transcription of target genes through association with co-activators including p300. It is not clear, however, how activated Smad complexes are removed from target genes. In this study, we show that TGF-{beta} enhances the mono-ubiquitination of Smad4. Smad4 mono-ubiquitination was promoted by p300 and suppressed by the c-Ski co-repressor. Smad4 mono-ubiquitination disrupted the interaction with Smad2 in the presence of constitutively active TGF-{beta} type I receptor. Furthermore, mono-ubiquitinated Smad4 was not found in DNA-binding Smadmore » complexes. A Smad4-Ubiquitin fusion protein, which mimics mono-ubiquitinated Smad4, enhanced localization to the cytoplasm. These results suggest that mono-ubiquitination of Smad4 occurs in the transcriptional activator complex and facilitates the turnover of Smad complexes at target genes.« less

Roles of mono-ubiquitinated Smad4 in the formation of Smad transcriptional complexes.

PubMed

Wang, Bei; Suzuki, Hiroyuki; Kato, Mitsuyasu

2008-11-14

TGF-beta activates receptor-regulated Smad (R-Smad) through phosphorylation by type I receptors. Activated R-Smad binds to Smad4 and the complex translocates into the nucleus and stimulates the transcription of target genes through association with co-activators including p300. It is not clear, however, how activated Smad complexes are removed from target genes. In this study, we show that TGF-beta enhances the mono-ubiquitination of Smad4. Smad4 mono-ubiquitination was promoted by p300 and suppressed by the c-Ski co-repressor. Smad4 mono-ubiquitination disrupted the interaction with Smad2 in the presence of constitutively active TGF-beta type I receptor. Furthermore, mono-ubiquitinated Smad4 was not found in DNA-binding Smad complexes. A Smad4-Ubiquitin fusion protein, which mimics mono-ubiquitinated Smad4, enhanced localization to the cytoplasm. These results suggest that mono-ubiquitination of Smad4 occurs in the transcriptional activator complex and facilitates the turnover of Smad complexes at target genes.

Multi-scale modeling of urban air pollution: development and application of a Street-in-Grid model (v1.0) by coupling MUNICH (v1.0) and Polair3D (v1.8.1)

NASA Astrophysics Data System (ADS)

Kim, Youngseob; Wu, You; Seigneur, Christian; Roustan, Yelva

2018-02-01

A new multi-scale model of urban air pollution is presented. This model combines a chemistry-transport model (CTM) that includes a comprehensive treatment of atmospheric chemistry and transport on spatial scales down to 1 km and a street-network model that describes the atmospheric concentrations of pollutants in an urban street network. The street-network model is the Model of Urban Network of Intersecting Canyons and Highways (MUNICH), which consists of two main components: a street-canyon component and a street-intersection component. MUNICH is coupled to the Polair3D CTM of the Polyphemus air quality modeling platform to constitute the Street-in-Grid (SinG) model. MUNICH is used to simulate the concentrations of the chemical species in the urban canopy, which is located in the lowest layer of Polair3D, and the simulation of pollutant concentrations above rooftops is performed with Polair3D. Interactions between MUNICH and Polair3D occur at roof level and depend on a vertical mass transfer coefficient that is a function of atmospheric turbulence. SinG is used to simulate the concentrations of nitrogen oxides (NOx) and ozone (O3) in a Paris suburb. Simulated concentrations are compared to NOx concentrations measured at two monitoring stations within a street canyon. SinG shows better performance than MUNICH for nitrogen dioxide (NO2) concentrations. However, both SinG and MUNICH underestimate NOx. For the case study considered, the model performance for NOx concentrations is not sensitive to using a complex chemistry model in MUNICH and the Leighton NO-NO2-O3 set of reactions is sufficient.

CRTC1 Nuclear Translocation Following Learning Modulates Memory Strength via Exchange of Chromatin Remodeling Complexes on the Fgf1 Gene.

PubMed

Uchida, Shusaku; Teubner, Brett J W; Hevi, Charles; Hara, Kumiko; Kobayashi, Ayumi; Dave, Rutu M; Shintaku, Tatsushi; Jaikhan, Pattaporn; Yamagata, Hirotaka; Suzuki, Takayoshi; Watanabe, Yoshifumi; Zakharenko, Stanislav S; Shumyatsky, Gleb P

2017-01-10

Memory is formed by synapse-to-nucleus communication that leads to regulation of gene transcription, but the identity and organizational logic of signaling pathways involved in this communication remain unclear. Here we find that the transcription cofactor CRTC1 is a critical determinant of sustained gene transcription and memory strength in the hippocampus. Following associative learning, synaptically localized CRTC1 is translocated to the nucleus and regulates Fgf1b transcription in an activity-dependent manner. After both weak and strong training, the HDAC3-N-CoR corepressor complex leaves the Fgf1b promoter and a complex involving the translocated CRTC1, phosphorylated CREB, and histone acetyltransferase CBP induces transient transcription. Strong training later substitutes KAT5 for CBP, a process that is dependent on CRTC1, but not on CREB phosphorylation. This in turn leads to long-lasting Fgf1b transcription and memory enhancement. Thus, memory strength relies on activity-dependent changes in chromatin and temporal regulation of gene transcription on specific CREB/CRTC1 gene targets. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

An LXR–NCOA5 gene regulatory complex directs inflammatory crosstalk-dependent repression of macrophage cholesterol efflux

PubMed Central

Gillespie, Mark A; Gold, Elizabeth S; Ramsey, Stephen A; Podolsky, Irina; Aderem, Alan; Ranish, Jeffrey A

2015-01-01

LXR–cofactor complexes activate the gene expression program responsible for cholesterol efflux in macrophages. Inflammation antagonizes this program, resulting in foam cell formation and atherosclerosis; however, the molecular mechanisms underlying this antagonism remain to be fully elucidated. We use promoter enrichment-quantitative mass spectrometry (PE-QMS) to characterize the composition of gene regulatory complexes assembled at the promoter of the lipid transporter Abca1 following downregulation of its expression. We identify a subset of proteins that show LXR ligand- and binding-dependent association with the Abca1 promoter and demonstrate they differentially control Abca1 expression. We determine that NCOA5 is linked to inflammatory Toll-like receptor (TLR) signaling and establish that NCOA5 functions as an LXR corepressor to attenuate Abca1 expression. Importantly, TLR3–LXR signal crosstalk promotes recruitment of NCOA5 to the Abca1 promoter together with loss of RNA polymerase II and reduced cholesterol efflux. Together, these data significantly expand our knowledge of regulatory inputs impinging on the Abca1 promoter and indicate a central role for NCOA5 in mediating crosstalk between pro-inflammatory and anti-inflammatory pathways that results in repression of macrophage cholesterol efflux. PMID:25755249

Exploring the Active Center of the LSD1/CoREST Complex by Molecular Dynamics Simulation Utilizing Its Co-crystallized Co-factor Tetrahydrofolate as a Probe.

PubMed

Zalloum, Waleed A; Zalloum, Hiba M

2017-12-26

Epigenetic targeting of cancer is a recent effort to manipulate the gene without destroying the genetic material. Lysine-specific demethylase 1 (LSD1) is one of the enzymes associated with the chromatin for post-translational modifications, where it demethylates lysine amino acid in the chromatin H3 tail. Many studies showed that inhibiting LSD1 could potentially be used to treat cancer epigenetically. LSD1 is associated with its corepressor protein CoREST, and it uses tetrahydrofolate as a co-factor to accept CH 2 from the demethylation process. In this study, the co-crystallized co-factor tetrahydrofolate was utilized to determine possible binding regions in the active center of the LSD1/CoREST complex. Also, the flexibility of the complex has been investigated by molecular dynamics simulation and subsequent analysis by clustering and principal component analysis. This research supported other studies and showed that LSD1/CoREST complex exists in two main conformational structures: open and closed. Furthermore, this study showed that tetrahydrofolate stably binds to the LSD1/CoREST complex, in its open conformation, at its entrance. It then binds to the core of the complex, inducing the closed conformation. Furthermore, the interactions of tetrahydrofolate to these two binding regions and the corresponding binding mode of tetrahydrofolate were investigated to be used in structure-based drug design.

Epigenetic activation of SIN1 promotes NSCLC cell proliferation and metastasis by affecting the epithelial–mesenchymal transition

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

Hu, Zhongwu; Wang, Yaqin; Wang, Yuemei

Stress-activated protein kinase (SAPK) interacting protein 1 (SIN1) is an essential component of mTORC2. Previous studies have shown that SIN1 is a key regulator of Akt pathway which plays an important role in various pathological conditions including cancer. While its effects and mechanisms on the progression of NSCLC remain unknown. In this study, we report that SIN1 is able to promote the growth and migration of NSCLC cells both in vitro and in vivo. Overexpression of SIN1 promoted A549 and H1299 cells proliferation by both MTT and colony formation assays. Consistently, knockdown of SIN1 inhibited the proliferation of these cells. In transwell assay,more » overexpression of SIN1 increased the migration of A549 and H1299 cells, while SIN1 knockdown reduced their migration. In a tumor xenograft model, overexpression of SIN1 promoted tumor growth of A549 cells in vivo, while SIN1 knockdown suppresses the tumor growth. We also found a mechanistic link between SIN1 and H3K4me3, H3K4me3 is involved in SIN1 upregulation. Moreover, SIN1 can significantly promote the in vitro migration and invasion of NSCLC cells via induction epithelial mesenchymal transition (EMT) process, which subsequently leads to transcriptional downregulation of epithelial marker E-cadherin and upregulation of mesenchymal markers N-cadherin and Vimentin expression. Together, our results reveal that SIN1 plays an important role in NSCLC and SIN1 is a potential biomarker and a promising target in the treatment of NSCLC.« less

Alien/CSN2 gene expression is regulated by thyroid hormone in rat brain.

PubMed

Tenbaum, Stephan P; Juenemann, Stefan; Schlitt, Thomas; Bernal, Juan; Renkawitz, Rainer; Muñoz, Alberto; Baniahmad, Aria

2003-02-01

Alien has been described as a corepressor for the thyroid hormone receptor (TR). Corepressors are coregulators that mediate gene silencing of DNA-bound transcriptional repressors. We describe here that Alien gene expression in vivo is regulated by thyroid hormone both in the rat brain and in cultured cells. In situ hybridization revealed that Alien is widely expressed in the mouse embryo and also throughout the rat brain. Hypothyroid animals exhibit lower expression of both Alien mRNAs and protein levels as compared with normal animals. Accordingly, we show that Alien gene is inducible after thyroid hormone treatment both in vivo and in cell culture. In cultured cells, the hormonal induction is mediated by either TRalpha or TRbeta, while cells lacking detectable amounts of functional TR lack hormonal induction of Alien. We have detected two Alien-specific mRNAs by Northern experiments and two Alien-specific proteins in vivo and in cell lines by Western analysis, one of the two forms representing the CSN2 subunit of the COP9 signalosome. Interestingly, both Alien mRNAs and both detected proteins are regulated by thyroid hormone in vivo and in cell lines. Furthermore, we provide evidence for the existence of at least two Alien genes in rodents. Taken together, we conclude that Alien gene expression is under control of TR and thyroid hormone. This suggests a negative feedback mechanism between TR and its own corepressor. Thus, the reduction of corepressor levels may represent a control mechanism of TR-mediated gene silencing.

Senescence-associated SIN3B promotes inflammation and pancreatic cancer progression

PubMed Central

Rielland, Maïté; Cantor, David J.; Graveline, Richard; Hajdu, Cristina; Mara, Lisa; de Diego Diaz, Beatriz; Miller, George; David, Gregory

2014-01-01

Pancreatic ductal adenocarcinoma (PDAC) is strikingly resistant to conventional therapeutic approaches. We previously demonstrated that the histone deacetylase–associated protein SIN3B is essential for oncogene-induced senescence in cultured cells. Here, using a mouse model of pancreatic cancer, we have demonstrated that SIN3B is required for activated KRAS-induced senescence in vivo. Surprisingly, impaired senescence as the result of genetic inactivation of Sin3B was associated with delayed PDAC progression and correlated with an impaired inflammatory response. In murine and human pancreatic cells and tissues, levels of SIN3B correlated with KRAS-induced production of IL-1α. Furthermore, evaluation of human pancreatic tissue and cancer cells revealed that Sin3B was decreased in control and PDAC samples, compared with samples from patients with pancreatic inflammation. These results indicate that senescence-associated inflammation positively correlates with PDAC progression and suggest that SIN3B has potential as a therapeutic target for inhibiting inflammation-driven tumorigenesis. PMID:24691445

Dual Regulation of Bacillus subtilis kinB Gene Encoding a Sporulation Trigger by SinR through Transcription Repression and Positive Stringent Transcription Control.

PubMed

Fujita, Yasutaro; Ogura, Mitsuo; Nii, Satomi; Hirooka, Kazutake

2017-01-01

It is known that transcription of kinB encoding a trigger for Bacillus subtilis sporulation is under repression by SinR, a master repressor of biofilm formation, and under positive stringent transcription control depending on the adenine species at the transcription initiation nucleotide (nt). Deletion and base substitution analyses of the kinB promoter (P kinB ) region using lacZ fusions indicated that either a 5-nt deletion (Δ5, nt -61/-57, +1 is the transcription initiation nt) or the substitution of G at nt -45 with A (G-45A) relieved kinB repression. Thus, we found a pair of SinR-binding consensus sequences (GTTCTYT; Y is T or C) in an inverted orientation (SinR-1) between nt -57/-42, which is most likely a SinR-binding site for kinB repression. This relief from SinR repression likely requires SinI, an antagonist of SinR. Surprisingly, we found that SinR is essential for positive stringent transcription control of P kinB . Electrophoretic mobility shift assay (EMSA) analysis indicated that SinR bound not only to SinR-1 but also to SinR-2 (nt -29/-8) consisting of another pair of SinR consensus sequences in a tandem repeat arrangement; the two sequences partially overlap the '-35' and '-10' regions of P kinB . Introduction of base substitutions (T-27C C-26T) in the upstream consensus sequence of SinR-2 affected positive stringent transcription control of P kinB , suggesting that SinR binding to SinR-2 likely causes this positive control. EMSA also implied that RNA polymerase and SinR are possibly bound together to SinR-2 to form a transcription initiation complex for kinB transcription. Thus, it was suggested in this work that derepression of kinB from SinR repression by SinI induced by Spo0A∼P and occurrence of SinR-dependent positive stringent transcription control of kinB might induce effective sporulation cooperatively, implying an intimate interplay by stringent response, sporulation, and biofilm formation.

New Methods for the Detection and Interception of Frequency-Hopped Waveforms

DTIC Science & Technology

1990-11-01

that £[p2 Q2 /O] = uF + 2 + o(cos 0 + 6 sin9)2 + 4n(acos0+/3sin)(7ycos0+6sinO)+o r(acos0+sinO)2 I + ( acosO +/3sinO) 2(Tcos9+ 6sin O)2 (3.134) i which...Jcins I lopk ins lI mvtrsi! t3 A pplied Physics Laborator Before1 NII After Figure 4.4: Deconvolut ion Applivod to Oi-fFci i r 100 The Johns 11opkins...Arlington, VA 20360 Library 2 Naval Postgraduate School Monterey, CA 92940 Library 2 Naval Research Laborator . Washington, DC 20375 Library 2 J. W

A series of uranium (IV, V, VI) tritylimido complexes, their molecular and electronic structures and reactivity with CO2.

PubMed

Schmidt, Anna-Corina; Heinemann, Frank W; Maron, Laurent; Meyer, Karsten

2014-12-15

A series of uranium tritylimido complexes with structural continuity across complexes in different oxidation states, namely U(IV), U(V), and U(VI), is reported. This series was successfully synthesized by employing the trivalent uranium precursor, [(((nP,Me)ArO)3tacn)U(III)] (1) (where ((nP,Me)ArO)3tacn(3-) = trianion of 1,4,7-tris(2-hydroxy-5-methyl-3-neopentylbenzyl)-1,4,7-triazacyclononane), with the organic azides Me3SiN3, Me3SnN3, and Ph3CN3 (tritylazide). While the reaction with Me3SiN3 yields an inseparable mixture of both the azido and imido uranium complexes, applying the heavier Sn homologue yields the bis-μ-azido complex [{(((nP,Me)ArO)3tacn)U(IV)}2(μ-N3)2] (2) exclusively. In contrast to this one-electron redox chemistry, the reaction of precursor 1 with tritylazide solely leads to the two-electron oxidized U(V) imido [(((nP,Me)ArO)3tacn)U(V)(N-CPh3)] (3). Oxidation and reduction of 3 yield the corresponding U(VI) and U(IV) complexes [(((nP,Me)ArO)3tacn)U(VI)(N-CPh3)][B(C6F5)4] (4) and K[(((nP,Me)ArO)3tacn)U(IV)(N-CPh3)] (5), respectively. In addition, the U(V) imido 3 engages in a H atom abstraction reaction with toluene to yield the closely related amido complex [(((nP,Me)ArO)3tacn)U(IV)(N(H)-CPh3)] (6). Complex 6 and the three tritylimido complexes 3, 4, and 5, with oxidation states ranging from +IV to +VI and homologous core structures, were investigated by X-ray diffraction analyses and magnetochemical and spectroscopic studies as well as density functional theory (DFT) computational analysis. The series of structurally very similar imido complexes provides a unique opportunity to study electronic properties and to probe the uranium imido reactivity solely as a function of electron count of the metal-imido entity. Evidence for the U-N bond covalency and f-orbital participation in complexes 3-6 was drawn from the in-depth and comparative DFT study. The reactivity of the imido and amido complexes with CO2 was probed, and conclusions about the influence of the formal oxidation state are reported.

PHD Domain-Mediated E3 Ligase Activity Directs Intramolecular Sumoylation of an Adjacent Bromodomain which is Required for Gene Silencing

PubMed Central

Ivanov, Alexey V.; Peng, Hongzhuang; Yurchenko, Vyacheslav; Yap, Kyoko L.; Negorev, Dmitri G.; Schultz, David C.; Psulkowski, Elyse; Fredericks, William J.; White, David E.; Maul, Gerd G.; Sadofsky, Moshe J.; Zhou, Ming-Ming; Rauscher, Frank J.

2015-01-01

SUMMARY Tandem PHD and bromodomains are often found in chromatin-associated proteins and have been shown to cooperate in gene silencing. Each domain can bind specifically modified histones: the mechanisms of cooperation between these domains are unknown. We show that the PHD domain of the KAP1 corepressor functions as an intramolecular E3 ligase for sumoylation of the adjacent bromodomain. The RING finger-like structure of the PHD domain is required for both Ubc9 binding and sumoylation and directs modification to specific lysine residues in the bromodomain. Sumoylation is required for KAP1-mediated gene silencing and functions by directly recruiting the SETDB1 histone methyltransferase and the CHD3/Mi2 component of the NuRD complex via SUMO interacting motifs. Sumoylated KAP1 stimulates the histone methyltransferase activity of SETDB1. These data provide a mechanistic explanation for the cooperation of PHD and bromodomains in gene regulation and describe a new function of the PHD domain as an intramolecular E3 SUMO ligase. PMID:18082607

An HDAC3-PROX1 corepressor module acts on HNF4α to control hepatic triglycerides.

PubMed

Armour, Sean M; Remsberg, Jarrett R; Damle, Manashree; Sidoli, Simone; Ho, Wesley Y; Li, Zhenghui; Garcia, Benjamin A; Lazar, Mitchell A

2017-09-15

The histone deacetylase HDAC3 is a critical mediator of hepatic lipid metabolism, and liver-specific deletion of HDAC3 leads to fatty liver. To elucidate the underlying mechanism, here we report a method of cross-linking followed by mass spectrometry to define a high-confidence HDAC3 interactome in vivo that includes the canonical NCoR-HDAC3 complex as well as Prospero-related homeobox 1 protein (PROX1). HDAC3 and PROX1 co-localize extensively on the mouse liver genome, and are co-recruited by hepatocyte nuclear factor 4α (HNF4α). The HDAC3-PROX1 module controls the expression of a gene program regulating lipid homeostasis, and hepatic-specific ablation of either component increases triglyceride content in liver. These findings underscore the importance of specific combinations of transcription factors and coregulators in the fine tuning of organismal metabolism.HDAC3 is a critical mediator of hepatic lipid metabolism and its loss leads to fatty liver. Here, the authors characterize the liver HDAC3 interactome in vivo, provide evidence that HDAC3 interacts with PROX1, and show that HDAC3 and PROX1 control expression of genes regulating lipid homeostasis.

Effects of atorvastatin metabolites on induction of drug-metabolizing enzymes and membrane transporters through human pregnane X receptor

PubMed Central

Hoffart, E; Ghebreghiorghis, L; Nussler, AK; Thasler, WE; Weiss, TS; Schwab, M; Burk, O

2012-01-01

BACKGROUND AND PURPOSE Atorvastatin metabolites differ in their potential for drug interaction because of differential inhibition of drug-metabolizing enzymes and transporters. We here investigate whether they exert differential effects on the induction of these genes via activation of pregnane X receptor (PXR) and constitutive androstane receptor (CAR). EXPERIMENTAL APPROACH Ligand binding to PXR or CAR was analysed by mammalian two-hybrid assembly and promoter/reporter gene assays. Additionally, surface plasmon resonance was used to analyse ligand binding to CAR. Primary human hepatocytes were treated with atorvastatin metabolites, and mRNA and protein expression of PXR-regulated genes was measured. Two-hybrid co-activator interaction and co-repressor release assays were utilized to elucidate the molecular mechanism of PXR activation. KEY RESULTS All atorvastatin metabolites induced the assembly of PXR and activated CYP3A4 promoter activity. Ligand binding to CAR could not be proven. In primary human hepatocytes, the para-hydroxy metabolite markedly reduced or abolished induction of cytochrome P450 and transporter genes. While significant differences in co-activator recruitment were not observed, para-hydroxy atorvastatin demonstrated only 50% release of co-repressors. CONCLUSIONS AND IMPLICATIONS Atorvastatin metabolites are ligands of PXR but not of CAR. Atorvastatin metabolites demonstrate differential induction of PXR target genes, which results from impaired release of co-repressors. Consequently, the properties of drug metabolites have to be taken into account when analysing PXR-dependent induction of drug metabolism and transport. The drug interaction potential of the active metabolite, para-hydroxy atorvastatin, might be lower than that of the parent compound. PMID:21913896

Structure-function analysis of RBP-J-interacting and tubulin-associated (RITA) reveals regions critical for repression of Notch target genes.

PubMed

Tabaja, Nassif; Yuan, Zhenyu; Oswald, Franz; Kovall, Rhett A

2017-06-23

The Notch pathway is a cell-to-cell signaling mechanism that is essential for tissue development and maintenance, and aberrant Notch signaling has been implicated in various cancers, congenital defects, and cardiovascular diseases. Notch signaling activates the expression of target genes, which are regulated by the transcription factor CSL (CBF1/RBP-J, Su(H), Lag-1). CSL interacts with both transcriptional corepressor and coactivator proteins, functioning as both a repressor and activator, respectively. Although Notch activation complexes are relatively well understood at the structural level, less is known about how CSL interacts with corepressors. Recently, a new RBP-J (mammalian CSL ortholog)-interacting protein termed RITA has been identified and shown to export RBP-J out of the nucleus, thereby leading to the down-regulation of Notch target gene expression. However, the molecular details of RBP-J/RITA interactions are unclear. Here, using a combination of biochemical/cellular, structural, and biophysical techniques, we demonstrate that endogenous RBP-J and RITA proteins interact in cells, map the binding regions necessary for RBP-J·RITA complex formation, and determine the X-ray structure of the RBP-J·RITA complex bound to DNA. To validate the structure and glean more insights into function, we tested structure-based RBP-J and RITA mutants with biochemical/cellular assays and isothermal titration calorimetry. Whereas our structural and biophysical studies demonstrate that RITA binds RBP-J similarly to the RAM (RBP-J-associated molecule) domain of Notch, our biochemical and cellular assays suggest that RITA interacts with additional regions in RBP-J. Taken together, these results provide molecular insights into the mechanism of RITA-mediated regulation of Notch signaling, contributing to our understanding of how CSL functions as a transcriptional repressor of Notch target genes. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Nuclear Translocation of MEK1 Triggers a Complex T cell Response through the Co-repressor Silencing Mediator of Retinoid and Thyroid Hormone Receptor (SMRT)

PubMed Central

Guo, Lei; Chen, Chaoyu; Liang, Qiaoling; Karim, Md. Zunayet; Gorska, Magdalena M.; Alam, Rafeul

2012-01-01

MEK1 phosphorylates ERK1/2 and regulates T cell generation, differentiation and function. MEK1 has recently been shown to translocate to the nucleus. Its nuclear function is largely unknown. By studying human CD4 T cells we demonstrate that a low level of MEK1 is present in the nucleus of CD4 T cells under basal conditions. T cell activation further increases the nuclear translocation of MEK1. MEK1 interacts with the nuclear receptor co-repressor SMRT. MEK1 reduces the nuclear level of SMRT in an activation-dependent manner. MEK1 is recruited to the promoter of c-Fos upon TCR stimulation. Conversely, SMRT is bound to the c-Fos promoter under basal conditions and is removed upon TCR stimulation. We examined the role of SMRT in regulation of T cell function. siRNA-mediated knockdown of SMRT results in a biphasic effect on cytokine production. The production of the cytokines—IL2, IL4, IL10 and IFNγ increases in the early phase (8 hr) and then decreases in the late phase (48 hr). The late phase decrease is associated with inhibition of T cell proliferation. The late phase inhibition of T cell activation is, in part, mediated by IL10 that is produced in the early phase, and in part, by β-catenin signaling. Thus, we have identified a novel nuclear function of MEK1. MEK1 triggers a complex pattern of early T cell activation followed by a late inhibition through its interaction with SMRT. This biphasic dual effect likely reflects a homeostatic regulation of T cell function by MEK1. PMID:23225884

Transforming growth factor β suppresses peroxisome proliferator-activated receptor γ expression via both SMAD binding and novel TGF-β inhibitory elements.

PubMed

Lakshmi, Sowmya P; Reddy, Aravind T; Reddy, Raju C

2017-04-24

Transforming growth factor β (TGF-β) contributes to wound healing and, when dysregulated, to pathological fibrosis. TGF-β and the anti-fibrotic nuclear hormone receptor peroxisome proliferator-activated receptor γ (PPARγ) repress each other's expression, and such PPARγ down-regulation is prominent in fibrosis and mediated, via previously unknown SMAD-signaling mechanisms. Here, we show that TGF-β induces the association of SMAD3 with both SMAD4, needed for translocation of the complex into the nucleus, and the essential context-sensitive co-repressors E2F4 and p107. The complex mediates TGF-β-induced repression by binding to regulatory elements in the target promoter. In the PPARG promoter, we found that the SMAD3-SMAD4 complex binds both to a previously unknown consensus TGF-β inhibitory element (TIE) and also to canonical SMAD-binding elements (SBEs). Furthermore, the TIE and SBEs independently mediated the partial repression of PPARG transcription, the first demonstration of a TIE and SBEs functioning within the same promoter. Also, TGF-β-treated fibroblasts contained SMAD complexes that activated a SMAD target gene in addition to those repressing PPARG transcription, the first finding of such dual activity within the same cell. These findings describe in detail novel mechanisms by which TGF-β represses PPARG transcription, thereby facilitating its own pro-fibrotic activity. © 2017 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society.

Transcription factor 19 interacts with histone 3 lysine 4 trimethylation and controls gluconeogenesis via the nucleosome-remodeling-deacetylase complex.

PubMed

Sen, Sabyasachi; Sanyal, Sulagna; Srivastava, Dushyant Kumar; Dasgupta, Dipak; Roy, Siddhartha; Das, Chandrima

2017-12-15

Transcription factor 19 (TCF19) has been reported as a type 1 diabetes-associated locus involved in maintenance of pancreatic β cells through a fine-tuned regulation of cell proliferation and apoptosis. TCF19 also exhibits genomic association with type 2 diabetes, although the precise molecular mechanism remains unknown. It harbors both a plant homeodomain and a forkhead-associated domain implicated in epigenetic recognition and gene regulation, a phenomenon that has remained unexplored. Here, we show that TCF19 selectively interacts with histone 3 lysine 4 trimethylation through its plant homeodomain finger. Knocking down TCF19 under high-glucose conditions affected many metabolic processes, including gluconeogenesis. We found that TCF19 overexpression represses de novo glucose production in HepG2 cells. The transcriptional repression of key genes, induced by TCF19, coincided with NuRD (nucleosome-remodeling-deacetylase) complex recruitment to the promoters of these genes. TCF19 interacted with CHD4 (chromodomain helicase DNA-binding protein 4), which is a part of the NuRD complex, in a glucose concentration-independent manner. In summary, our results show that TCF19 interacts with an active transcription mark and recruits a co-repressor complex to regulate gluconeogenic gene expression in HepG2 cells. Our study offers critical insights into the molecular mechanisms of transcriptional regulation of gluconeogenesis and into the roles of chromatin readers in metabolic homeostasis. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Discovering Hematopoietic Mechanisms Through Genome-Wide Analysis of GATA Factor Chromatin Occupancy

PubMed Central

Fujiwara, Tohru; O'Geen, Henriette; Keles, Sunduz; Blahnik, Kimberly; Linnemann, Amelia K.; Kang, Yoon-A; Choi, Kyunghee; Farnham, Peggy J.; Bresnick, Emery H.

2009-01-01

SUMMARY GATA factors interact with simple DNA motifs (WGATAR) to regulate critical processes, including hematopoiesis, but very few WGATAR motifs are occupied in genomes. Given the rudimentary knowledge of mechanisms underlying this restriction, and how GATA factors establish genetic networks, we used ChIP-seq to define GATA-1 and GATA-2 occupancy genome-wide in erythroid cells. Coupled with genetic complementation analysis and transcriptional profiling, these studies revealed a rich collection of targets containing a characteristic binding motif of greater complexity than WGATAR. GATA factors occupied loci encoding multiple components of the Scl/TAL1 complex, a master regulator of hematopoiesis and leukemogenic target. Mechanistic analyses provided evidence for cross-regulatory and autoregulatory interactions among components of this complex, including GATA-2 induction of the hematopoietic corepressor ETO-2 and an ETO-2 negative autoregulatory loop. These results establish fundamental principles underlying GATA factor mechanisms in chromatin and illustrate a complex network of considerable importance for the control of hematopoiesis. PMID:19941826

Fully constrained Majorana neutrino mass matrices using \\varvec{Σ(72× 3)}

NASA Astrophysics Data System (ADS)

Krishnan, R.; Harrison, P. F.; Scott, W. G.

2018-01-01

In 2002, two neutrino mixing ansatze having trimaximally mixed middle (ν _2) columns, namely tri-chi-maximal mixing ( {T}χ {M}) and tri-phi-maximal mixing ( {T}φ {M}), were proposed. In 2012, it was shown that {T}χ {M} with χ =± π /16 as well as {T}φ {M} with φ = ± π /16 leads to the solution, sin ^2 θ _{13} = 2/3 sin ^2 π /16, consistent with the latest measurements of the reactor mixing angle, θ _{13}. To obtain {T}χ {M}_{(χ =± π /16)} and {T}φ {M}_{(φ =± π /16)}, the type I see-saw framework with fully constrained Majorana neutrino mass matrices was utilised. These mass matrices also resulted in the neutrino mass ratios, m_1:m_2:m_3=( 2+√{2}) /1+√{2(2+√{2)}}:1:( 2+√{2}) /-1+√{2(2+√{2)}}. In this paper we construct a flavour model based on the discrete group Σ (72× 3) and obtain the aforementioned results. A Majorana neutrino mass matrix (a symmetric 3× 3 matrix with six complex degrees of freedom) is conveniently mapped into a flavon field transforming as the complex six-dimensional representation of Σ (72× 3). Specific vacuum alignments of the flavons are used to arrive at the desired mass matrices.

DNA wrapping and distortion by an oligomeric homeodomain protein.

PubMed

Williams, Hannah; Jayaraman, Padma-Sheela; Gaston, Kevin

2008-10-31

Many transcription factors alter DNA or chromatin structure. Changes in chromatin structure are often brought about by the recruitment of chromatin-binding proteins, chromatin-modifying proteins, or other transcription co-activator or co-repressor proteins. However, some transcription factors form oligomeric assemblies that may themselves induce changes in DNA conformation and chromatin structure. The proline-rich homeodomain (PRH/Hex) protein is a transcription factor that regulates cell differentiation and cell proliferation, and has multiple roles in embryonic development. Earlier, we showed that PRH can repress transcription by multiple mechanisms, including the recruitment of co-repressor proteins belonging to the TLE family of chromatin-binding proteins. Our in vivo crosslinking studies have shown that PRH forms oligomeric complexes in cells and a variety of biophysical techniques suggest that the protein forms octamers. However, as yet we have little knowledge of the role played by PRH oligomerisation in the regulation of promoter activity or of the architecture of promoters that are regulated directly by PRH in cells. Here, we compare the binding of PRH and the isolated PRH homeodomain to DNA fragments with single and multiple PRH sites, using gel retardation assays and DNase I and chemical footprinting. We show that the PRH oligomer binds to multiple sites within the human Goosecoid promoter with high affinity and that the binding of PRH brings about DNA distortion. We suggest that PRH octamers wrap DNA in order to bring about transcriptional repression.

Oxygen-dependent acetylation and dimerization of the corepressor CtBP2 in neural stem cells

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

Karaca, Esra; Lewicki, Jakub; Hermanson, Ola, E-mail: Ola.Hermanson@ki.se

2015-03-01

The transcriptional corepressor CtBP2 is essential for proper development of the nervous system. The factor exerts its repression by interacting in complexes with chromatin-modifying factors such as histone deacetylases (HDAC) 1/2 and the histone demethylase LSD1/KDM1. Notably, the histone acetyl transferase p300 acetylates CtBP2 and this is an important regulatory event of the activity and subcellular localization of the protein. We recently demonstrated an essential role for CtBPs as sensors of microenvironmental oxygen levels influencing the differentiation potential of neural stem cells (NSCs), but it is not known whether oxygen levels influence the acetylation levels of CtBP factors. Here wemore » show by using proximity ligation assay (PLA) that CtBP2 acetylation levels increased significantly in undifferentiated, proliferating NSCs under hypoxic conditions. CtBP2 interacted with the class III HDAC Sirt1 but this interaction was unaltered in hypoxic conditions, and treatment with the Sirt1 inhibitor Ex527 did not result in any significant change in total CtBP2 acetylation levels. Instead, we revealed a significant decrease in PLA signal representing CtBP2 dimerization in NSCs under hypoxic conditions, negatively correlating with the acetylation levels. Our results suggest that microenvironmental oxygen levels influence the dimerization and acetylation levels, and thereby the activity, of CtBP2 in proliferating NSCs.« less

MicroRNAs Are Mediators of Androgen Action in Prostate and Muscle

PubMed Central

Narayanan, Ramesh; Jiang, Jinmai; Gusev, Yuriy; Jones, Amanda; Kearbey, Jeffrey D.; Miller, Duane D.; Schmittgen, Thomas D.; Dalton, James T.

2010-01-01

Androgen receptor (AR) function is critical for the development of male reproductive organs, muscle, bone and other tissues. Functionally impaired AR results in androgen insensitivity syndrome (AIS). The interaction between AR and microRNA (miR) signaling pathways was examined to understand the role of miRs in AR function. Reduction of androgen levels in Sprague-Dawley rats by castration inhibited the expression of a large set of miRs in prostate and muscle, which was reversed by treatment of castrated rats with 3 mg/day dihydrotestosterone (DHT) or selective androgen receptor modulators. Knockout of the miR processing enzyme, DICER, in LNCaP prostate cancer cells or tissue specifically in mice inhibited AR function leading to AIS. Since the only function of miRs is to bind to 3′ UTR and inhibit translation of target genes, androgens might induce miRs to inhibit repressors of AR function. In concordance, knock-down of DICER in LNCaP cells and in tissues in mice induced the expression of corepressors, NCoR and SMRT. These studies demonstrate a feedback loop between miRs, corepressors and AR and the imperative role of miRs in AR function in non-cancerous androgen-responsive tissues. PMID:21048966

Structure and electrochemical behaviour of 4,7-diazaheptyl-trimethoxy-silane and vinyl-trialkoxy-silane adsorbed at silver surface

NASA Astrophysics Data System (ADS)

Łuczak, Teresa; Pankiewicz, Radosław; Łęska, Bogusława; Schroeder, Grzegorz; Bełtowska-Brzezinska, Maria; Brzezinski, Bogumil

2006-12-01

Novel self-assembled monolayers were obtained on silver using 4,7-diazaheptyl-trimethoxy-silane (SiN) and vinyl-trialkoxy-silane (SiVA, where the alkyl group is 3,6,9,12,15,18,21,24,27,30,33,36,39,42,45,48,51,54,57,60-eicozaoxa- hexaheptaconan). It was shown that thus modified metal surface was protected against electrooxidation. A densely packed monolayer remained stable and did not desorb from the Ag electrode on the potential cycling. The structure of SiN and SiVA as well as their complexes with Li + cations were calculated and visualised by the AM1d and PM5 semi-empirical methods.

Auditory brainstem response to complex sounds predicts self-reported speech-in-noise performance.

PubMed

Anderson, Samira; Parbery-Clark, Alexandra; White-Schwoch, Travis; Kraus, Nina

2013-02-01

To compare the ability of the auditory brainstem response to complex sounds (cABR) to predict subjective ratings of speech understanding in noise on the Speech, Spatial, and Qualities of Hearing Scale (SSQ; Gatehouse & Noble, 2004) relative to the predictive ability of the Quick Speech-in-Noise test (QuickSIN; Killion, Niquette, Gudmundsen, Revit, & Banerjee, 2004) and pure-tone hearing thresholds. Participants included 111 middle- to older-age adults (range = 45-78) with audiometric configurations ranging from normal hearing levels to moderate sensorineural hearing loss. In addition to using audiometric testing, the authors also used such evaluation measures as the QuickSIN, the SSQ, and the cABR. Multiple linear regression analysis indicated that the inclusion of brainstem variables in a model with QuickSIN, hearing thresholds, and age accounted for 30% of the variance in the Speech subtest of the SSQ, compared with significantly less variance (19%) when brainstem variables were not included. The authors' results demonstrate the cABR's efficacy for predicting self-reported speech-in-noise perception difficulties. The fact that the cABR predicts more variance in self-reported speech-in-noise (SIN) perception than either the QuickSIN or hearing thresholds indicates that the cABR provides additional insight into an individual's ability to hear in background noise. In addition, the findings underscore the link between the cABR and hearing in noise.

CRISPR screen identifies the NCOR/HDAC3 complex as a major suppressor of differentiation in rhabdomyosarcoma

PubMed Central

Phelps, Michael P.; Bailey, Jenna N.; Vleeshouwer-Neumann, Terra

2016-01-01

Dysregulated gene expression resulting from abnormal epigenetic alterations including histone acetylation and deacetylation has been demonstrated to play an important role in driving tumor growth and progression. However, the mechanisms by which specific histone deacetylases (HDACs) regulate differentiation in solid tumors remains unclear. Using pediatric rhabdomyosarcoma (RMS) as a paradigm to elucidate the mechanism blocking differentiation in solid tumors, we identified HDAC3 as a major suppressor of myogenic differentiation from a high-efficiency Clustered regularly interspaced short palindromic repeats (CRISPR)-based phenotypic screen of class I and II HDAC genes. Detailed characterization of the HDAC3-knockout phenotype in vitro and in vivo using a tamoxifen-inducible CRISPR targeting strategy demonstrated that HDAC3 deacetylase activity and the formation of a functional complex with nuclear receptor corepressors (NCORs) were critical in restricting differentiation in RMS. The NCOR/HDAC3 complex specifically functions by blocking myoblast determination protein 1 (MYOD1)-mediated activation of myogenic differentiation. Interestingly, there was also a transient up-regulation of growth-promoting genes upon initial HDAC3 targeting, revealing a unique cancer-specific response to the forced transition from a neoplastic state to terminal differentiation. Our study applied modifications of CRISPR/CRISPR-associated endonuclease 9 (Cas9) technology to interrogate the function of essential cancer genes and pathways and has provided insights into cancer cell adaptation in response to altered differentiation status. Because current pan-HDAC inhibitors have shown disappointing results in clinical trials of solid tumors, therapeutic targets specific to HDAC3 function represent a promising option for differentiation therapy in malignant tumors with dysregulated HDAC3 activity. PMID:27956629

CRISPR screen identifies the NCOR/HDAC3 complex as a major suppressor of differentiation in rhabdomyosarcoma.

PubMed

Phelps, Michael P; Bailey, Jenna N; Vleeshouwer-Neumann, Terra; Chen, Eleanor Y

2016-12-27

Dysregulated gene expression resulting from abnormal epigenetic alterations including histone acetylation and deacetylation has been demonstrated to play an important role in driving tumor growth and progression. However, the mechanisms by which specific histone deacetylases (HDACs) regulate differentiation in solid tumors remains unclear. Using pediatric rhabdomyosarcoma (RMS) as a paradigm to elucidate the mechanism blocking differentiation in solid tumors, we identified HDAC3 as a major suppressor of myogenic differentiation from a high-efficiency Clustered regularly interspaced short palindromic repeats (CRISPR)-based phenotypic screen of class I and II HDAC genes. Detailed characterization of the HDAC3-knockout phenotype in vitro and in vivo using a tamoxifen-inducible CRISPR targeting strategy demonstrated that HDAC3 deacetylase activity and the formation of a functional complex with nuclear receptor corepressors (NCORs) were critical in restricting differentiation in RMS. The NCOR/HDAC3 complex specifically functions by blocking myoblast determination protein 1 (MYOD1)-mediated activation of myogenic differentiation. Interestingly, there was also a transient up-regulation of growth-promoting genes upon initial HDAC3 targeting, revealing a unique cancer-specific response to the forced transition from a neoplastic state to terminal differentiation. Our study applied modifications of CRISPR/CRISPR-associated endonuclease 9 (Cas9) technology to interrogate the function of essential cancer genes and pathways and has provided insights into cancer cell adaptation in response to altered differentiation status. Because current pan-HDAC inhibitors have shown disappointing results in clinical trials of solid tumors, therapeutic targets specific to HDAC3 function represent a promising option for differentiation therapy in malignant tumors with dysregulated HDAC3 activity.

Synthesis and reactivity of bis(tetramethylcyclopentadienyl) yttrium metallocenes including the reduction of Me(3)SiN(3) to [(Me(3)Si)(2)N](-) with [(C(5)Me(4)H)(2)Y(THF)](2)(mu-eta(2):eta(2)-N(2)).

PubMed

Lorenz, Sara E; Schmiege, Benjamin M; Lee, David S; Ziller, Joseph W; Evans, William J

2010-07-19

The metallocene precursors needed to provide the tetramethylcyclopentadienyl yttrium complexes (C(5)Me(4)H)(3)Y, [(C(5)Me(4)H)(2)Y(THF)](2)(mu-eta(2):eta(2)-N(2)), and [(C(5)Me(4)H)(2)Y(mu-H)](2) for reactivity studies have been synthesized and fully characterized, and their reaction chemistry has led to an unexpected conversion of an azide to an amide. (C(5)Me(4)H)(2)Y(mu-Cl)(2)K(THF)(x), 1, synthesized from YCl(3) and KC(5)Me(4)H reacts with allylmagnesium chloride to make (C(5)Me(4)H)(2)Y(eta(3)-C(3)H(5)), 2, which is converted to [(C(5)Me(4)H)(2)Y][(mu-Ph)(2)BPh(2)], 3, with [Et(3)NH][BPh(4)]. Complex 3 reacts with KC(5)Me(4)H to form (C(5)Me(4)H)(3)Y, 4. The reduced dinitrogen complex, [(C(5)Me(4)H)(2)Y(THF)](2)(mu-eta(2):eta(2)-N(2)), 5, can be synthesized from either [(C(5)Me(4)H)(2)Y](2)[(mu-Ph)(2)BPh(2)], 3, or (C(5)Me(4)H)(3)Y, 4, with potassium graphite under a dinitrogen atmosphere. The (15)N labeled analogue, [(C(5)Me(4)H)(2)Y(THF)](2)(mu-eta(2):eta(2)-(15)N(2)), 5-(15)N, has also been prepared, and the (15)N NMR data have been compared to previously characterized reduced dinitrogen complexes. Complex 2 reacts with H(2) to form the corresponding hydride, [(C(5)Me(4)H)(2)Y(mu-H)](2), 6. Complex 5 displays similar reactivity to that of the analogous [(C(5)Me(4)H)(2)Ln(THF)](2)(mu-eta(2):eta(2)-N(2)) complexes (Ln = La, Lu), with substrates such as phenazine, anthracene, and CO(2). In addition, 5 reduces Me(3)SiN(3) to form (C(5)Me(4)H)(2)Y[N(SiMe(3))(2)], 7.

48 CFR 538.7004 - Solicitation provisions and contract clauses.

Code of Federal Regulations, 2010 CFR

2010-10-01

...— (1) Schedule 70; (2) The Consolidated Schedule containing information technology SINs; and (3... Schedule containing information technology SINs; and (3) Schedule 84. (c) The contracting officer shall... information technology SINs; and (3) Schedule 84. (d) See 552.101-70 for authorized FAR deviations. [73 FR...

48 CFR 538.7004 - Solicitation provisions and contract clauses.

Code of Federal Regulations, 2011 CFR

2011-10-01

...— (1) Schedule 70; (2) The Consolidated Schedule containing information technology SINs; and (3... Schedule containing information technology SINs; and (3) Schedule 84. (c) The contracting officer shall... information technology SINs; and (3) Schedule 84. (d) See 552.101-70 for authorized FAR deviations. [73 FR...

DNA-PKcs is important for Akt activation and gemcitabine resistance in PANC-1 pancreatic cancer cells.

PubMed

Hu, Hao; Gu, Yuanlong; Qian, Yi; Hu, Benshun; Zhu, Congyuan; Wang, Gaohe; Li, Jianping

2014-09-12

Pancreatic cancer is one of the most aggressive human malignancies with extremely poor prognosis. The moderate activity of the current standard gemcitabine and gemcitabine-based regimens was due to pre-existing or acquired chemo-resistance of pancreatic cancer cells. In this study, we explored the potential role of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) in gemcitabine resistance, and studied the underlying mechanisms. We found that NU-7026 and NU-7441, two DNA-PKcs inhibitors, enhanced gemcitabine-induced cytotoxicity and apoptosis in PANC-1 pancreatic cancer cells. Meanwhile, PANC-1 cells with siRNA-knockdown of DNA-PKcs were more sensitive to gemcitabine than control PANC-1 cells. Through the co-immunoprecipitation (Co-IP) assay, we found that DNA-PKcs formed a complex with SIN1, the latter is an indispensable component of mammalian target of rapamycin (mTOR) complex 2 (mTORC2). DNA-PKcs-SIN1 complexation was required for Akt activation in PANC-1 cells, while inhibition of this complex by siRNA knockdown of DNA-PKcs/SIN1, or by DNA-PKcs inhibitors, prevented Akt phosphorylation in PANC-1 cells. Further, SIN1 siRNA-knockdown also facilitated gemcitabine-induced apoptosis in PANC-1 cells. Finally, DNA-PKcs and p-Akt expression was significantly higher in human pancreatic cancer tissues than surrounding normal tissues. Together, these results show that DNA-PKcs is important for Akt activation and gemcitabine resistance in PANC-1 pancreatic cancer cells. Copyright © 2014 Elsevier Inc. All rights reserved.

Gas diffusion ultrabarriers on polymer substrates using Al2O3 atomic layer deposition and SiN plasma-enhanced chemical vapor deposition

NASA Astrophysics Data System (ADS)

Carcia, P. F.; McLean, R. S.; Groner, M. D.; Dameron, A. A.; George, S. M.

2009-07-01

Thin films grown by Al2O3 atomic layer deposition (ALD) and SiN plasma-enhanced chemical vapor deposition (PECVD) have been tested as gas diffusion barriers either individually or as bilayers on polymer substrates. Single films of Al2O3 ALD with thicknesses of ≥10 nm had a water vapor transmission rate (WVTR) of ≤5×10-5 g/m2 day at 38 °C/85% relative humidity (RH), as measured by the Ca test. This WVTR value was limited by H2O permeability through the epoxy seal, as determined by the Ca test for the glass lid control. In comparison, SiN PECVD films with a thickness of 100 nm had a WVTR of ˜7×10-3 g/m2 day at 38 °C/85% RH. Significant improvements resulted when the SiN PECVD film was coated with an Al2O3 ALD film. An Al2O3 ALD film with a thickness of only 5 nm on a SiN PECVD film with a thickness of 100 nm reduced the WVTR from ˜7×10-3 to ≤5×10-5 g/m2 day at 38 °C/85% RH. The reduction in the permeability for Al2O3 ALD on the SiN PECVD films was attributed to either Al2O3 ALD sealing defects in the SiN PECVD film or improved nucleation of Al2O3 ALD on SiN.

Transducin β-like 1, X-linked and nuclear receptor co-‍repressor cooperatively augment the ligand-independent stimulation of TRH and TSHβ gene promoters by thyroid hormone receptors.

PubMed

Takamizawa, Tetsuya; Satoh, Tetsurou; Miyamoto, Tomoko; Nakajima, Yasuyo; Ishizuka, Takahiro; Tomaru, Takuya; Yoshino, Satoshi; Katano-Toki, Akiko; Nishikido, Ayaka; Sapkota, Santosh; Watanabe, Takuya; Okamura, Takashi; Ishida, Emi; Horiguchi, Kazuhiko; Matsumoto, Syunichi; Ishii, Sumiyasu; Ozawa, Atsushi; Shibusawa, Nobuyuki; Okada, Shuichi; Yamada, Masanobu

2018-05-23

Mutations in TBL1X, a component of the nuclear receptor co-repressor (N-CoR) and silencing mediator of retinoic acid and thyroid hormone receptor co-repressor complexes, have recently been implicated in isolated central hypothyroidism (CeH). However, the mechanisms by which TBL1X mutations affect negative feedback regulation in the hypothalamus-pituitary-thyroid axis remain unclear. N-CoR was previously reported to paradoxically enhance the ligand-independent stimulation of TRH and TSHβ gene promoters by thyroid hormone receptors (TR) in cell culture systems. We herein investigated whether TBL1X affects the unliganded TR-mediated stimulation of the promoter activities of genes negatively regulated by T3 in cooperation with N-CoR. In a hypothalamic neuronal cell line, the unliganded TR-mediated stimulation of the TRH gene promoter was significantly enhanced by co-transfected TBL1X, and the co-transfection of TBL1X with N-CoR further enhanced promoter activity. In contrast, the knockdown of endogenous Tbl1x using short interfering RNA significantly attenuated the N-CoR-mediated enhancement of promoter activity in the presence of unliganded TR. The co-transfection of N365Y or Y458C, TBL1X mutants identified in CeH patients, showed impaired co-activation with N-CoR for the ligand-independent stimulation of the TRH promoter by TR. In the absence of T3, similar or impaired enhancement of the TSHβ gene promoter by the wild type or TBL1X mutants, respectively, was observed in the presence of co-transfected TR and N-CoR in CV-1 cells. These results suggest that TBL1X is needed for the full activation of TRH and TSHβ gene promoters by unliganded TR. Mutations in TBL1X may cause CeH due to the impaired up-regulation of TRH and/or TSHβ gene transcription despite low T3 levels.

Determining protein complex connectivity using a probabilistic deletion network derived from quantitative proteomics.

PubMed

Sardiu, Mihaela E; Gilmore, Joshua M; Carrozza, Michael J; Li, Bing; Workman, Jerry L; Florens, Laurence; Washburn, Michael P

2009-10-06

Protein complexes are key molecular machines executing a variety of essential cellular processes. Despite the availability of genome-wide protein-protein interaction studies, determining the connectivity between proteins within a complex remains a major challenge. Here we demonstrate a method that is able to predict the relationship of proteins within a stable protein complex. We employed a combination of computational approaches and a systematic collection of quantitative proteomics data from wild-type and deletion strain purifications to build a quantitative deletion-interaction network map and subsequently convert the resulting data into an interdependency-interaction model of a complex. We applied this approach to a data set generated from components of the Saccharomyces cerevisiae Rpd3 histone deacetylase complexes, which consists of two distinct small and large complexes that are held together by a module consisting of Rpd3, Sin3 and Ume1. The resulting representation reveals new protein-protein interactions and new submodule relationships, providing novel information for mapping the functional organization of a complex.

Sumoylation of the net inhibitory domain (NID) is stimulated by PIAS1 and has a negative effect on the transcriptional activity of Net.

PubMed

Wasylyk, Christine; Criqui-Filipe, Paola; Wasylyk, Bohdan

2005-01-27

Net (Elk-3, Sap-2, Erp) and the related ternary complex factors Elk-1 and Sap-1 are effectors of multiple signalling pathways at the transcriptional level and play a key role in the dynamic regulation of gene expression. Net is distinct from Elk-1 and Sap-1, in that it is a strong repressor of transcription that is converted to an activator by the Ras/Erk signalling pathway. Two autonomous repression domains of Net, the NID and the CID, mediate repression. We have previously shown that the co-repressor CtBP is implicated in repression by the CID. In this report we show that repression by the NID involves a different pathway, sumoylation by Ubc9 and PIAS1. PIAS1 interacts with the NID in the two-hybrid assay and in vitro. Ubc9 and PIAS1 stimulate sumoylation in vivo of lysine 162 in the NID. Sumoylation of lysine 162 increases repression by Net and decreases the positive activity of Net. These results increase our understanding of how one of the ternary complex factors regulates transcription, and contribute to the understanding of how different domains of a transcription factor participate in the complexity of regulation of gene expression.

The Control of Human Arm Movement: Models and Mechanical Constraints

DTIC Science & Technology

1990-06-01

joints o linear joint angle sensors These assumptions may be refined as needed (e.g., muscle geometry may be included), but such additional complexity... C +y (2.4) 26 where W_ = (a, a2 Y = (1 0 1 O )T, = , 9 and cos( o ’) cos(o4) cos(q1) sin( o ) sin(44) sin(01) C 1= (2.5) coS(qS) coS(02) coS(0b) The least...squares solution is o = (CTC)-1CT(-y). A unique solution is guaranteed provided that the columns of C are independent. Observe that the columns of C

SIN3A mutations are rare in men with azoospermia.

PubMed

Miyamoto, T; Koh, E; Tsujimura, A; Miyagawa, Y; Minase, G; Ueda, Y; Namiki, M; Sengoku, K

2015-11-01

A loss of function of the murine Sin3A gene resulted in male infertility with Sertoli cell-only syndrome (SCOS) phenotype in mice. Here, we investigated the relevance of this gene to human male infertility with azoospermia caused by SCOS. Mutation analysis of SIN3A in the coding region was performed on 80 Japanese patients. However, no variants could be detected. This study suggests a lack of association of SIN3A gene sequence variants with azoospermia caused by SCOS in humans. © 2014 Blackwell Verlag GmbH.

Computation of the Quantities Describing the Lunar Librations in the Astronomical Almanac

DTIC Science & Technology

2010-08-01

this system ~e ( COS( -(3) cost >. + 180’ - tt)) cost -(3) sine>. + 180’ - tt) sin(-(3) , (1) Consid~r neXt, point M referred to axes OX’’z’ iIi...now write (7) as the three equl\\tions " cos b cos(1 + LM - tt) = cosj3 cost >. - tt - N) cos b sin(1 + LM - tt) ,= cos Lcosj3si,n(>’,- tt -’N) ,- sin...8217?’~ on . .the sel~~~centric sphere. The geocentric right ascension and declination of the Moon are 0:, 0 and so the right ascension and declination of

Proto-oncogene FBI-1 represses transcription of p21CIP1 by inhibition of transcription activation by p53 and Sp1.

PubMed

Choi, Won-Il; Jeon, Bu-Nam; Yun, Chae-Ok; Kim, Pyung-Hwan; Kim, Sung-Eun; Choi, Kang-Yell; Kim, Se Hoon; Hur, Man-Wook

2009-05-08

Aberrant transcriptional repression through chromatin remodeling and histone deacetylation has been postulated as the driving force for tumorigenesis. FBI-1 (formerly called Pokemon) is a member of the POK family of transcriptional repressors. Recently, FBI-1 was characterized as a critical oncogenic factor that specifically represses transcription of the tumor suppressor gene ARF, potentially leading indirectly to p53 inactivation. Our investigations on transcriptional repression of the p53 pathway revealed that FBI-1 represses transcription of ARF, Hdm2 (human analogue of mouse double minute oncogene), and p21CIP1 (hereafter indicated as p21) but not of p53. FBI-1 showed a more potent repressive effect on p21 than on p53. Our data suggested that FBI-1 is a master controller of the ARF-Hdm2-p53-p21 pathway, ultimately impinging on cell cycle arrest factor p21, by inhibiting upstream regulators at the transcriptional and protein levels. FBI-1 acted as a competitive transcriptional repressor of p53 and Sp1 and was shown to bind the proximal Sp1-3 GC-box and the distal p53-responsive elements of p21. Repression involved direct binding competition of FBI-1 with Sp1 and p53. FBI-1 also interacted with corepressors, such as mSin3A, NCoR, and SMRT, thereby deacetylating Ac-H3 and Ac-H4 histones at the promoter. FBI-1 caused cellular transformation, promoted cell cycle proliferation, and significantly increased the number of cells in S phase. FBI-1 is aberrantly overexpressed in many human solid tumors, particularly in adenocarcinomas and squamous carcinomas. The role of FBI-1 as a master controller of the p53 pathway therefore makes it an attractive therapeutic target.

Proto-oncogene FBI-1 Represses Transcription of p21CIP1 by Inhibition of Transcription Activation by p53 and Sp1*S⃞

PubMed Central

Choi, Won-Il; Jeon, Bu-Nam; Yun, Chae-Ok; Kim, Pyung-Hwan; Kim, Sung-Eun; Choi, Kang-Yell; Kim, Se Hoon; Hur, Man-Wook

2009-01-01

Aberrant transcriptional repression through chromatin remodeling and histone deacetylation has been postulated as the driving force for tumorigenesis. FBI-1 (formerly called Pokemon) is a member of the POK family of transcriptional repressors. Recently, FBI-1 was characterized as a critical oncogenic factor that specifically represses transcription of the tumor suppressor gene ARF, potentially leading indirectly to p53 inactivation. Our investigations on transcriptional repression of the p53 pathway revealed that FBI-1 represses transcription of ARF, Hdm2 (human analogue of mouse double minute oncogene), and p21CIP1 (hereafter indicated as p21) but not of p53. FBI-1 showed a more potent repressive effect on p21 than on p53. Our data suggested that FBI-1 is a master controller of the ARF-Hdm2-p53-p21 pathway, ultimately impinging on cell cycle arrest factor p21, by inhibiting upstream regulators at the transcriptional and protein levels. FBI-1 acted as a competitive transcriptional repressor of p53 and Sp1 and was shown to bind the proximal Sp1–3 GC-box and the distal p53-responsive elements of p21. Repression involved direct binding competition of FBI-1 with Sp1 and p53. FBI-1 also interacted with corepressors, such as mSin3A, NCoR, and SMRT, thereby deacetylating Ac-H3 and Ac-H4 histones at the promoter. FBI-1 caused cellular transformation, promoted cell cycle proliferation, and significantly increased the number of cells in S phase. FBI-1 is aberrantly overexpressed in many human solid tumors, particularly in adenocarcinomas and squamous carcinomas. The role of FBI-1 as a master controller of the p53 pathway therefore makes it an attractive therapeutic target. PMID:19244234

Autoregulatory loop of nuclear corepressor 1 expression controls invasion, tumor growth, and metastasis

PubMed Central

Martínez-Iglesias, Olaia A.; Alonso-Merino, Elvira; Gómez-Rey, Sara; Velasco-Martín, Juan Pedro; Martín Orozco, Rosa; Luengo, Enrique; García Martín, Rosa; Ibáñez de Cáceres, Inmaculada; Fernández, Agustín F.; Fraga, Mario F.; González-Peramato, Pilar; Varona, Constantino; Palacios, José; Regadera, Javier; Aranda, Ana

2016-01-01

Nuclear corepressor 1 (NCoR) associates with nuclear receptors and other transcription factors leading to transcriptional repression. We show here that NCoR depletion enhances cancer cell invasion and increases tumor growth and metastatic potential in nude mice. These changes are related to repressed transcription of genes associated with increased metastasis and poor prognosis in patients. Strikingly, transient NCoR silencing leads to heterochromatinization and stable silencing of the NCoR gene, suggesting that NCoR loss can be propagated, contributing to tumor progression even in the absence of NCoR gene mutations. Down-regulation of the thyroid hormone receptor β1 (TRβ) appears to be associated with cancer onset and progression. We found that expression of TRβ increases NCoR levels and that this induction is essential in mediating inhibition of tumor growth and metastasis by this receptor. Moreover, NCoR is down-regulated in human hepatocarcinomas and in the more aggressive breast cancer tumors, and its expression correlates positively with that of TRβ. These data provide a molecular basis for the anticancer actions of this corepressor and identify NCoR as a potential molecular target for development of novel cancer therapies. PMID:26729869

SnoN co-repressor binds and represses smad7 gene promoter.

PubMed

Briones-Orta, Marco A; Sosa-Garrocho, Marcela; Moreno-Alvarez, Paola; Fonseca-Sánchez, Miguel A; Macías-Silva, Marina

2006-03-17

SnoN and Ski oncoproteins are co-repressors for Smad proteins and repress TGF-beta-responsive gene expression. The smad7 gene is a TGF-beta target induced by Smad signaling, and its promoter contains the Smad-binding element (SBE) required for a positive regulation by the TGF-beta/Smad pathway. SnoN and Ski co-repressors also bind SBE but regulate negatively smad7 gene. Ski along with Smad4 binds and represses the smad7 promoter, whereas the repression mechanism by SnoN is not clear. Ski and SnoN overexpression inhibits smad7 reporter expression induced through TGF-beta signaling. Using chromatin immunoprecipitation assays, we found that SnoN binds smad7 promoter at the basal condition, whereas after a short TGF-beta treatment for 15-30 min SnoN is downregulated and no longer bound smad7 promoter. Interestingly, after a prolonged TGF-beta treatment SnoN is upregulated and returns to its position on the smad7 promoter, functioning probably as a negative feedback control. Thus, SnoN also seems to regulate negatively the TGF-beta-responsive smad7 gene by binding and repressing its promoter in a similar way to Ski.

Role of transcription factor KLF11 and its diabetes-associated gene variants in pancreatic beta cell function

PubMed Central

Neve, Bernadette; Fernandez-Zapico, Martin E.; Ashkenazi-Katalan, Vered; Dina, Christian; Hamid, Yasmin H.; Joly, Erik; Vaillant, Emmanuel; Benmezroua, Yamina; Durand, Emmanuelle; Bakaher, Nicolas; Delannoy, Valerie; Vaxillaire, Martine; Cook, Tiffany; Dallinga-Thie, Geesje M.; Jansen, Hans; Charles, Marie-Aline; Clément, Karine; Galan, Pilar; Hercberg, Serge; Helbecque, Nicole; Charpentier, Guillaume; Prentki, Marc; Hansen, Torben; Pedersen, Oluf; Urrutia, Raul; Melloul, Danielle; Froguel, Philippe

2005-01-01

KLF11 (TIEG2) is a pancreas-enriched transcription factor that has elicited significant attention because of its role as negative regulator of exocrine cell growth in vitro and in vivo. However, its functional role in the endocrine pancreas remains to be established. Here, we report, for the first time, to our knowledge, the characterization of KLF11 as a glucose-inducible regulator of the insulin gene. A combination of random oligonucleotide binding, EMSA, luciferase reporter, and chromatin immunoprecipitation assays shows that KLF11 binds to the insulin promoter and regulates its activity in beta cells. Genetic analysis of the KLF11 gene revealed two rare variants (Ala347Ser and Thr220Met) that segregate with diabetes in families with early-onset type 2 diabetes, and significantly impair its transcriptional activity. In addition, analysis of 1,696 type 2 diabetes mellitus and 1,776 normoglycemic subjects show a frequent polymorphic Gln62Arg variant that significantly associates with type 2 diabetes mellitus in North European populations (OR = 1.29, P = 0.00033). Moreover, this variant alters the corepressor mSin3A-binding activity of KLF11, impairs the activation of the insulin promoter and shows lower levels of insulin expression in pancreatic beta cells. In addition, subjects carrying the Gln62Arg allele show decreased plasma insulin after an oral glucose challenge. Interestingly, all three nonsynonymous KLF11 variants show increased repression of the catalase 1 promoter, suggesting a role in free radical clearance that may render beta cells more sensitive to oxidative stress. Thus, both functional and genetic analyses reveal that KLF11 plays a role in the regulation of pancreatic beta cell physiology, and its variants may contribute to the development of diabetes. PMID:15774581

Modulation of the cyclin-dependent kinase inhibitor p21(WAF1/Cip1) gene by Zac1 through the antagonistic regulators p53 and histone deacetylase 1 in HeLa Cells.

PubMed

Liu, Pei-Yao; Chan, James Yi-Hsin; Lin, Hsiu-Chen; Wang, Sung-Ling; Liu, Shu-Ting; Ho, Ching-Liang; Chang, Li-Chien; Huang, Shih-Ming

2008-07-01

Zac1 is a novel seven-zinc finger protein which possesses the ability to bind specifically to GC-rich DNA elements. Zac1 not only promotes apoptosis and cell cycle arrest but also acts as a transcriptional cofactor for p53 and a number of nuclear receptors. Our previous study indicated that the enhancement of p53 activity by Zac1 is much more pronounced in HeLa cells compared with other cell lines tested. This phenomenon might be due to the coactivator effect of Zac1 on p53 and the ability of Zac1 to reverse E6 inhibition of p53. In the present study, we showed that Zac1 acted synergistically with either p53 or a histone deacetylase inhibitor, trichostatin A, to enhance p21(WAF1/Cip1) promoter activity. We showed that Zac1 physically interacted with some nuclear receptor corepressors such as histone deacetylase 1 (HDAC1) and mSin3a, and the induction of p21(WAF1/Cip1) gene and protein by Zac1 was suppressed by either overexpressing HDAC1 or its deacetylase-dead mutant. In addition, our data suggest that trichostatin A-induced p21(WAF1/Cip1) protein expression might be mediated through a p53-independent and HDAC deacetylase-independent pathway. Taken together, our data suggest that Zac1 might be involved in regulating the p21(WAF1/Cip1) gene and protein expression through its protein-protein interaction with p53 and HDAC1 in HeLa cells.

Cognition and speech-in-noise recognition: the role of proactive interference.

PubMed

Ellis, Rachel J; Rönnberg, Jerker

2014-01-01

Complex working memory (WM) span tasks have been shown to predict speech-in-noise (SIN) recognition. Studies of complex WM span tasks suggest that, rather than indexing a single cognitive process, performance on such tasks may be governed by separate cognitive subprocesses embedded within WM. Previous research has suggested that one such subprocess indexed by WM tasks is proactive interference (PI), which refers to difficulties memorizing current information because of interference from previously stored long-term memory representations for similar information. The aim of the present study was to investigate phonological PI and to examine the relationship between PI (semantic and phonological) and SIN perception. A within-subjects experimental design was used. An opportunity sample of 24 young listeners with normal hearing was recruited. Measures of resistance to, and release from, semantic and phonological PI were calculated alongside the signal-to-noise ratio required to identify 50% of keywords correctly in a SIN recognition task. The data were analyzed using t-tests and correlations. Evidence of release from and resistance to semantic interference was observed. These measures correlated significantly with SIN recognition. Limited evidence of phonological PI was observed. The results show that capacity to resist semantic PI can be used to predict SIN recognition scores in young listeners with normal hearing. On the basis of these findings, future research will focus on investigating whether tests of PI can be used in the treatment and/or rehabilitation of hearing loss. American Academy of Audiology.

Conformation and Complexation of Tannins: NMR Spectra and Molecular Search Modeling of Flavan-3-ols

Treesearch

Richard W. Hemingway; Fred L. Tohiason; G. Wayne McGraw; Jan P. Steynberg

1996-01-01

Studies offlavan-3-01sin their biologically significant phenolic form show that both H-6 and C-6 resonances are downfield from H-8 and C-8. Therefore, assignments for the H atoms of the A-ring are inverse to those commonly reported. By contrast, in the methyl ether and methyl ether acetate derivatives, both H-8 and C-8 are downfield from H-6 and C-6 and assignments...

The nuclear receptor corepressor (NCoR) controls thyroid hormone sensitivity and the set point of the hypothalamic-pituitary-thyroid axis.

PubMed

Astapova, Inna; Vella, Kristen R; Ramadoss, Preeti; Holtz, Kaila A; Rodwin, Benjamin A; Liao, Xiao-Hui; Weiss, Roy E; Rosenberg, Michael A; Rosenzweig, Anthony; Hollenberg, Anthony N

2011-02-01

The role of nuclear receptor corepressor (NCoR) in thyroid hormone (TH) action has been difficult to discern because global deletion of NCoR is embryonic lethal. To circumvent this, we developed mice that globally express a modified NCoR protein (NCoRΔID) that cannot be recruited to the thyroid hormone receptor (TR). These mice present with low serum T(4) and T(3) concentrations accompanied by normal TSH levels, suggesting central hypothyroidism. However, they grow normally and have increased energy expenditure and normal or elevated TR-target gene expression across multiple tissues, which is not consistent with hypothyroidism. Although these findings imply an increased peripheral sensitivity to TH, the hypothalamic-pituitary-thyroid axis is not more sensitive to acute changes in TH concentrations but appears to be reset to recognize the reduced TH levels as normal. Furthermore, the thyroid gland itself, although normal in size, has reduced levels of nonthyroglobulin-bound T(4) and T(3) and demonstrates decreased responsiveness to TSH. Thus, the TR-NCoR interaction controls systemic TH sensitivity as well as the set point at all levels of the hypothalamic-pituitary-thyroid axis. These findings suggest that NCoR levels could alter cell-specific TH action that would not be reflected by the serum TSH.

Specialized sugar sensing in diverse fungi.

PubMed

Brown, Victoria; Sabina, Jeffrey; Johnston, Mark

2009-03-10

S. cerevisiae senses glucose and galactose differently. Glucose is detected through sensors that reside in the cellular plasma membrane. When activated, the sensors initiate a signal-transduction cascade that ultimately inactivates the Rgt1 transcriptional repressor by causing degradation of its corepressors Mth1 and Std1. This results in the expression of many HXT genes encoding glucose transporters. The ensuing flood of glucose into the cell activates Mig1, a transcriptional repressor that mediates "glucose repression" of many genes, including the GAL genes; hence, glucose sensing hinders galactose utilization. Galactose is sensed in the cytoplasm via Gal3. Upon binding galactose (and ATP), Gal3 sequesters the Gal80 protein, thereby emancipating the Gal4 transcriptional activator of the GAL genes. Gal4 also activates expression of MTH1, encoding a corepressor critical for Rgt1 function. Thus, galactose inhibits glucose assimilation by encouraging repression of HXT genes. C. albicans senses glucose similarly to S. cerevisiae but does not sense galactose through Gal3-Gal80-Gal4. Its genome harbors no GAL80 ortholog, and the severely truncated CaGal4 does not regulate CaGAL genes. We present evidence that C. albicans senses galactose with its Hgt4 glucose sensor, a capability that is enabled by transcriptional "rewiring" of its sugar-sensing signal-transduction pathways. We suggest that galactose sensing through Hgt4 is ancestral in fungi.

The Groucho Co-repressor Is Primarily Recruited to Local Target Sites in Active Chromatin to Attenuate Transcription

PubMed Central

Jennings, Barbara H.

2014-01-01

Gene expression is regulated by the complex interaction between transcriptional activators and repressors, which function in part by recruiting histone-modifying enzymes to control accessibility of DNA to RNA polymerase. The evolutionarily conserved family of Groucho/Transducin-Like Enhancer of split (Gro/TLE) proteins act as co-repressors for numerous transcription factors. Gro/TLE proteins act in several key pathways during development (including Notch and Wnt signaling), and are implicated in the pathogenesis of several human cancers. Gro/TLE proteins form oligomers and it has been proposed that their ability to exert long-range repression on target genes involves oligomerization over broad regions of chromatin. However, analysis of an endogenous gro mutation in Drosophila revealed that oligomerization of Gro is not always obligatory for repression in vivo. We have used chromatin immunoprecipitation followed by DNA sequencing (ChIP-seq) to profile Gro recruitment in two Drosophila cell lines. We find that Gro predominantly binds at discrete peaks (<1 kilobase). We also demonstrate that blocking Gro oligomerization does not reduce peak width as would be expected if Gro oligomerization induced spreading along the chromatin from the site of recruitment. Gro recruitment is enriched in “active” chromatin containing developmentally regulated genes. However, Gro binding is associated with local regions containing hypoacetylated histones H3 and H4, which is indicative of chromatin that is not fully open for efficient transcription. We also find that peaks of Gro binding frequently overlap the transcription start sites of expressed genes that exhibit strong RNA polymerase pausing and that depletion of Gro leads to release of polymerase pausing and increased transcription at a bona fide target gene. Our results demonstrate that Gro is recruited to local sites by transcription factors to attenuate rather than silence gene expression by promoting histone deacetylation and polymerase pausing. PMID:25165826

Analysis of the NuRD subunits reveals a histone deacetylase core complex and a connection with DNA methylation

PubMed Central

Zhang, Yi; Ng, Huck-Hui; Erdjument-Bromage, Hediye; Tempst, Paul; Bird, Adrian; Reinberg, Danny

1999-01-01

ATP-dependent nucleosome remodeling and core histone acetylation and deacetylation represent mechanisms to alter nucleosome structure. NuRD is a multisubunit complex containing nucleosome remodeling and histone deacetylase activities. The histone deacetylases HDAC1 and HDAC2 and the histone binding proteins RbAp48 and RbAp46 form a core complex shared between NuRD and Sin3-histone deacetylase complexes. The histone deacetylase activity of the core complex is severely compromised. A novel polypeptide highly related to the metastasis-associated protein 1, MTA2, and the methyl-CpG-binding domain-containing protein, MBD3, were found to be subunits of the NuRD complex. MTA2 modulates the enzymatic activity of the histone deacetylase core complex. MBD3 mediates the association of MTA2 with the core histone deacetylase complex. MBD3 does not directly bind methylated DNA but is highly related to MBD2, a polypeptide that binds to methylated DNA and has been reported to possess demethylase activity. MBD2 interacts with the NuRD complex and directs the complex to methylated DNA. NuRD may provide a means of gene silencing by DNA methylation. PMID:10444591

The role of LANP and ataxin 1 in E4F-mediated transcriptional repression

PubMed Central

Cvetanovic, Marija; Rooney, Robert J; Garcia, Jesus J; Toporovskaya, Nataliya; Zoghbi, Huda Y; Opal, Puneet

2007-01-01

The leucine-rich acidic nuclear protein (LANP) belongs to the INHAT family of corepressors that inhibits histone acetyltransferases. The mechanism by which LANP restricts its repression to specific genes is unknown. Here, we report that LANP forms a complex with transcriptional repressor E4F and modulates its activity. As LANP interacts with ataxin 1—a protein mutated in the neurodegenerative disease spinocerebellar ataxia type 1 (SCA1)—we tested whether ataxin 1 can alter the E4F–LANP interaction. We show that ataxin 1 relieves the transcriptional repression induced by the LANP–E4F complex by competing with E4F for LANP. These results provide the first functional link, to our knowledge, between LANP and ataxin 1, and indicate a potential mechanism for the transcriptional aberrations observed in SCA1. PMID:17557114

Structure of the C-terminal effector-binding domain of AhrC bound to its corepressor l-arginine

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

Garnett, James A.; Baumberg, Simon; Stockley, Peter G.

2007-11-01

The crystal structure of the C-terminal domain hexameric core of AhrC, with bound corepressor (l-arginine), has been solved at 1.95 Å resolution. Binding of l-arginine results in a rotation between the two trimers of the hexamer, leading to the activation of the DNA-binding state. The arginine repressor/activator protein (AhrC) from Bacillus subtilis belongs to a large family of multifunctional transcription factors that are involved in the regulation of bacterial arginine metabolism. AhrC interacts with operator sites in the promoters of arginine biosynthetic and catabolic operons, acting as a transcriptional repressor at biosynthetic sites and an activator of transcription at catabolicmore » sites. AhrC is a hexamer of identical subunits, each having two domains. The C-terminal domains form the core of the protein and are involved in oligomerization and l-arginine binding. The N-terminal domains lie on the outside of the compact core and play a role in binding to 18 bp DNA operators called ARG boxes. The C-terminal domain of AhrC has been expressed, purified and characterized, and also crystallized as a hexamer with the bound corepressor l-arginine. Here, the crystal structure refined to 1.95 Å is presented.« less

Crystallization and preliminary X-ray diffraction analysis of the arginine repressor of the hyperthermophile Thermotoga neapolitana

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

Massant, Jan, E-mail: jan.massant@vub.ac.be; Peeters, Eveline; Charlier, Daniel

2006-01-01

The arginine repressor of the hyperthermophile T. neapolitana was crystallized with and without its corepressor arginine. Both crystals diffracted to high resolution and belong to the orthorhombic space group P2{sub 1}2{sub 1}2{sub 1}, with similar unit-cell parameters. The arginine repressor of Thermotoga neapolitana (ArgRTnp) is a member of the family of multifunctional bacterial arginine repressors involved in the regulation of arginine metabolism. This hyperthermophilic repressor shows unique DNA-binding features that distinguish it from its homologues. ArgRTnp exists as a homotrimeric protein that assembles into hexamers at higher protein concentrations and/or in the presence of arginine. ArgRTnp was crystallized with andmore » without its corepressor arginine using the hanging-drop vapour-diffusion method. Crystals of the aporepressor diffracted to a resolution of 2.1 Å and belong to the orthorhombic P2{sub 1}2{sub 1}2{sub 1} space group, with unit-cell parameters a = 117.73, b = 134.15, c = 139.31 Å. Crystals of the repressor in the presence of its corepressor arginine diffracted to a resolution of 2.4 Å and belong to the same space group, with similar unit-cell parameters.« less

A novel principle for partial agonism of liver X receptor ligands. Competitive recruitment of activators and repressors.

PubMed

Albers, Michael; Blume, Beatrix; Schlueter, Thomas; Wright, Matthew B; Kober, Ingo; Kremoser, Claus; Deuschle, Ulrich; Koegl, Manfred

2006-02-24

Partial, selective activation of nuclear receptors is a central issue in molecular endocrinology but only partly understood. Using LXRs as an example, we show here that purely agonistic ligands can be clearly and quantitatively differentiated from partial agonists by the cofactor interactions they induce. Although a pure agonist induces a conformation that is incompatible with the binding of repressors, partial agonists such as GW3965 induce a state where the interaction not only with coactivators, but also corepressors is clearly enhanced over the unliganded state. The activities of the natural ligand 22(R)-hydroxycholesterol and of a novel quinazolinone ligand, LN6500 can be further differentiated from GW3965 and T0901317 by their weaker induction of coactivator binding. Using biochemical and cell-based assays, we show that the natural ligand of LXR is a comparably weak partial agonist. As predicted, we find that a change in the coactivator to corepressor ratio in the cell will affect NCoR recruiting compounds more dramatically than NCoR-dissociating compounds. Our data show how competitive binding of coactivators and corepressors can explain the tissue-specific behavior of partial agonists and open up new routes to a rational design of partial agonists for LXRs.

Musician enhancement for speech-in-noise.

PubMed

Parbery-Clark, Alexandra; Skoe, Erika; Lam, Carrie; Kraus, Nina

2009-12-01

To investigate the effect of musical training on speech-in-noise (SIN) performance, a complex task requiring the integration of working memory and stream segregation as well as the detection of time-varying perceptual cues. Previous research has indicated that, in combination with lifelong experience with musical stream segregation, musicians have better auditory perceptual skills and working memory. It was hypothesized that musicians would benefit from these factors and perform better on speech perception in noise than age-matched nonmusician controls. The performance of 16 musicians and 15 nonmusicians was compared on clinical measures of speech perception in noise-QuickSIN and Hearing-In-Noise Test (HINT). Working memory capacity and frequency discrimination were also assessed. All participants had normal hearing and were between the ages of 19 and 31 yr. To be categorized as a musician, participants needed to have started musical training before the age of 7 yr, have 10 or more years of consistent musical experience, and have practiced more than three times weekly within the 3 yr before study enrollment. Nonmusicians were categorized by the failure to meet the musician criteria, along with not having received musical training within the 7 yr before the study. Musicians outperformed the nonmusicians on both QuickSIN and HINT, in addition to having more fine-grained frequency discrimination and better working memory. Years of consistent musical practice correlated positively with QuickSIN, working memory, and frequency discrimination but not HINT. The results also indicate that working memory and frequency discrimination are more important for QuickSIN than for HINT. Musical experience appears to enhance the ability to hear speech in challenging listening environments. Large group differences were found for QuickSIN, and the results also suggest that this enhancement is derived in part from musicians' enhanced working memory and frequency discrimination. For HINT, in which performance was not linked to frequency discrimination ability and was only moderately linked to working memory, musicians still performed significantly better than the nonmusicians. The group differences for HINT were evident in the most difficult condition in which the speech and noise were presented from the same location and not spatially segregated. Understanding which cognitive and psychoacoustic factors as well as which lifelong experiences contribute to SIN may lead to more effective remediation programs for clinical populations for whom SIN poses a particular perceptual challenge. These results provide further evidence for musical training transferring to nonmusical domains and highlight the importance of taking musical training into consideration when evaluating a person's SIN ability in a clinical setting.

Corepressors TLE1 and TLE3 interact with HESX1 and PROP1.

PubMed

Carvalho, Luciani R; Brinkmeier, Michelle L; Castinetti, Frederic; Ellsworth, Buffy S; Camper, Sally A

2010-04-01

Pituitary hormone deficiency causes short stature in one in 4000 children born and can be caused by mutations in transcription factor genes, including HESX1, PROP1, and POU1F1. HESX1 interacts with a member of the groucho-related gene family, TLE1, through an engrailed homology domain and represses PROP1 activity. Mice with Prop1 deficiency exhibit failed differentiation of the POU1F1 lineage, resulting in lack of TSH, GH, and prolactin. In addition, these mutants exhibit profound pituitary dysmorphology and excess Hesx1 and Tle3 expression. The ability of HESX1 to interact with TLE3 has not been explored previously. We tested the ability of TLE3 to enhance HESX1-mediated repression of PROP1 in cell culture. Both TLE3 and TLE1 repress PROP1 in conjunction with HESX1 with similar efficiencies. TLE1 and TLE3 can each repress PROP1 in the absence of HESX1 via a protein-protein interaction. We tested the functional consequences of ectopic TLE3 and HESX1 expression in transgenic mice by driving constitutive expression in pituitary thyrotrophs and gonadotrophs. Terminal differentiation of these cells was suppressed by HESX1 alone and by TLE3 and HESX1 together but not by TLE3 alone. In summary, we present evidence that HESX1 is a strong repressor that can be augmented by the corepressors TLE1 and TLE3. Our in vitro studies suggest that TLE1 and TLE3 might also play roles independent of HESX1 by interacting with other transcription factors like PROP1.

Neural Correlates of Early Sound Encoding and their Relationship to Speech-in-Noise Perception

PubMed Central

Coffey, Emily B. J.; Chepesiuk, Alexander M. P.; Herholz, Sibylle C.; Baillet, Sylvain; Zatorre, Robert J.

2017-01-01

Speech-in-noise (SIN) perception is a complex cognitive skill that affects social, vocational, and educational activities. Poor SIN ability particularly affects young and elderly populations, yet varies considerably even among healthy young adults with normal hearing. Although SIN skills are known to be influenced by top-down processes that can selectively enhance lower-level sound representations, the complementary role of feed-forward mechanisms and their relationship to musical training is poorly understood. Using a paradigm that minimizes the main top-down factors that have been implicated in SIN performance such as working memory, we aimed to better understand how robust encoding of periodicity in the auditory system (as measured by the frequency-following response) contributes to SIN perception. Using magnetoencephalograpy, we found that the strength of encoding at the fundamental frequency in the brainstem, thalamus, and cortex is correlated with SIN accuracy. The amplitude of the slower cortical P2 wave was previously also shown to be related to SIN accuracy and FFR strength; we use MEG source localization to show that the P2 wave originates in a temporal region anterior to that of the cortical FFR. We also confirm that the observed enhancements were related to the extent and timing of musicianship. These results are consistent with the hypothesis that basic feed-forward sound encoding affects SIN perception by providing better information to later processing stages, and that modifying this process may be one mechanism through which musical training might enhance the auditory networks that subserve both musical and language functions. PMID:28890684

Auxin-dependent compositional change in Mediator in ARF7- and ARF19-mediated transcription.

PubMed

Ito, Jun; Fukaki, Hidehiro; Onoda, Makoto; Li, Lin; Li, Chuanyou; Tasaka, Masao; Furutani, Masahiko

2016-06-07

Mediator is a multiprotein complex that integrates the signals from transcription factors binding to the promoter and transmits them to achieve gene transcription. The subunits of Mediator complex reside in four modules: the head, middle, tail, and dissociable CDK8 kinase module (CKM). The head, middle, and tail modules form the core Mediator complex, and the association of CKM can modify the function of Mediator in transcription. Here, we show genetic and biochemical evidence that CKM-associated Mediator transmits auxin-dependent transcriptional repression in lateral root (LR) formation. The AUXIN/INDOLE 3-ACETIC ACID 14 (Aux/IAA14) transcriptional repressor inhibits the transcriptional activity of its binding partners AUXIN RESPONSE FACTOR 7 (ARF7) and ARF19 by making a complex with the CKM-associated Mediator. In addition, TOPLESS (TPL), a transcriptional corepressor, forms a bridge between IAA14 and the CKM component MED13 through the physical interaction. ChIP assays show that auxin induces the dissociation of MED13 but not the tail module component MED25 from the ARF7 binding region upstream of its target gene. These findings indicate that auxin-induced degradation of IAA14 changes the module composition of Mediator interacting with ARF7 and ARF19 in the upstream region of their target genes involved in LR formation. We suggest that this regulation leads to a quick switch of signal transmission from ARFs to target gene expression in response to auxin.

Role of the Neddylation Enzyme Uba3, a New Estrogen Receptor Corepressor, in Breast Cancer

DTIC Science & Technology

2005-09-01

downstream targets Cancer Res 64:8184-8192 (cover article ). *This DOD award is acknowledged in these publications. Presentations 1. Fan M, Park A...www.endoiournals.org/. The final copy edited article can be found at 15 http://www.endojoumals.org/. The Endocrine Society disclaims any responsibility or...8217Hutnan Cancer Genetics Program, Departtent of Molecular Virology, Inmunology , and Medical Genetics, Comprehensive Cancer Center, The Ohio State Universit

The Sin3p PAH Domains Provide Separate Functions Repressing Meiotic Gene Transcription in Saccharomyces cerevisiae ▿

PubMed Central

Mallory, Michael J.; Law, Michael J.; Buckingham, Lela E.; Strich, Randy

2010-01-01

Meiotic genes in budding yeast are repressed during vegetative growth but are transiently induced during specific stages of meiosis. Sin3p represses the early meiotic gene (EMG) by bridging the DNA binding protein Ume6p to the histone deacetylase Rpd3p. Sin3p contains four paired amphipathic helix (PAH) domains, one of which (PAH3) is required for repressing several genes expressed during mitotic cell division. This report examines the roles of the PAH domains in mediating EMG repression during mitotic cell division and following meiotic induction. PAH2 and PAH3 are required for mitotic EMG repression, while electrophoretic mobility shift assays indicate that only PAH2 is required for stable Ume6p-promoter interaction. Unlike mitotic repression, reestablishing EMG repression following transient meiotic induction requires PAH3 and PAH4. In addition, the role of Sin3p in reestablishing repression is expanded to include additional loci that it does not control during vegetative growth. These findings indicate that mitotic and postinduction EMG repressions are mediated by two separate systems that utilize different Sin3p domains. PMID:20971827

MeCP2 co-ordinates liver lipid metabolism with the NCoR1/HDAC3 corepressor complex

PubMed Central

Kyle, Stephanie M.; Saha, Pradip K.; Brown, Hannah M.; Chan, Lawrence C.; Justice, Monica J.

2016-01-01

Rett syndrome (RTT; OMIM 312750), a progressive neurological disorder, is caused by mutations in methyl-CpG-binding protein 2 (MECP2; OMIM 300005), a ubiquitously expressed factor. A genetic suppressor screen designed to identify therapeutic targets surprisingly revealed that downregulation of the cholesterol biosynthesis pathway improves neurological phenotypes in Mecp2 mutant mice. Here, we show that MeCP2 plays a direct role in regulating lipid metabolism. Mecp2 deletion in mice results in a host of severe metabolic defects caused by lipid accumulation, including insulin resistance, fatty liver, perturbed energy utilization, and adipose inflammation by macrophage infiltration. We show that MeCP2 regulates lipid homeostasis by anchoring the repressor complex containing NCoR1 and HDAC3 to its lipogenesis targets in hepatocytes. Consistently, we find that liver targeted deletion of Mecp2 causes fatty liver disease and dyslipidemia similar to HDAC3 liver-specific deletion. These findings position MeCP2 as a novel component in metabolic homeostasis. Rett syndrome patients also show signs of peripheral dyslipidemia; thus, together these data suggest that RTT should be classified as a neurological disorder with systemic metabolic components. We previously showed that treatment of Mecp2 mice with statin drugs alleviated motor symptoms and improved health and longevity. Lipid metabolism is a highly treatable target; therefore, our results shed light on new metabolic pathways for treatment of Rett syndrome. PMID:27288453

Optimal Guidance Trajectories for a Nanosat Docking with a Non Cooperative Resident Space Object

DTIC Science & Technology

2014-03-07

12 − 3 sin 2 rref sin 2(kt)/2− (1 + cos 2iref)/8] + fx ÿ = −2(nc)ẋ− 3n2J2(R2e/2rref) sin2 iref sin(2kt) + fy z̈ = −(3c2 − 2)n2z + fz (24) where fx ...dynamics assumes three normalized controls: u = [ fx fxmax fy fymax fz fzmax ] (26) For simplicity, it is assumed that fimax = 1m/s2 for i = x, y, z...American Institute of Aeronautics and Astro - nautics, 2010. [7] G. Boyarko, O. Yakimenko, and M. Romano, Optimal rendezvous trajectories of a controlled

Differintegration: The One Branch of Calculus

ERIC Educational Resources Information Center

Berry, Andrew J.

2007-01-01

How might one define a functional operator D[superscript I]f(x), say for f(x) = 1 + x[superscript 2] + sin x, such that D[superscript +1](1 + x[superscript 2] + sin x) = 2x + cos x and D[superscript -1](1 + x[superscript 2] + sin x) = x + x[superscript 3]/3 - cos x? Our task in this article is to describe such an operator using a single formula…

Role of the Neddylation Enzyme Uba3, A New Estrogen Receptor Corepressor in Breast Cancer

DTIC Science & Technology

2006-09-01

cells acquire ICI 182,780 resistance while retaining expres- sion of ER. MATERIALS AND METHODS Materials The following antibodies and reagents were used...protein assay kit; FBS and csFBS (Hy- Clone Laboratories, Inc., Logan, UT); LipofectAMINE Plus Reagent , geneticin, and other cell culture reagents were...plasmid DNA (adjusted by corresponding empty vectors) by using LipofectAMINE Plus Reagent according to the manufacturer’s guidelines. Five hours later

LEUNIG_HOMOLOG transcriptional co-repressor mediates aluminium sensitivity through PECTIN METHYLESTERASE46-modulated root cell wall pectin methylesterification in Arabidopsis.

PubMed

Geng, Xiaoyu; Horst, Walter J; Golz, John F; Lee, Joanne E; Ding, Zhaojun; Yang, Zhong-Bao

2017-05-01

A major factor determining aluminium (Al) sensitivity in higher plants is the binding of Al to root cell walls. The Al binding capacity of cell walls is closely linked to the extent of pectin methylesterification, as the presence of methyl groups attached to the pectin backbone reduces the net negative charge of this polymer and hence limits Al binding. Despite recent progress in understanding the molecular basis of Al resistance in a wide range of plants, it is not well understood how the methylation status of pectin is mediated in response to Al stress. Here we show in Arabidopsis that mutants lacking the gene LEUNIG_HOMOLOG (LUH), a member of the Groucho-like family of transcriptional co-repressor, are less sensitive to Al-mediated repression of root growth. This phenotype is correlated with increased levels of methylated pectin in the cell walls of luh roots as well as altered expression of cell wall-related genes. Among the LUH-repressed genes, PECTIN METHYLESTERASE46 (PME46) was identified as reducing Al binding to cell walls and hence alleviating Al-induced root growth inhibition by decreasing PME enzyme activity. seuss-like2 (slk2) mutants responded to Al in a similar way as luh mutants suggesting that a LUH-SLK2 complex represses the expression of PME46. The data are integrated into a model in which it is proposed that PME46 is a major inhibitor of pectin methylesterase activity within root cell walls. © 2017 The Authors The Plant Journal © 2017 John Wiley & Sons Ltd.

Molecular basis for repression of liver X receptor-mediated gene transcription by receptor-interacting protein 140

PubMed Central

Jakobsson, Tomas; Osman, Waffa; Gustafsson, Jan-Åke; Zilliacus, Johanna; Wärnmark, Anette

2007-01-01

Similarities in physiological roles of LXR (liver X receptors) and co-repressor RIP140 (receptor-interacting protein 140) in regulating energy homoeostasis and lipid and glucose metabolism suggest that the effects of LXR could at least partly be mediated by recruitment of the co-repressor RIP140. In the present study, we have elucidated the molecular basis for regulation of LXR transcriptional activity by RIP140. LXR is evenly localized in the nucleus and neither the N-terminal domain nor the LBD (ligand-binding domain) is necessary for nuclear localization. Both LXR subtypes, LXRα and LXRβ, interact with RIP140 and co-localize in diffuse large nuclear domains. Interaction and co-localization are dependent on the LBD of the receptor. The C-terminal domain of RIP140 is sufficient for full repressive effect. None of the C-terminal NR (nuclear receptor)-boxes is required for the co-repressor activity, whereas the NR-box-like motif as well as additional elements in the C-terminal region are required for full repressive function. The C-terminal NR-box-like motif is necessary for interaction with LXRβ, whereas additional elements are needed for strong interaction with LXRα. In conclusion, our results suggest that co-repression of LXR activity by RIP140 involves an atypical binding mode of RIP140 and a repression element in the RIP140 C-terminus. PMID:17391100

A homozygous mutation in HESX1 is associated with evolving hypopituitarism due to impaired repressor-corepressor interaction

PubMed Central

Carvalho, Luciani R.; Woods, Kathryn S.; Mendonca, Berenice B.; Marcal, Nathalie; Zamparini, Andrea L.; Stifani, Stefano; Brickman, Joshua M.; Arnhold, Ivo J.P.; Dattani, Mehul T.

2003-01-01

The paired-like homeobox gene expressed in embryonic stem cells Hesx1/HESX1 encodes a developmental repressor and is expressed in early development in a region fated to form the forebrain, with subsequent localization to Rathke’s pouch, the primordium of the anterior pituitary gland. Mutations within the gene have been associated with septo-optic dysplasia, a constellation of phenotypes including eye, forebrain, and pituitary abnormalities, or milder degrees of hypopituitarism. We identified a novel homozygous nonconservative missense mutation (I26T) in the critical Engrailed homology repressor domain (eh1) of HESX1, the first, to our knowledge, to be described in humans, in a girl with evolving combined pituitary hormone deficiency born to consanguineous parents. Neuroimaging revealed a thin pituitary stalk with anterior pituitary hypoplasia and an ectopic posterior pituitary, but no midline or optic nerve abnormalities. This I26T mutation did not affect the DNA-binding ability of HESX1 but led to an impaired ability to recruit the mammalian Groucho homolog/Transducin-like enhancer of split-1 (Gro/TLE1), a crucial corepressor for HESX1, thereby leading to partial loss of repression. Thus, the novel pituitary phenotype highlighted here appears to be a specific consequence of the inability of HESX1 to recruit Groucho-related corepressors, suggesting that other molecular mechanisms govern HESX1 function in the forebrain. PMID:14561704

Microcomputers and the Electrical Engineer.

DTIC Science & Technology

1984-07-01

B6 10*SIN(B4*B1I) 12 BII+B6 10*SIN(B4*812) 13 B12+B6 1O*SIN(B4*BI3) 14 B13+B6 10*SIN(B4*B14) 15 B14+B6 10*SIN(B4*BI5) 16 B15+B6 10*SIN(B4* Bl6 ) 17 B16 ...C15)),AND(D15,NOT(EI5 16 0 0 1 0 OR(AND( B16 ,NOT(C16)),AND(D16,NOT(E16 a17 0 0 0 1 OR(AND(B17,NOT(C17)),AND(D17,NOT(E17 18 0 0 0 0 OR(AND(B18,NOT(C18...NOT(E15)) 16 0 0 010 AND(AND( Bl6 ,NOT(Cl7)),AND(D16,NOT(E16)) 18 0) 0 0 0 AND(AND(B18,NOT(C18)),AND(D18,NOT(E18)) 19 Figure 3 I A IIBIJCIIDIIEII F I 1

Modification of silicon nitride surfaces with GOPES and APTES for antibody immobilization: computational and experimental studies

NASA Astrophysics Data System (ADS)

Dien To, Thien; Nguyen, Anh Tuan; Nhat Thanh Phan, Khoa; Thu Thi Truong, An; Doan, Tin Chanh Duc; Mau Dang, Chien

2015-12-01

Chemical modification of silicon nitride (SiN) surfaces by silanization has been widely studied especially with 3-(aminopropyl)triethoxysilane (APTES) and 3-(glycidyloxypropyl) dimethylethoxysilane (GOPES). However few reports performed the experimental and computational studies together. In this study, surface modification of SiN surfaces with GOPES and APTES covalently bound with glutaraldehyde (GTA) was investigated for antibody immobilization. The monoclonal anti-cytokeratin-FITC (MACF) antibody was immobilized on the modified SiN surfaces. The modified surfaces were characterized by water contact angle measurements, atomic force microscopy and fluorescence microscopy. The FITC-fluorescent label indicated the existence of MACF antibody on the SiN surfaces and the efficiency of the silanization reaction. Absorption of APTES and GOPES on the oxidized SiN surfaces was computationally modeled and calculated by Materials Studio software. The computational and experimental results showed that modification of the SiN surfaces with APTES and GTA was more effective than the modification with GOPES.

Exploiting the Reactivity of Actinide Fluoride Bonds for the Synthesis of a New Class of Bis(azide) Uranium Complexes

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

Erickson, Karla A.; Lichtscheidl, Alejandro G.; Monreal, Marisa Jennifer

The terminal actinide fluoride bonds in (C 5Me 5) 2ThF 2(py) (py = pyridine) and (C 5Me 5) 2UF 2(O=PR 3) (R = Me, Ph) react with two equivalents of Me 3SiN 3 in toluene to form the polymeric thorium bis(azide), [(C 5Me 5) 2Th(N 3)2] ∞, and a new class of monometallic uranium bis(azide) complexes, (C 5Me 5) 2U(N 3)2(O=PR 3), respectively. Full characterization of the novel complexes (C 5Me 5) 2ThF 2(py) and (C 5Me 5) 2UF 2(O=PR 3) are reported, including the solid-state structures of (C 5Me 5) 2ThF 2(py) and (C 5Me 5) 2U(N 3) 2(O=PPhmore » 3). Lastly, electronic absorption spectral data are also reported for (C 5Me 5) 2AnF 2(py) (An = Th, U) and (C 5Me 5) 2U(N 3) 2(O=PR 3) to confirm metal oxidation state and enable elucidation of the fluoride and azide ligand bonding in these complexes.« less

Exploiting the Reactivity of Actinide Fluoride Bonds for the Synthesis of a New Class of Bis(azide) Uranium Complexes

DOE PAGES

Erickson, Karla A.; Lichtscheidl, Alejandro G.; Monreal, Marisa Jennifer; ...

2017-11-04

The terminal actinide fluoride bonds in (C 5Me 5) 2ThF 2(py) (py = pyridine) and (C 5Me 5) 2UF 2(O=PR 3) (R = Me, Ph) react with two equivalents of Me 3SiN 3 in toluene to form the polymeric thorium bis(azide), [(C 5Me 5) 2Th(N 3)2] ∞, and a new class of monometallic uranium bis(azide) complexes, (C 5Me 5) 2U(N 3)2(O=PR 3), respectively. Full characterization of the novel complexes (C 5Me 5) 2ThF 2(py) and (C 5Me 5) 2UF 2(O=PR 3) are reported, including the solid-state structures of (C 5Me 5) 2ThF 2(py) and (C 5Me 5) 2U(N 3) 2(O=PPhmore » 3). Lastly, electronic absorption spectral data are also reported for (C 5Me 5) 2AnF 2(py) (An = Th, U) and (C 5Me 5) 2U(N 3) 2(O=PR 3) to confirm metal oxidation state and enable elucidation of the fluoride and azide ligand bonding in these complexes.« less

Mutational dynamics of the SARS coronavirus in cell culture and human populations isolated in 2003

PubMed Central

Vega, Vinsensius B; Ruan, Yijun; Liu, Jianjun; Lee, Wah Heng; Wei, Chia Lin; Se-Thoe, Su Yun; Tang, Kin Fai; Zhang, Tao; Kolatkar, Prasanna R; Ooi, Eng Eong; Ling, Ai Ee; Stanton, Lawrence W; Long, Philip M; Liu, Edison T

2004-01-01

Background The SARS coronavirus is the etiologic agent for the epidemic of the Severe Acute Respiratory Syndrome. The recent emergence of this new pathogen, the careful tracing of its transmission patterns, and the ability to propagate in culture allows the exploration of the mutational dynamics of the SARS-CoV in human populations. Methods We sequenced complete SARS-CoV genomes taken from primary human tissues (SIN3408, SIN3725V, SIN3765V), cultured isolates (SIN848, SIN846, SIN842, SIN845, SIN847, SIN849, SIN850, SIN852, SIN3408L), and five consecutive Vero cell passages (SIN2774_P1, SIN2774_P2, SIN2774_P3, SIN2774_P4, SIN2774_P5) arising from SIN2774 isolate. These represented individual patient samples, serial in vitro passages in cell culture, and paired human and cell culture isolates. Employing a refined mutation filtering scheme and constant mutation rate model, the mutation rates were estimated and the possible date of emergence was calculated. Phylogenetic analysis was used to uncover molecular relationships between the isolates. Results Close examination of whole genome sequence of 54 SARS-CoV isolates identified before 14th October 2003, including 22 from patients in Singapore, revealed the mutations engendered during human-to-Vero and Vero-to-human transmission as well as in multiple Vero cell passages in order to refine our analysis of human-to-human transmission. Though co-infection by different quasipecies in individual tissue samples is observed, the in vitro mutation rate of the SARS-CoV in Vero cell passage is negligible. The in vivo mutation rate, however, is consistent with estimates of other RNA viruses at approximately 5.7 × 10-6 nucleotide substitutions per site per day (0.17 mutations per genome per day), or two mutations per human passage (adjusted R-square = 0.4014). Using the immediate Hotel M contact isolates as roots, we observed that the SARS epidemic has generated four major genetic groups that are geographically associated: two Singapore isolates, one Taiwan isolate, and one North China isolate which appears most closely related to the putative SARS-CoV isolated from a palm civet. Non-synonymous mutations are centered in non-essential ORFs especially in structural and antigenic genes such as the S and M proteins, but these mutations did not distinguish the geographical groupings. However, no non-synonymous mutations were found in the 3CLpro and the polymerase genes. Conclusions Our results show that the SARS-CoV is well adapted to growth in culture and did not appear to undergo specific selection in human populations. We further assessed that the putative origin of the SARS epidemic was in late October 2002 which is consistent with a recent estimate using cases from China. The greater sequence divergence in the structural and antigenic proteins and consistent deletions in the 3' – most portion of the viral genome suggest that certain selection pressures are interacting with the functional nature of these validated and putative ORFs. PMID:15347429

Solar tidal variations of coefficients of second harmonic of gravitational potential of Mercury

NASA Astrophysics Data System (ADS)

Ferrandiz, Jose; Barkin, Yury

2010-05-01

Variations of coefficients of the second harmonic of Mercury potential caused by the solar tides have been studied. In the paper we use analytical expressions for tidal variations of Stoks coefficients obtained for model of the elastic celestial body with concentric distributions of masses and elastic parameters (Love numbers) and their reduced form with using fundamental elastic parameter k2 of the Mercury. Taking into account the resonant properties of the Mercury motion variations of the Mercury potential coefficients we present in the form of Fourier series on the multiple of corresponding arguments of the Mercury orbital theory. Evaluations of the amplitudes and periods of observed variations of Mercury potential have been tabulated for base elastic model of the Mercury characterized by hypothetic elastic parameter (Love number) k2=0.37 (Dehant et al., 2005). Tidal variations of polar moment of inertia of the Mercury (due to tidal deformations) lead to remarkable variations of the Mercury rotation. Tidal variations of the Mercury axial rotation also have been determined and tabulated. From our results it follows that the tide periodic variations of gravitational coefficients of the Mercury in a few orders bigger then corresponding tidal variations of Earth's geopotential coefficients (Ferrandiz, Getino, 1993). Variations coefficients of the second harmonic of Mercury potential. These variations are determined by the known formulae for variations of coefficients of the second harmonic of geopotential (Ferrandiz, Getino, 1993). Here we present these formulae in some special form as applied to the considered problem about the Mercury tidal deformations: ( ) δJ2 = - 3Tα23-2, δC22 = T α21 - α22 -4, δS22 = T α1α2-2, δC21 = Tα1α3, δS21 = T α2α3. Here T = k2(M R3 -ma3 ) = 1.667 × 10-7 is a estimation of some conditional coefficient of tidal deformation of Mercury. m and Rare the mass and the mean radius of Mercury. Here we have used standard values of ratio of mass of the Sun and Mercury m-M = 6023600, mean radius of Mercury R = 2439.7 km. a = 0.3870983098 AU is an unperturbed value of major semi-axis of Mercury orbit. k2=0.37. αjis direction cosines of the radius-vector of the Sun in Mercury principal axes of inertia. The central problem of the work was a construction of trigonometric developments of the producta and squares of these direction cosines multiplied on function(a-r)3, where r is a value of radius-vector of the Sun anda is a major semi-axis of orbit of Mercury (unperturbed value): (a-r)3αiαj. Omiting sufficiently long procedure on construction of developments for mentioned products we present final formulas for solar tidal variations of coefficients of Mercury gravitational potential: M--(R-)3Σ δJ2 = - 3k2m a [R0,ν(ρ,t)cos? ν + r0,ν(ρ,t)sin ?ν] ν ( ) 1 M-- R- 3Σ Σ [ (ɛ) (ɛ) ] δS22 = - 8k2m a R2,ν cos(2g +2l- ɛ? ν)- r2,ν sin (2g - ɛ?ν) , ν ɛ 1 M (R )3Σ Σ [ (ɛ) (ɛ) ] δC21 = - 4k2m- -a R1,ν cos (g + l- ɛ? ν)- r1,ν sin(g+ l- ɛ?ν) , ν ɛ ( )3Σ Σ [ ] δS21 = - 1 k2 M- R- R (ɛ1,)ν cos(g+ l- ɛ?ν)- r(1ɛ),ν sin(g- ɛ? ν). 4 m a ν ɛ For simplicity here we put the value of the angle ? = 00, that means that in unperturbed rotational motion of Mercury its vector of angular momentum consides with the polar principial axis of inertia. Here ɛ = ±1; ?ν are arguments located on multiple of mean longitudes of planets (Mercury, Venus, the Earth, Mars, Jupiter, Saturn, Uran and the Neptune): ?ν = ν1LMe + ν2LV + ν3LE + ν4LMa + ν5LJu + ν6LSa + ν7LUr + ν8LNe; ν = (ν1,ν2,ν3,...,ν8) are corresponding sets of integer indexes. Here all functions R and r are special inclination functions depending from angle ρof inclination of vector of angular momentum of Mercury with respect to normal to base (Laplace) plane and coefficients:Aν(j), Bν(j) and aν(j), bν(j): R0,ν(ρ,t) = - 1 (3 cos2ρ - 1)A(ν0)- 1sin2ρA(ν1)- 1sin2ρA(ν2), 6 2 4 1 ( ) 1 1 r0,ν(ρ,t) = -- 3cos2ρ- 1 a(ν0)- -sin2ρa(1ν)- - sin2 ρa(ν2), 6 2 4 ( ) R(1ɛ,ν)= sin 2ρ A (0ν)- 1A (2ν) - 2cos2ρA(ν1) + 2ɛ cos ρB(ν1) - ɛ sinρB (2ν), 2 ( 1 ) r(1ɛ,ν)= 2cosρb(ν1)- sinρb(2ν)- ɛsin2ρ a(0ν)- -a(ν2) + 2ɛcos2ρa(ν1), 2 (ɛ) ( 1 ) R2,ν = A(ν2)+ sin2ρ A(ν0)- 2A(ν2) - sin2ρA(ν1)+ 2ɛsinρB (ν1)+ ɛ cosρB (ν2), r2,ν(ɛ) = 2sinρbν(1) + cosρbν(2) - ɛaν(2) - ɛsin2ρ( (0) 1 (2)) aν - 2aν + ɛsin2ρaν(1) (ɛ = ±1). As particular case from our inclination functions of corresponding expression of Kinoshita's functions are obtained. In accordance with generalized Cassini-Colombo laws it inclination is evaluated as ρ= 2'1 on modern data of radiolocation of Mercury. First estimation of this parameter was about 1'6 (Barkin, 1984). Coefficients Aν(j), Bν(j) and aν(j), bν(j)with high accuracy have been presented as quadratic functions of the time which take into account secular planetary perturbations in the Mercury orbital motion (Kudrjavsev, 2009; Barkin, Kudrjavsev, Barkin, 2009): Aν(j) = Aν;0(j) + Aν;1(j) × t + Aν;2(j) × t2, A = (A,B,a,b), j = (0,1,2). These coefficients generalize similar Kinoshita's coefficients (in Earth rotation theory) and represent full and exact developments of following functions of heliocentric spherical coordinates of Mercury (r, φ and λ): 1( a)3(1 - 3sin2φ ) =Σ A(0)cos? +a(0)sin? , 2 r ν ν ν ν ν ( ) a-3cos2φ cos2 (λ - h) =Σ A (2)cos? ν + a(2)sin ?ν, r ν ν ν ( )3 Σ a- cos2φ sin2 (λ - h) = B (2ν)sin ?ν + b(ν2)cos?ν, r ν ( a)3 Σ -- sinφ cosφ sin (λ - h) = A (1ν)cos?ν + a(1ν)sin ?ν, r ν ( a)3 Σ (1) (1) r- sinφ cosφ cos(λ- h) = B ν sin?ν + bν cos?ν. ν The new expansions are valid over 2000 years, 1000AI 3000AD, have a form similar to that of Kinoshita's series. The latest long-term numerical ephemerides of the Moon and planets DE-406 are used as the source of disturbing bodies coordinates. The mentioned developments have been constructed not only for the problem about Mercury rotation but also for the problems about Earth rotation, Venus rotation and in theory of the Moon rotation (Kudrjavsev, 2009; Barkin, Kudrjavsev, Barkin, 2009). Corresponding developments of Kinoshita in the Earth rotation theory are obtained as particular case from above mentioned formulae by restricting conditions: r = a = b = 0. In the work we analize and evaluate amplitudes, frequencies and phases of solar tidal variations of coefficients of second harmonic of gravitational potential of Mercury. Also tidal perturbations of the Mercury axial rotation caused by variations of polar moment of inertia are determined and analized. The Barkin's work partially was financially accepted by Spanish grants, Japanese-Russian grant N-09-02-92113-JF and by RFBR grant N 08-02-00367.

New Spectroscopic Solution of the Eclipsing Binary HX Vel A

NASA Astrophysics Data System (ADS)

Sürgit, D.; Erdem, A.; Özkardeş, B.; Butland, R.; Budding, E.

2015-07-01

We present a preliminary analysis of new spectroscopic observations of the southern binary HX Vel A. High-resolution spectroscopic observations were made at the Mt. John University Observatory in 2014. Radial velocities for HX Vel A were determined from the Gaussian profile-fitting method. The Keplerian radial velocity model gives the close binary mass ratio as 0.57±0.06. The resulting orbital elements are a1sin i=0.0086 ±0.0003 au, a2sin i=0.0151 ±0.0003 au, M1 sin3i =0.887 ±0.046 M⊙, and M2 sin3i =0.504 ±0.032 M⊙.

Fixed interface charges between AlGaN barrier and gate stack composed of in situ grown SiN and Al{sub 2}O{sub 3} in AlGaN/GaN high electron mobility transistors with normally off capability

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

Capriotti, M., E-mail: mattia.capriotti@tuwien.ac.at; Alexewicz, A.; Fleury, C.

2014-03-17

Using a generalized extraction method, the fixed charge density N{sub int} at the interface between in situ deposited SiN and 5 nm thick AlGaN barrier is evaluated by measurements of threshold voltage V{sub th} of an AlGaN/GaN metal insulator semiconductor high electron mobility transistor as a function of SiN thickness. The thickness of the originally deposited 50 nm thick SiN layer is reduced by dry etching. The extracted N{sub int} is in the order of the AlGaN polarization charge density. The total removal of the in situ SiN cap leads to a complete depletion of the channel region resulting in V{sub th} = +1 V.more » Fabrication of a gate stack with Al{sub 2}O{sub 3} as a second cap layer, deposited on top of the in situ SiN, is not introducing additional fixed charges at the SiN/Al{sub 2}O{sub 3} interface.« less

Regulating Toxin-Antitoxin Expression: Controlled Detonation of Intracellular Molecular Timebombs

PubMed Central

Hayes, Finbarr; Kędzierska, Barbara

2014-01-01

Genes for toxin-antitoxin (TA) complexes are widely disseminated in bacteria, including in pathogenic and antibiotic resistant species. The toxins are liberated from association with the cognate antitoxins by certain physiological triggers to impair vital cellular functions. TAs also are implicated in antibiotic persistence, biofilm formation, and bacteriophage resistance. Among the ever increasing number of TA modules that have been identified, the most numerous are complexes in which both toxin and antitoxin are proteins. Transcriptional autoregulation of the operons encoding these complexes is key to ensuring balanced TA production and to prevent inadvertent toxin release. Control typically is exerted by binding of the antitoxin to regulatory sequences upstream of the operons. The toxin protein commonly works as a transcriptional corepressor that remodels and stabilizes the antitoxin. However, there are notable exceptions to this paradigm. Moreover, it is becoming clear that TA complexes often form one strand in an interconnected web of stress responses suggesting that their transcriptional regulation may prove to be more intricate than currently understood. Furthermore, interference with TA gene transcriptional autoregulation holds considerable promise as a novel antibacterial strategy: artificial release of the toxin factor using designer drugs is a potential approach to induce bacterial suicide from within. PMID:24434949

Zeb2 recruits HDAC-NuRD to inhibit Notch and controls Schwann cell differentiation and remyelination.

PubMed

Wu, Lai Man Natalie; Wang, Jincheng; Conidi, Andrea; Zhao, Chuntao; Wang, Haibo; Ford, Zachary; Zhang, Liguo; Zweier, Christiane; Ayee, Brian G; Maurel, Patrice; Zwijsen, An; Chan, Jonah R; Jankowski, Michael P; Huylebroeck, Danny; Lu, Q Richard

2016-08-01

The mechanisms that coordinate and balance a complex network of opposing regulators to control Schwann cell (SC) differentiation remain elusive. Here we demonstrate that zinc-finger E-box-binding homeobox 2 (Zeb2, also called Sip1) transcription factor is a critical intrinsic timer that controls the onset of SC differentiation by recruiting histone deacetylases HDAC 1 and 2 (HDAC1/2) and nucleosome remodeling and deacetylase complex (NuRD) co-repressor complexes in mice. Zeb2 deletion arrests SCs at an undifferentiated state during peripheral nerve development and inhibits remyelination after injury. Zeb2 antagonizes inhibitory effectors including Notch and Sox2. Importantly, genome-wide transcriptome analysis reveals a Zeb2 target gene encoding the Notch effector Hey2 as a potent inhibitor for Schwann cell differentiation. Strikingly, a genetic Zeb2 variant associated with Mowat-Wilson syndrome disrupts the interaction with HDAC1/2-NuRD and abolishes Zeb2 activity for SC differentiation. Therefore, Zeb2 controls SC maturation by recruiting HDAC1/2-NuRD complexes and inhibiting a Notch-Hey2 signaling axis, pointing to the critical role of HDAC1/2-NuRD activity in peripheral neuropathies caused by ZEB2 mutations.

Sensory-Cognitive Interaction in the Neural Encoding of Speech in Noise: A Review

PubMed Central

Anderson, Samira; Kraus, Nina

2011-01-01

Background Speech-in-noise (SIN) perception is one of the most complex tasks faced by listeners on a daily basis. Although listening in noise presents challenges for all listeners, background noise inordinately affects speech perception in older adults and in children with learning disabilities. Hearing thresholds are an important factor in SIN perception, but they are not the only factor. For successful comprehension, the listener must perceive and attend to relevant speech features, such as the pitch, timing, and timbre of the target speaker’s voice. Here, we review recent studies linking SIN and brainstem processing of speech sounds. Purpose To review recent work that has examined the ability of the auditory brainstem response to complex sounds (cABR), which reflects the nervous system’s transcription of pitch, timing, and timbre, to be used as an objective neural index for hearing-in-noise abilities. Study Sample We examined speech-evoked brainstem responses in a variety of populations, including children who are typically developing, children with language-based learning impairment, young adults, older adults, and auditory experts (i.e., musicians). Data Collection and Analysis In a number of studies, we recorded brainstem responses in quiet and babble noise conditions to the speech syllable /da/ in all age groups, as well as in a variable condition in children in which /da/ was presented in the context of seven other speech sounds. We also measured speech-in-noise perception using the Hearing-in-Noise Test (HINT) and the Quick Speech-in-Noise Test (QuickSIN). Results Children and adults with poor SIN perception have deficits in the subcortical spectrotemporal representation of speech, including low-frequency spectral magnitudes and the timing of transient response peaks. Furthermore, auditory expertise, as engendered by musical training, provides both behavioral and neural advantages for processing speech in noise. Conclusions These results have implications for future assessment and management strategies for young and old populations whose primary complaint is difficulty hearing in background noise. The cABR provides a clinically applicable metric for objective assessment of individuals with SIN deficits, for determination of the biologic nature of disorders affecting SIN perception, for evaluation of appropriate hearing aid algorithms, and for monitoring the efficacy of auditory remediation and training. PMID:21241645

Role of the Neddylation Enzyme Uba3, A New Estrogen Receptor Corepressor, in Breast Cancer

DTIC Science & Technology

2005-05-01

Nawaz Z, Lonard DM, Dennis AP, Smith CL, O’Malley BW position 3997, within the intron); reverse primer, 5’- ACCA - 1999 Proteasome-dependent degradation of...ERE) and control reporter constructs for the functional analyses of ERa. could account for this discrepancy. In the present study, an estrogen...pathways. Huang). The costs of publication of this article were defrayed in part by the payment of page In this study, we investigated whether the removal

Core Histones and HIRIP3, a Novel Histone-Binding Protein, Directly Interact with WD Repeat Protein HIRA

PubMed Central

Lorain, Stéphanie; Quivy, Jean-Pierre; Monier-Gavelle, Frédérique; Scamps, Christine; Lécluse, Yann; Almouzni, Geneviève; Lipinski, Marc

1998-01-01

The human HIRA gene has been named after Hir1p and Hir2p, two corepressors which together appear to act on chromatin structure to control gene transcription in Saccharomyces cerevisiae. HIRA homologs are expressed in a regulated fashion during mouse and chicken embryogenesis, and the human gene is a major candidate for the DiGeorge syndrome and related developmental disorders caused by a reduction to single dose of a fragment of chromosome 22q. Western blot analysis and double-immunofluorescence experiments using a specific antiserum revealed a primary nuclear localization of HIRA. Similar to Hir1p, HIRA contains seven amino-terminal WD repeats and probably functions as part of a multiprotein complex. HIRA and core histone H2B were found to physically interact in a yeast double-hybrid protein interaction trap, in GST pull-down assays, and in coimmunoprecipitation experiments performed from cellular extracts. In vitro, HIRA also interacted with core histone H4. H2B- and H4-binding domains were overlapping but distinguishable in the carboxy-terminal region of HIRA, and the region for HIRA interaction was mapped to the amino-terminal tail of H2B and the second α helix of H4. HIRIP3 (HIRA-interacting protein 3) is a novel gene product that was identified from its HIRA-binding properties in the yeast protein interaction trap. In vitro, HIRIP3 directly interacted with HIRA but also with core histones H2B and H3, suggesting that a HIRA-HIRIP3-containing complex could function in some aspects of chromatin and histone metabolism. Insufficient production of HIRA, which we report elsewhere interacts with homeodomain-containing DNA-binding factors during mammalian embryogenesis, could perturb the stoichiometric assembly of multimolecular complexes required for normal embryonic development. PMID:9710638

THE POSTERIOR DISTRIBUTION OF sin(i) VALUES FOR EXOPLANETS WITH M{sub T} sin(i) DETERMINED FROM RADIAL VELOCITY DATA

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

Ho, Shirley; Turner, Edwin L., E-mail: cwho@lbl.gov

2011-09-20

Radial velocity (RV) observations of an exoplanet system giving a value of M{sub T} sin(i) condition (i.e., give information about) not only the planet's true mass M{sub T} but also the value of sin(i) for that system (where i is the orbital inclination angle). Thus, the value of sin(i) for a system with any particular observed value of M{sub T} sin(i) cannot be assumed to be drawn randomly from a distribution corresponding to an isotropic i distribution, i.e., the presumptive prior distribution. Rather, the posterior distribution from which it is drawn depends on the intrinsic distribution of M{sub T} formore » the exoplanet population being studied. We give a simple Bayesian derivation of this relationship and apply it to several 'toy models' for the intrinsic distribution of M{sub T} , on which we have significant information from available RV data in some mass ranges but little or none in others. The results show that the effect can be an important one. For example, even for simple power-law distributions of M{sub T} , the median value of sin(i) in an observed RV sample can vary between 0.860 and 0.023 (as compared to the 0.866 value for an isotropic i distribution) for indices of the power law in the range between -2 and +1, respectively. Over the same range of indices, the 95% confidence interval on M{sub T} varies from 1.0001-2.405 ({alpha} = -2) to 1.13-94.34 ({alpha} = +2) times larger than M{sub T} sin(i) due to sin(i) uncertainty alone. More complex, but still simple and plausible, distributions of M{sub T} yield more complicated and somewhat unintuitive posterior sin(i) distributions. In particular, if the M{sub T} distribution contains any characteristic mass scale M{sub c} , the posterior sin(i) distribution will depend on the ratio of M{sub T} sin(i) to M{sub c} , often in a non-trivial way. Our qualitative conclusion is that RV studies of exoplanets, both individual objects and statistical samples, should regard the sin(i) factor as more than a 'numerical constant of order unity' with simple and well-understood statistical properties. We argue that reports of M{sub T} sin(i) determinations should be accompanied by a statement of the corresponding confidence bounds on M{sub T} at, say, the 95% level based on an explicitly stated assumed form of the true M{sub T} distribution in order to reflect more accurately the mass uncertainties associated with RV studies.« less

Development of a test battery for evaluating speech perception in complex listening environments.

PubMed

Brungart, Douglas S; Sheffield, Benjamin M; Kubli, Lina R

2014-08-01

In the real world, spoken communication occurs in complex environments that involve audiovisual speech cues, spatially separated sound sources, reverberant listening spaces, and other complicating factors that influence speech understanding. However, most clinical tools for assessing speech perception are based on simplified listening environments that do not reflect the complexities of real-world listening. In this study, speech materials from the QuickSIN speech-in-noise test by Killion, Niquette, Gudmundsen, Revit, and Banerjee [J. Acoust. Soc. Am. 116, 2395-2405 (2004)] were modified to simulate eight listening conditions spanning the range of auditory environments listeners encounter in everyday life. The standard QuickSIN test method was used to estimate 50% speech reception thresholds (SRT50) in each condition. A method of adjustment procedure was also used to obtain subjective estimates of the lowest signal-to-noise ratio (SNR) where the listeners were able to understand 100% of the speech (SRT100) and the highest SNR where they could detect the speech but could not understand any of the words (SRT0). The results show that the modified materials maintained most of the efficiency of the QuickSIN test procedure while capturing performance differences across listening conditions comparable to those reported in previous studies that have examined the effects of audiovisual cues, binaural cues, room reverberation, and time compression on the intelligibility of speech.

The Spinal Instability Neoplastic Score: Impact on Oncologic Decision-Making.

PubMed

Versteeg, Anne L; Verlaan, Jorrit-Jan; Sahgal, Arjun; Mendel, Ehud; Quraishi, Nasir A; Fourney, Daryl R; Fisher, Charles G

2016-10-15

Systematic literature review. To address the following questions in a systematic literature review: 1. How is spinal neoplastic instability defined or classified in the literature before and after the introduction of the Spinal Instability Neoplastic Score (SINS)? 2. How has SINS affected daily clinical practice? 3. Can SINS be used as a prognostic tool? Spinal neoplastic-related instability was defined in 2010 and simultaneously SINS was introduced as a novel tool with criteria agreed upon by expert consensus to assess the degree of spinal stability. PubMed, Embase, and clinical trial databases were searched with the key words "spinal neoplasm," "spinal instability," "spinal instability neoplastic score," and synonyms. Studies describing spinal neoplastic-related instability were eligible for inclusion. Primary outcomes included studies describing and/or defining neoplastic-related instability, SINS, and studies using SINS as a prognostic factor. The search identified 1414 articles, of which 51 met the inclusion criteria. No precise definition or validated assessment tool was used specific to spinal neoplastic-related instability prior to the introduction of SINS. Since the publication of SINS in 2010, the vast majority of the literature regarding spinal instability has used SINS to assess or describe instability. Twelve studies specifically investigated the prognostic value of SINS in patients who underwent radiotherapy or surgery. No consensus could be determined regarding the definition, assessment, or reporting of neoplastic-related instability before introduction of SINS. Defining spinal neoplastic-related instability and the introduction of SINS have led to improved uniform reporting within the spinal neoplastic literature. Currently, the prognostic value of SINS is controversial. N/A.

Reciprocity in Vector Acoustics

DTIC Science & Technology

2017-03-01

and a phase function that accounts for grid spacing, ψ̂m(kz) = −2 j √ jR0 2πk sin(kz zs) * , 1 − k2z k2 + - 1 4 e j kz dz 2 , (A.4) where the...Equation (A.4) becomes ψ̂v (kz) = −2 j √ jR0 2πk [ j Az sin(kz[zs + ∆z]) − j Az sin(kz[zs − ∆z]) ] * , 1 − k2z k2 + - 1 4 e j kz dz 2 (A.7) When this...sin(kz zs) + A3 sin(kz[zs + 2∆z]) +A4 sin(kz[zs + 4∆z]) ] * , 1 − k2z k2 + - 1 4 e j kz dz 2 . With this starter field, MMPE outputs pressure, radial

Myocardial motion estimation of tagged cardiac magnetic resonance images using tag motion constraints and multi-level b-splines interpolation.

PubMed

Liu, Hong; Yan, Meng; Song, Enmin; Wang, Jie; Wang, Qian; Jin, Renchao; Jin, Lianghai; Hung, Chih-Cheng

2016-05-01

Myocardial motion estimation of tagged cardiac magnetic resonance (TCMR) images is of great significance in clinical diagnosis and the treatment of heart disease. Currently, the harmonic phase analysis method (HARP) and the local sine-wave modeling method (SinMod) have been proven as two state-of-the-art motion estimation methods for TCMR images, since they can directly obtain the inter-frame motion displacement vector field (MDVF) with high accuracy and fast speed. By comparison, SinMod has better performance over HARP in terms of displacement detection, noise and artifacts reduction. However, the SinMod method has some drawbacks: 1) it is unable to estimate local displacements larger than half of the tag spacing; 2) it has observable errors in tracking of tag motion; and 3) the estimated MDVF usually has large local errors. To overcome these problems, we present a novel motion estimation method in this study. The proposed method tracks the motion of tags and then estimates the dense MDVF by using the interpolation. In this new method, a parameter estimation procedure for global motion is applied to match tag intersections between different frames, ensuring specific kinds of large displacements being correctly estimated. In addition, a strategy of tag motion constraints is applied to eliminate most of errors produced by inter-frame tracking of tags and the multi-level b-splines approximation algorithm is utilized, so as to enhance the local continuity and accuracy of the final MDVF. In the estimation of the motion displacement, our proposed method can obtain a more accurate MDVF compared with the SinMod method and our method can overcome the drawbacks of the SinMod method. However, the motion estimation accuracy of our method depends on the accuracy of tag lines detection and our method has a higher time complexity. Copyright © 2015 Elsevier Inc. All rights reserved.

A PRECISION MEASUREMENT OF THE NEUTRINO MIXING ANGLE THETA (SUB 13) USING REACTOR ANTINEUTRINOS AT DAYA BAY.

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

KETTELL, S.; ET AL.

2006-10-16

This document describes the design of the Daya Bay reactor neutrino experiment. Recent discoveries in neutrino physics have shown that the Standard Model of particle physics is incomplete. The observation of neutrino oscillations has unequivocally demonstrated that the masses of neutrinos are nonzero. The smallness of the neutrino masses (<2 eV) and the two surprisingly large mixing angles measured have thus far provided important clues and constraints to extensions of the Standard Model. The third mixing angle, {delta}{sub 13}, is small and has not yet been determined; the current experimental bound is sin{sup 2} 2{theta}{sub 13} < 0.17 at 90%more » confidence level (from Chooz) for {Delta}m{sub 31}{sup 2} = 2.5 x 10{sup -3} eV{sup 2}. It is important to measure this angle to provide further insight on how to extend the Standard Model. A precision measurement of sin{sup 2} 2{theta}{sub 13} using nuclear reactors has been recommended by the 2004 APS Multi-divisional Study on the Future of Neutrino Physics as well as a recent Neutrino Scientific Assessment Group (NUSAG) report. We propose to perform a precision measurement of this mixing angle by searching for the disappearance of electron antineutrinos from the nuclear reactor complex in Daya Bay, China. A reactor-based determination of sin{sup 2} 2{theta}{sub 13} will be vital in resolving the neutrino-mass hierarchy and future measurements of CP violation in the lepton sector because this technique cleanly separates {theta}{sub 13} from CP violation and effects of neutrino propagation in the earth. A reactor-based determination of sin{sup 2} 2{theta}{sub 13} will provide important, complementary information to that from long-baseline, accelerator-based experiments. The goal of the Daya Bay experiment is to reach a sensitivity of 0.01 or better in sin{sup 2} 2{theta}{sub 13} at 90% confidence level.« less

Direct Role for the Rpd3 Complex in Transcriptional Induction of the Anaerobic DAN/TIR Genes in Yeast▿‡

PubMed Central

Sertil, Odeniel; Vemula, Arvind; Salmon, Sharon L.; Morse, Randall H.; Lowry, Charles V.

2007-01-01

Saccharomyces cerevisiae adapts to hypoxia by expressing a large group of “anaerobic” genes. Among these, the eight DAN/TIR genes are regulated by the repressors Rox1 and Mot3 and the activator Upc2/Mox4. In attempting to identify factors recruited by the DNA binding repressor Mot3 to enhance repression of the DAN/TIR genes, we found that the histone deacetylase and global repressor complex, Rpd3-Sin3-Sap30, was not required for repression. Strikingly, the complex was instead required for activation. In addition, the histone H3 and H4 amino termini, which are targets of Rpd3, were also required for DAN1 expression. Epistasis tests demonstrated that the Rpd3 complex is not required in the absence of the repressor Mot3. Furthermore, the Rpd3 complex was required for normal function and stable binding of the activator Upc2 at the DAN1 promoter. Moreover, the Swi/Snf chromatin remodeling complex was strongly required for activation of DAN1, and chromatin immunoprecipitation analysis showed an Rpd3-dependent reduction in DAN1 promoter-associated nucleosomes upon induction. Taken together, these data provide evidence that during anaerobiosis, the Rpd3 complex acts at the DAN1 promoter to antagonize the chromatin-mediated repression caused by Mot3 and Rox1 and that chromatin remodeling by Swi/Snf is necessary for normal expression. PMID:17210643

Deacetylase activity of histone deacetylase 3 is required for productive VDJ recombination and B-cell development

PubMed Central

Stengel, Kristy R.; Barnett, Kelly R.; Wang, Jing; Liu, Qi; Hodges, Emily; Hiebert, Scott W.; Bhaskara, Srividya

2017-01-01

Histone deacetylase 3 (HDAC3) is the catalytic component of NCoR/SMRT corepressor complexes that mediate the actions of transcription factors implicated in the regulation of B-cell development and function. We crossed Hdac3 conditional knockout mice with Mb1-Cre knockin animals to delete Hdac3 in early progenitor B cells. The spleens of Hdac3F/−Mb1-Cre+/− mice were virtually devoid of mature B cells, and B220+CD43+ B-cell progenitors accumulated within the bone marrow. Quantitative deep sequencing of the Ig heavy chain locus from B220+CD43+ populations identified a defect in VHDJH recombination with a severe reduction in productive rearrangements, which directly corresponded to the loss of pre-B cells from Hdac3Δ/− bone marrow. For Hdac3Δ/− B cells that did show productive VDJ rearrangement, there was significant skewing toward the incorporation of proximal VH gene segments and a corresponding reduction in distal VH gene segment use. Although transcriptional effects within these loci were modest, Hdac3Δ/− progenitor cells displayed global changes in chromatin structure that likely hindered effective distal V-DJ recombination. Reintroduction of wild-type Hdac3 restored normal B-cell development, whereas an Hdac3 point mutant lacking deacetylase activity failed to complement this defect. Thus, the deacetylase activity of Hdac3 is required for the generation of mature B cells. PMID:28739911

Adaptor proteins GIR1 and GIR2. II. Interaction with the co-repressor TOPLESS and promotion of histone deacetylation of target chromatin.

PubMed

Wu, Renhong; Citovsky, Vitaly

2017-07-08

Understanding how root hair development is controlled is important for understanding of many fundamental aspects of plant biology. Previously, we identified two plant-specific adaptor proteins GIR1 and GIR2 that interact with the major regulator of root hair development GL2 and suppress formation of root hair. Here, we show that GIR1 and GIR2 also interact with the co-repressor TOPLESS (TPL). This interaction required the GIR1 protein EAR motif, and was essential for the transcriptional repressor activity of GIR1. Both GIR1 and GIR2 promoted histone hypoacetylation of their target chromatin. Potentially, GIR1 and GIR2 might may link TPL to and participate in epigenetic regulation of root hair development. Copyright © 2017 Elsevier Inc. All rights reserved.

Cdyl: a new transcriptional co-repressor

PubMed Central

Caron, Cécile; Pivot-Pajot, Christophe; van Grunsven, Leo A.; Col, Edwige; Lestrat, Cécile; Rousseaux, Sophie; Khochbin, Saadi

2003-01-01

Cdyl (chromodomain-Y-like) is a chromodomain-containing protein that is predominantly expressed during mouse spermiogenesis. In its carboxy-terminal portion, there is a domain with homology to the coenzyme A (CoA) pocket of the enoyl-CoA hydratase/isomerase, which is shown here to be able to bind CoA and histone deacetylases (HDACs). It also efficiently represses transcription. Moreover, the binding of Hdac1 represses the ability of Cdyl to bind CoA, and a Cdyl–CoA interaction only occurs in the absence of HDACs. These data suggest that Cdyl is primarily a transcriptional co-repressor. However, the degradation of cellular Hdac1 and Hdac2, as observed here in the elongating spermatids, may provide an HDAC-free environment in which Cdyl could bind CoA and participate in the global chromatin remodelling that occurs in these cells. PMID:12947414

DAX1 suppresses FXR transactivity as a novel co-repressor

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

Li, Jin; Lu, Yan; Liu, Ruya

2011-09-09

Highlights: {yields} DAX1 is co-localized with FXR and interacts with FXR. {yields} DAX1 acts as a negative regulator of FXR. {yields} Three LXXLL motifs in the N-terminus of DAX1 were required. {yields} DAX1 suppresses FXR transactivation by competing with co-activators. -- Abstract: Bile acid receptor FXR (farnesoid X receptor) is a key regulator of hepatic bile acid, glucose and lipid homeostasis through regulation of numerous genes involved in the process of bile acid, triglyceride and glucose metabolism. DAX1 (dosage-sensitive sex reversal adrenal hypoplasia congenital critical region on X chromosome, gene 1) is an atypical member of the nuclear receptor familymore » due to lack of classical DNA-binding domains and acts primarily as a co-repressor of many nuclear receptors. Here, we demonstrated that DAX1 is co-localized with FXR in the nucleus and acted as a negative regulator of FXR through a physical interaction with FXR. Our study showed that over-expression of DAX1 down-regulated the expression of FXR target genes, whereas knockdown of DAX1 led to their up-regulation. Furthermore, three LXXLL motifs in the N-terminus of DAX1 were required for the full repression of FXR transactivation. In addition, our study characterized that DAX1 suppresses FXR transactivation via competing with co-activators such as SRC-1 and PGC-1{alpha}. In conclusion, DAX1 acts as a co-repressor to negatively modulate FXR transactivity.« less

The Corepressor NCoR1 Antagonizes PGC-1α and Estrogen-Related Receptor α in the Regulation of Skeletal Muscle Function and Oxidative Metabolism

PubMed Central

Pérez-Schindler, Joaquín; Summermatter, Serge; Salatino, Silvia; Zorzato, Francesco; Beer, Markus; Balwierz, Piotr J.; van Nimwegen, Erik; Feige, Jérôme N.; Auwerx, Johan

2012-01-01

Skeletal muscle exhibits a high plasticity and accordingly can quickly adapt to different physiological and pathological stimuli by changing its phenotype largely through diverse epigenetic mechanisms. The nuclear receptor corepressor 1 (NCoR1) has the ability to mediate gene repression; however, its role in regulating biological programs in skeletal muscle is still poorly understood. We therefore studied the mechanistic and functional aspects of NCoR1 function in this tissue. NCoR1 muscle-specific knockout mice exhibited a 7.2% higher peak oxygen consumption (VO2peak), a 11% reduction in maximal isometric force, and increased ex vivo fatigue resistance during maximal stimulation. Interestingly, global gene expression analysis revealed a high overlap between the effects of NCoR1 deletion and peroxisome proliferator-activated receptor gamma (PPARγ) coactivator 1α (PGC-1α) overexpression on oxidative metabolism in muscle. Importantly, PPARβ/δ and estrogen-related receptor α (ERRα) were identified as common targets of NCoR1 and PGC-1α with opposing effects on the transcriptional activity of these nuclear receptors. In fact, the repressive effect of NCoR1 on oxidative phosphorylation gene expression specifically antagonizes PGC-1α-mediated coactivation of ERRα. We therefore delineated the molecular mechanism by which a transcriptional network controlled by corepressor and coactivator proteins determines the metabolic properties of skeletal muscle, thus representing a potential therapeutic target for metabolic diseases. PMID:23028049

Proteomic identification of Profilin1 as a corepressor of estrogen receptor alpha in MCF7 breast cancer cells.

PubMed

Kanaujiya, Jitendra Kumar; Lochab, Savita; Kapoor, Isha; Pal, Pooja; Datta, Dipak; Bhatt, Madan L B; Sanyal, Sabyasachi; Behre, Gerhard; Trivedi, Arun Kumar

2013-07-01

Nuclear receptor coregulators play an important role in the transcriptional regulation of nuclear receptors. In the present study, we aimed to identify estrogen receptor α (ERα) interacting proteins in Tamoxifen treated MCF7 cells. Using in vitro GST-pull down assay with ERα ligand-binding domain (ERα-LBD) and MS-based proteomics approach we identified Profilin1 as a novel ERα interacting protein. Profilin1 contains I/LXX/L/H/I amino acid signature motif required for corepressor interaction with ERα. We show that these two proteins physically interact with each other both in vitro as well as in vivo by GST-pull down and coimmunoprecipitation, respectively. We further show that these two proteins also colocalize together in the nucleus. Previous studies have reported reduced expression of Profilin1 in breast cancer; and here we found that Tamoxifen increases Profilin1 expression in MCF7 cells. Our data demonstrate that over expression of Profilin1 inhibits ERα-mediated transcriptional activation as well as its downstream target genes in ERα positive breast cancer cells MCF7. In addition, Profilin1 overexpression in MCF7 cells leads to inhibition of cell proliferation that apparently is due to enhanced apoptosis. In nutshell, these data indicate that MS-based proteomics approach identifies a novel ERα interacting protein Profilin1 that serves as a putative corepressor of ERα functions. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

hnRNP K Coordinates Transcriptional Silencing by SETDB1 in Embryonic Stem Cells

PubMed Central

Thompson, Peter J.; Dulberg, Vered; Moon, Kyung-Mee; Foster, Leonard J.; Chen, Carol; Karimi, Mohammad M.; Lorincz, Matthew C.

2015-01-01

Retrotransposition of endogenous retroviruses (ERVs) poses a substantial threat to genome stability. Transcriptional silencing of a subset of these parasitic elements in early mouse embryonic and germ cell development is dependent upon the lysine methyltransferase SETDB1, which deposits H3K9 trimethylation (H3K9me3) and the co-repressor KAP1, which binds SETDB1 when SUMOylated. Here we identified the transcription co-factor hnRNP K as a novel binding partner of the SETDB1/KAP1 complex in mouse embryonic stem cells (mESCs) and show that hnRNP K is required for ERV silencing. RNAi-mediated knockdown of hnRNP K led to depletion of H3K9me3 at ERVs, concomitant with de-repression of proviral reporter constructs and specific ERV subfamilies, as well as a cohort of germline-specific genes directly targeted by SETDB1. While hnRNP K recruitment to ERVs is dependent upon KAP1, SETDB1 binding at these elements requires hnRNP K. Furthermore, an intact SUMO conjugation pathway is necessary for SETDB1 recruitment to proviral chromatin and depletion of hnRNP K resulted in reduced SUMOylation at ERVs. Taken together, these findings reveal a novel regulatory hierarchy governing SETDB1 recruitment and in turn, transcriptional silencing in mESCs. PMID:25611934

Study on UKF based federal integrated navigation for high dynamic aviation

NASA Astrophysics Data System (ADS)

Zhao, Gang; Shao, Wei; Chen, Kai; Yan, Jie

2011-08-01

High dynamic aircraft is a very attractive new generation vehicles, in which provides near space aviation with large flight envelope both speed and altitude, for example the hypersonic vehicles. The complex flight environments for high dynamic vehicles require high accuracy and stability navigation scheme. Since the conventional Strapdown Inertial Navigation System (SINS) and Global Position System (GPS) federal integrated scheme based on EKF (Extended Kalman Filter) is invalidation in GPS single blackout situation because of high speed flight, a new high precision and stability integrated navigation approach is presented in this paper, in which the SINS, GPS and Celestial Navigation System (CNS) is combined as a federal information fusion configuration based on nonlinear Unscented Kalman Filter (UKF) algorithm. Firstly, the new integrated system state error is modeled. According to this error model, the SINS system is used as the navigation solution mathematic platform. The SINS combine with GPS constitute one error estimation filter subsystem based on UKF to obtain local optimal estimation, and the SINS combine with CNS constitute another error estimation subsystem. A non-reset federated configuration filter based on partial information is proposed to fuse two local optimal estimations to get global optimal error estimation, and the global optimal estimation is used to correct the SINS navigation solution. The χ 2 fault detection method is used to detect the subsystem fault, and the fault subsystem is isolation through fault interval to protect system away from the divergence. The integrated system takes advantages of SINS, GPS and CNS to an immense improvement for high accuracy and reliably high dynamic navigation application. Simulation result shows that federated fusion of using GPS and CNS to revise SINS solution is reasonable and availably with good estimation performance, which are satisfied with the demands of high dynamic flight navigation. The UKF is superior than EKF based integrated scheme, in which has smaller estimation error and quickly convergence rate.

Atomic Layer Deposition of Wet-Etch Resistant Silicon Nitride Using Di(sec-butylamino)silane and N2 Plasma on Planar and 3D Substrate Topographies.

PubMed

Faraz, Tahsin; van Drunen, Maarten; Knoops, Harm C M; Mallikarjunan, Anupama; Buchanan, Iain; Hausmann, Dennis M; Henri, Jon; Kessels, Wilhelmus M M

2017-01-18

The advent of three-dimensional (3D) finFET transistors and emergence of novel memory technologies place stringent requirements on the processing of silicon nitride (SiN x ) films used for a variety of applications in device manufacturing. In many cases, a low temperature (<400 °C) deposition process is desired that yields high quality SiN x films that are etch resistant and also conformal when grown on 3D substrate topographies. In this work, we developed a novel plasma-enhanced atomic layer deposition (PEALD) process for SiN x using a mono-aminosilane precursor, di(sec-butylamino)silane (DSBAS, SiH 3 N( s Bu) 2 ), and N 2 plasma. Material properties have been analyzed over a wide stage temperature range (100-500 °C) and compared with those obtained in our previous work for SiN x deposited using a bis-aminosilane precursor, bis(tert-butylamino)silane (BTBAS, SiH 2 (NH t Bu) 2 ), and N 2 plasma. Dense films (∼3.1 g/cm 3 ) with low C, O, and H contents at low substrate temperatures (<400 °C) were obtained on planar substrates for this process when compared to other processes reported in the literature. The developed process was also used for depositing SiN x films on high aspect ratio (4.5:1) 3D trench nanostructures to investigate film conformality and wet-etch resistance (in dilute hydrofluoric acid, HF/H 2 O = 1:100) relevant for state-of-the-art device architectures. Film conformality was below the desired levels of >95% and attributed to the combined role played by nitrogen plasma soft saturation, radical species recombination, and ion directionality during SiN x deposition on 3D substrates. Yet, very low wet-etch rates (WER ≤ 2 nm/min) were observed at the top, sidewall, and bottom trench regions of the most conformal film deposited at low substrate temperature (<400 °C), which confirmed that the process is applicable for depositing high quality SiN x films on both planar and 3D substrate topographies.

Investigation of silicon surface passivation by silicon nitride film deposition

NASA Technical Reports Server (NTRS)

Olsen, L. C.

1984-01-01

The use of Sin sub x grown by plasma enhanced chemical vapor deposition (PECVO) for passivating silicon surfaces was studied. The application of PECVO SiN sub x films for passivations of silicon N+/P or P+/N solar cells is of particular interest. This program has involved the following areas of investigation: (1) Establishment of PECVO system and development of procedures for growth of SiN sub x; (2) Optical characterization of SiN sub x films; (3) Characterization of the SiN sub x/Si interface; (4) Surface recombination velocity deduced from photoresponse; (5) Current-Voltage analyses of silicon N+/P cells; and (6) Gated diode device studies.

A novel mechanism by which hepatocyte growth factor blocks tubular epithelial to mesenchymal transition.

PubMed

Yang, Junwei; Dai, Chunsun; Liu, Youhua

2005-01-01

Hepatocyte growth factor (HGF) is a potent antifibrotic cytokine that blocks tubular epithelial to mesenchymal transition (EMT) induced by TGF-beta1. However, the underlying mechanism remains largely unknown. This study investigated the signaling events that lead to HGF blockade of the TGF-beta1-initiated EMT. Incubation of human kidney epithelial cells HKC with HGF only marginally affected the expression of TGF-beta1 and its type I and type II receptors, suggesting that disruption of TGF-beta1 signaling likely plays a critical role in mediating HGF inhibition of TGF-beta1 action. However, HGF neither affected TGF-beta1-induced Smad-2 phosphorylation and its subsequent nuclear translocation nor influenced the expression of inhibitory Smad-6 and -7 in tubular epithelial cells. HGF specifically induced the expression of Smad transcriptional co-repressor SnoN but not Ski and TG-interacting factor at both mRNA and protein levels in HKC cells. SnoN physically interacted with activated Smad-2 by forming transcriptionally inactive complex and overrode the profibrotic action of TGF-beta1. In vivo, HGF did not affect Smad-2 activation and its nuclear accumulation in tubular epithelium, but it restored SnoN protein abundance in the fibrotic kidney in obstructive nephropathy. Hence, HGF blocks EMT by antagonizing TGF-beta1's action via upregulating Smad transcriptional co-repressor SnoN expression. These findings not only identify a novel mode of interaction between the signals activated by HGF receptor tyrosine kinase and TGF-beta receptor serine/threonine kinases but also illustrate the feasibility of confining Smad activity as an effective strategy for blocking renal fibrosis.

Thyroid hormone and COUP-TF1 regulate kallikrein-binding protein (KBP) gene expression.

PubMed

Liu, Yan-Yun; Nakatani, Teruyo; Kogai, Takahiko; Mody, Kaizeen; Brent, Gregory A

2011-03-01

Kallikrein-binding protein (KBP) is a component of the kallikrein-kinin system that mediates vasodilation and inhibits tumor growth by antagonizing vascular endothelial growth factor-mediated angiogenesis. We demonstrate that KBP gene expression is repressed by T(3) and modulated by the orphan nuclear receptor, chicken ovalbumin upstream promoter transcription factor 1 (COUP-TF1). In hypothyroid mice, KBP mRNA expression in the testis was increased 2.1-fold compared with euthyroid mice. We have identified two negative thyroid hormone response elements (nTREs) in the mouse KBP gene, nTRE1 located in the 5' flanking region (-53 to -29) and nTRE2, located in the first intron (104-132). We used functional assays, cofactor knockdown, and chromatin immunoprecipitation assays to characterize nTRE1 and nTRE2 in hepatic (HepG2) and testes (GC-1spg) cell lines. Reporter expression directed by both elements was enhanced with addition of thyroid hormone receptor and repressed with the addition of T(3). COUP-TF1 enhanced basal expression of both elements but blunted unliganded thyroid hormone receptor enhancement and T(3) repression of nTRE1 but not nTRE2. Both nTREs bound nuclear corepressor and binding increased in response to T(3). Nuclear corepressor knockdown resulted in loss of T(3) repression of both nTRE1 and nTRE2. COUP-TF1, which usually represses T(3) induction of positive thyroid hormone response elements, reverses T(3) repression mediated by nTRE1 in the mouse KBP gene. Endogenous KBP expression is repressed by T(3) and two functional nTREs, both of which are required, have been characterized in the KBP gene. COUP-TF1 may be an important factor to modulate expression of genes that are repressed by T(3).

Thyroid Hormone and COUP-TF1 Regulate Kallikrein-Binding Protein (KBP) Gene Expression

PubMed Central

Liu, Yan-Yun; Nakatani, Teruyo; Kogai, Takahiko; Mody, Kaizeen

2011-01-01

Kallikrein-binding protein (KBP) is a component of the kallikrein-kinin system that mediates vasodilation and inhibits tumor growth by antagonizing vascular endothelial growth factor-mediated angiogenesis. We demonstrate that KBP gene expression is repressed by T3 and modulated by the orphan nuclear receptor, chicken ovalbumin upstream promoter transcription factor 1 (COUP-TF1). In hypothyroid mice, KBP mRNA expression in the testis was increased 2.1-fold compared with euthyroid mice. We have identified two negative thyroid hormone response elements (nTREs) in the mouse KBP gene, nTRE1 located in the 5′ flanking region (−53 to −29) and nTRE2, located in the first intron (104–132). We used functional assays, cofactor knockdown, and chromatin immunoprecipitation assays to characterize nTRE1 and nTRE2 in hepatic (HepG2) and testes (GC-1spg) cell lines. Reporter expression directed by both elements was enhanced with addition of thyroid hormone receptor and repressed with the addition of T3. COUP-TF1 enhanced basal expression of both elements but blunted unliganded thyroid hormone receptor enhancement and T3 repression of nTRE1 but not nTRE2. Both nTREs bound nuclear corepressor and binding increased in response to T3. Nuclear corepressor knockdown resulted in loss of T3 repression of both nTRE1 and nTRE2. COUP-TF1, which usually represses T3 induction of positive thyroid hormone response elements, reverses T3 repression mediated by nTRE1 in the mouse KBP gene. Endogenous KBP expression is repressed by T3 and two functional nTREs, both of which are required, have been characterized in the KBP gene. COUP-TF1 may be an important factor to modulate expression of genes that are repressed by T3. PMID:21266512

Inactivation of the small GTP binding protein Rho induces multinucleate cell formation and apoptosis in murine T lymphoma EL4.

PubMed

Moorman, J P; Bobak, D A; Hahn, C S

1996-06-01

The small G-protein Rho regulates the actin microfilament-dependent cytoskeleton. Exoenzyme C3 of Clostridium botulinum ADP-ribosylates Rho at Asn41, a modification that functionally inactivates Rho. Using a Sindbis virus-based transient gene expression system, we studied the role of Rho in murine EL4 T lymphoma cells. We generated a double subgenomic infectious Sindbis virus (dsSIN:C3) recombinant which expressed C3 in >95% of EL4 cells. This intracellular C3 resulted in modification and inactivation of virtually all endogenous Rho. dsSIN:C3 infection led to the formation of multinucleate cells, likely by inhibiting the actin microfilament-dependent step of cytokinesis. Intriguingly, in spite of the inhibition of cytokinesis, karyokinesis continued, with the result that cells containing a nuclear DNA content as high as 16N (eight nuclei) were observed. In addition, dsSIN:C3-mediated inactivation of Rho was a potent activator of apoptosis in EL4 cells. To discern whether the formation of multinucleate cells was responsible for the activation of apoptosis, 5-fluorouracil (5-FUra) was used to induce cell cycle arrest. As expected, EL4 cells treated with 5-FUra were prevented from forming multinucleate cells upon infection with dsSIN:C3. dsSIN:C3 infection, however, still caused marked apoptosis in 5-FUra-treated cells, indicating that this activation of apoptosis was independent of multinucleate cell formation.

Differential effects of peroxynitrite on contractile protein properties in fast- and slow-twitch skeletal muscle fibers of rat.

PubMed

Dutka, T L; Mollica, J P; Lamb, G D

2011-03-01

Oxidative modification of contractile proteins is thought to be a key factor in muscle weakness observed in many pathophysiological conditions. In particular, peroxynitrite (ONOO(-)), a potent short-lived oxidant, is a likely candidate responsible for this contractile dysfunction. In this study ONOO(-) or 3-morpholinosydnonimine (Sin-1, a ONOO(-) donor) was applied to rat skinned muscle fibers to characterize the effects on contractile properties. Both ONOO(-) and Sin-1 exposure markedly reduced maximum force in slow-twitch fibers but had much less effect in fast-twitch fibers. The rate of isometric force development was also reduced without change in the number of active cross bridges. Sin-1 exposure caused a disproportionately large decrease in Ca(2+) sensitivity, evidently due to coproduction of superoxide, as it was prevented by Tempol, a superoxide dismutase mimetic. The decline in maximum force with Sin-1 and ONOO(-) treatments could be partially reversed by DTT, provided it was applied before the fiber was activated. Reversal by DTT indicates that the decrease in maximum force was due at least in part to oxidation of cysteine residues. Ascorbate caused similar reversal, further suggesting that the cysteine residues had undergone S-nitrosylation. The reduction in Ca(2+) sensitivity, however, was not reversed by either DTT or ascorbate. Western blot analysis showed cross-linking of myosin heavy chain (MHC) I, appearing as larger protein complexes after ONOO(-) exposure. The findings suggest that ONOO(-) initially decreases maximum force primarily by oxidation of cysteine residues on the myosin heads, and that the accompanying decrease in Ca(2+) sensitivity is likely due to other, less reversible actions of hydroxyl or related radicals.

ING2 is upregulated in colon cancer and increases invasion by enhanced MMP13 expression

PubMed Central

Kumamoto, Kensuke; Fujita, Kaori; Kurotani, Reiko; Saito, Motonobu; Unoki, Motoko; Hagiwara, Nobutoshi; Shiga, Hideaki; Bowman, Elise D.; Yanaihara, Nozomu; Okamura, Shu; Nagashima, Makoto; Miyamoto, Kotaro; Takenoshita, Seiichi; Yokota, Jun; Harris, Curtis C.

2009-01-01

Inhibitor of growth 2 (ING2) is associated with chromatin remodeling and regulation of gene expression by binding to a methylated histone H3K4 residue and recruiting HDAC complexes to the region. The aim of our study is to investigate the regulation of ING2 expression and the clinical significance of upregulated ING2 in colon cancer. Here, we show that the ING2 mRNA level in colon cancer tissue increased to more than twice than that in normal mucosa in the 45% of colorectal cancer cases that we examined. A putative NF-κB binding site was found in the ING2 promoter region. We confirmed that NF-κB could bind to the ING2 promoter by EMSA and luciferase assays. Subsequent microarray analyses revealed that ING2 upregulates expression of matrix metalloproteinase 13 (MMP13), which enhances cancer invasion and metastasis. ING2 regulation of MMP13 expression was confirmed in both ING2 overexpression and knock down experiments. MMP13 expression was further induced by coexpression of ING2 with HDAC1 or with mSin3A, suggesting that the ING2-HDAC1-mSin3A complex members regulates expression of MMP13. In vitro invasion assay was performed to determine functional significance of ING2 upregulation. ING2 overexpressed cells exhibited greater invasive potential. Taken together, upregulation of ING2 was associated with colon cancer and MMP13-dependent cellular invasion, indicating that ING2 expression might be involved with cancer invasion and metastasis. PMID:19437536

Cavity-enhanced measurements for determining dielectric-membrane thickness and complex index of refraction.

PubMed

Stambaugh, Corey; Durand, Mathieu; Kemiktarak, Utku; Lawall, John

2014-08-01

The material properties of silicon nitride (SiN) play an important role in the performance of SiN membranes used in optomechanical applications. An optimum design of a subwavelength high-contrast grating requires accurate knowledge of the membrane thickness and index of refraction, and its performance is ultimately limited by material absorption. Here we describe a cavity-enhanced method to measure the thickness and complex index of refraction of dielectric membranes with small, but nonzero, absorption coefficients. By determining Brewster's angle and an angle at which reflection is minimized by means of destructive interference, both the real part of the index of refraction and the sample thickness can be measured. A comparison of the losses in the empty cavity and the cavity containing the dielectric sample provides a measurement of the absorption.

Somatic mutations in the transcriptional corepressor gene BCORL1 in adult acute myelogenous leukemia.

PubMed

Li, Meng; Collins, Roxane; Jiao, Yuchen; Ouillette, Peter; Bixby, Dale; Erba, Harry; Vogelstein, Bert; Kinzler, Kenneth W; Papadopoulos, Nickolas; Malek, Sami N

2011-11-24

To further our understanding of the genetic basis of acute myelogenous leukemia (AML), we determined the coding exon sequences of ∼ 18 000 protein-encoding genes in 8 patients with secondary AML. Here we report the discovery of novel somatic mutations in the transcriptional corepressor gene BCORL1 that is located on the X-chromosome. Analysis of BCORL1 in an unselected cohort of 173 AML patients identified a total of 10 mutated cases (6%) with BCORL1 mutations, whereas analysis of 19 AML cell lines uncovered 4 (21%) BCORL1 mutated cell lines. The majority (87%) of the mutations in BCORL1 were predicted to inactivate the gene product as a result of nonsense mutations, splice site mutation, or out-of-frame insertions or deletions. These results indicate that BCORL1 by genetic criteria is a novel candidate tumor suppressor gene, joining the growing list of genes recurrently mutated in AML.

Pokemon decreases the transcriptional activity of RARα in the absence of ligand.

PubMed

Yang, Yutao; Li, Yueting; Di, Fei; Cui, Jiajun; Wang, Yue; David Xu, Zhi-Qing

2016-12-20

Pokemon is a transcriptional repressor that belongs to the POZ and Krüppel (POK) protein family. In this study, we investigated the potential interaction between Pokemon and retinoic acid receptor alpha (RARα) and determined the role of Pokemon in regulation of RARα transcriptional activity in the absence of ligand. We found that Pokemon could directly interact with RARα. Moreover, we demonstrated that Pokemon could decrease the transcriptional activity of RARα in the absence of ligand. Furthermore, we showed that Pokemon could repress the transcriptional activity of RARα by increasing the recruitment of nuclear receptor co-repressor (NCoR) and silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) to the retinoic acid response element (RARE) element. Taken together, these data suggest that Pokemon is a novel partner of RARα that acts as a co-repressor to regulate RARα transcriptional activity in the absence of ligand.

Expression Analysis of p16, c-Myc, and mSin3A in Non-small Cell Lung Cancer by Computer Aided Scoring and Analysis (CASA).

PubMed

Salmaninejad, Arash; Estiar, Mehrdad Asghari; Gill, Rajbir K; Shih, Joanna H; Hewitt, Stephen; Jeon, Hyo-Sung; Fukuoka, Junya; Shilo, Konstantin; Shakoori, Abbas; Jen, Jin

2015-01-01

Immunohistochemical analysis (IHC) of tissue microarray (TMA) slides enables large sets of tissue samples to be analyzed simultaneously on a single slide. However, manual evaluation of small cores on a TMA slide is time consuming and error prone. We describe a computer aided scoring and analysis (CASA) method to allow facile and reliable scoring of IHC staining using TMA containing 300 non-small cell lung cancer (NSCLC) cases. In the two previous published papers utilizing our TMA slides of lung cancer we examined 18 proteins involved in the chromatin machinery. We developed our study using more proteins of the chromatin complex and several transcription factors that facilitate the chromatin machinery. Then, a total of 78 antibodies were evaluated by CASA to derive a normalized intensity value that correlated with the overall staining status of the targeting protein. The intensity values for TMA cores were then examined for association to clinical variables and predictive significance individually and with other factors. RESULTs: Using our TMA, the intensity of several protein pairs were significantly correlated with an increased risk of death in NSCLC. These included c-Myc with p16, mSin3A with p16 and c-Myc with mSinA. Predictive values of these pairs remained significant when evaluated based on standard IHC scores. Our results demonstrate the usefulness of CASA as a valuable tool for systematic assessment of TMA slides to identify potential predictive biomarkers using a large set of primary human tissues.

Regional cardiac function analysis from tagged MRI images. Comparison of techniques: Harmonic-Phase (HARP) versus Sinusoidal-Modeling (SinMod) analysis.

PubMed

Ibrahim, El-Sayed H; Stojanovska, Jadranka; Hassanein, Azza; Duvernoy, Claire; Croisille, Pierre; Pop-Busui, Rodica; Swanson, Scott D

2018-05-16

Cardiac MRI tagging is a valuable technique for evaluating regional heart function. Currently, there are a number of different techniques for analyzing the tagged images. Specifically, k-space-based analysis techniques showed to be much faster than image-based techniques, where harmonic-phase (HARP) and sine-wave modeling (SinMod) stand as two famous techniques of the former group, which are frequently used in clinical studies. In this study, we compared HARP and SinMod and studied inter-observer variability between the two techniques for evaluating myocardial strain and apical-to-base torsion in numerical phantom, nine healthy controls, and thirty diabetic patients. Based on the ground-truth numerical phantom measurements (strain = -20% and rotation angle = -4.4°), HARP and SinMod resulted in overestimation (in absolute value terms) of strain by 1% and 5% (strain values), and of rotation angle by 0.4° and 2.0°, respectively. For the in-vivo results, global strain and torsion ranges were -10.6 to -35.3% and 1.8-12.7°/cm in patients, and -17.8 to -32.7% and 1.8-12.3°/cm in volunteers. On average, SinMod overestimated strain measurements by 5.7% and 5.9% (strain values) in the patients and volunteers, respectively, compared to HARP, and overestimated torsion measurements by 2.9°/cm and 2.5°/cm in the patients and volunteers, respectively, compared to HARP. Location-wise, the ranges for basal, mid-ventricular, and apical strain in patients (volunteers) were -8.4 to -31.5% (-11.6 to -33.3%), -6.3 to -37.2% (-17.8 to -33.3%), and -5.2 to -38.4% (-20.0 to -33.2%), respectively. SinMod overestimated strain in the basal, mid-ventricular, and apical slices by 4.7% (5.7%), 5.9% (5.5%), and 8.9% (6.8%), respectively, compared to HARP in the patients (volunteers). Nevertheless, there existed good correlation between the HARP and SinMod measurements. Finally, there were no significant strain or torsion measurement differences between patients and volunteers. There existed good inter-observer agreement, as all measurement differences lied within the Bland-Altman ± 2 standard-deviation (SD) difference limits. In conclusion, despite the consistency of the results by either HARP or SinMod and acceptable agreement of the generated strain and torsion patterns by both techniques, SinMod systematically overestimated the measurements compared to HARP. Under current operating conditions, the measurements from HARP and SinMod cannot be used interchangeably. Copyright © 2017. Published by Elsevier Inc.

Structural and Functional Analyses of a Conserved Hydrophobic Pocket of Flavivirus Methyltransferase

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

H Dong; L Liu; G Zou

2011-12-31

The flavivirus methyltransferase (MTase) sequentially methylates the N7 and 2'-O positions of the viral RNA cap (GpppA-RNA {yields} m(7)GpppA-RNA {yields} m(7)GpppAm-RNA), using S-adenosyl-l-methionine (AdoMet) as a methyl donor. We report here that sinefungin (SIN), an AdoMet analog, inhibits several flaviviruses through suppression of viral MTase. The crystal structure of West Nile virus MTase in complex with SIN inhibitor at 2.0-{angstrom} resolution revealed a flavivirus-conserved hydrophobic pocket located next to the AdoMet-binding site. The pocket is functionally critical in the viral replication and cap methylations. In addition, the N7 methylation efficiency was found to correlate with the viral replication ability. Thus,more » SIN analogs with modifications that interact with the hydrophobic pocket are potential specific inhibitors of flavivirus MTase.« less

The oncoprotein c-ski functions as a direct antagonist of the transforming growth factor-{beta} type I receptor.

PubMed

Ferrand, Nathalie; Atfi, Azeddine; Prunier, Céline

2010-11-01

The oncoprotein c-Ski has been implicated in the negative regulation of transforming growth factor-β (TGF-β) signaling owing to its ability to repress Smad transcriptional activity via recruitment of a transcriptional corepressor complex containing histone deacetylases. However, c-Ski has also been shown to localize to the cytoplasm, raising the interesting possibility that it might disable TGF-β signaling through alternative mechanisms. Here, we provide evidence that c-Ski can restrict TGF-β signaling by interacting directly with the activated TGF-β type I receptor (TβRI). We explored the physiologic relevance of the c-Ski/TβRI interaction and found that it can culminate in a constitutive association of TβRI with a nonfunctional R-Smad/Smad4 complex. Based on these findings, we hypothesize that the interaction between c-Ski and TβRI might interfere with nuclear translocation of the R-Smad/Smad4 complex, thereby attenuating TGF-β signaling. Such a mechanism may play a crucial role in tumor progression, because many tumors that express high levels of c-Ski also display impaired nuclear accumulation of Smads. ©2010 AACR.

Negative regulation of BMP signaling by the ski oncoprotein.

PubMed

Luo, Kunxin

2003-01-01

The bone morphogenetic proteins (BMPs) play important roles in the regulation of multiple aspects of vertebrate development. BMPs signal through the cell surface receptors and downstream Smad molecules. Upon stimulation with BMP, Smad1, Smad5, and Smad8 are phosphorylated by the activated BMP receptors, form a complex with Smad4, and translocate into the nucleus, where they regulate the expression of BMP target genes. The activity of this signal pathway can be modulated both by extracellular factors that regulate the binding of BMPs to the receptor and by intracellular proteins that interact with the Smad proteins. We have shown that Ski is an important negative regulator of the Smad proteins. Ski can bind to the BMP-Smad protein complexes in response to BMP and repress their ability to activate BMP target genes through disruption of a functional Smad complex and through recruitment of transcriptional co-repressors. The antagonism of BMP signaling by Ski results in neural specification in Xenopus embryos and inhibition of osteoblast differentiation in mouse bone-marrow stromal progenitor cells. This ability to modulate BMP signaling by Ski may play an important role in the regulation of craniofacial, neuronal, and skeletal muscle development.

Auditory Brainstem Response to Complex Sounds Predicts Self-Reported Speech-in-Noise Performance

ERIC Educational Resources Information Center

Anderson, Samira; Parbery-Clark, Alexandra; White-Schwoch, Travis; Kraus, Nina

2013-01-01

Purpose: To compare the ability of the auditory brainstem response to complex sounds (cABR) to predict subjective ratings of speech understanding in noise on the Speech, Spatial, and Qualities of Hearing Scale (SSQ; Gatehouse & Noble, 2004) relative to the predictive ability of the Quick Speech-in-Noise test (QuickSIN; Killion, Niquette,…

Fission yeast Tup1-like repressors repress chromatin remodeling at the fbp1+ promoter and the ade6-M26 recombination hotspot.

PubMed Central

Hirota, Kouji; Hoffman, Charles S; Shibata, Takehiko; Ohta, Kunihiro

2003-01-01

Chromatin remodeling plays crucial roles in the regulation of gene expression and recombination. Transcription of the fission yeast fbp1(+) gene and recombination at the meiotic recombination hotspot ade6-M26 (M26) are both regulated by cAMP responsive element (CRE)-like sequences and the CREB/ATF-type transcription factor Atf1*Pcr1. The Tup11 and Tup12 proteins, the fission yeast counterparts of the Saccharomyces cerevisiae Tup1 corepressor, are involved in glucose repression of the fbp1(+) transcription. We have analyzed roles of the Tup1-like corepressors in chromatin regulation around the fbp1(+) promoter and the M26 hotspot. We found that the chromatin structure around two regulatory elements for fbp1(+) was remodeled under derepressed conditions in concert with the robust activation of fbp1(+) transcription. Strains with tup11delta tup12delta double deletions grown in repressed conditions exhibited the chromatin state associated with wild-type cells grown in derepressed conditions. Interestingly, deletion of rst2(+), encoding a transcription factor controlled by the cAMP-dependent kinase, alleviated the tup11delta tup12delta defects in chromatin regulation but not in transcription repression. The chromatin at the M26 site in mitotic cultures of a tup11delta tup12delta mutant resembled that of wild-type meiotic cells. These observations suggest that these fission yeast Tup1-like corepressors repress chromatin remodeling at CRE-related sequences and that Rst2 antagonizes this function. PMID:14573465

Metabolic regulation of SIRT1 transcription via a HIC1:CtBP corepressor complex

PubMed Central

Zhang, Qinghong; Wang, Su-Yan; Fleuriel, Capucine; Leprince, Dominique; Rocheleau, Jonathan V.; Piston, David W.; Goodman, Richard H.

2007-01-01

The Sir2 histone deacetylases are important for gene regulation, metabolism, and longevity. A unique feature of these enzymes is their utilization of NAD+ as a cosubstrate, which has led to the suggestion that Sir2 activity reflects the cellular energy state. We show that SIRT1, a mammalian Sir2 homologue, is also controlled at the transcriptional level through a mechanism that is specific for this isoform. Treatment with the glycolytic blocker 2-deoxyglucose (2-DG) decreases association of the redox sensor CtBP with HIC1, an inhibitor of SIRT1 transcription. We propose that the reduction in transcriptional repression mediated by HIC1, due to the decrease of CtBP binding, increases SIRT1 expression. This mechanism allows the specific regulation of SIRT1 in response to nutrient deprivation. PMID:17213307

Therapeutic fetal-globin inducers reduce transcriptional repression in hemoglobinopathy erythroid progenitors through distinct mechanisms.

PubMed

Dai, Yan; Sangerman, Jose; Luo, Hong Yuan; Fucharoen, Suthat; Chui, David H K; Faller, Douglas V; Perrine, Susan P

2016-01-01

Pharmacologic augmentation of γ-globin expression sufficient to reduce anemia and clinical severity in patients with diverse hemoglobinopathies has been challenging. In studies here, representative molecules from four chemical classes, representing several distinct primary mechanisms of action, were investigated for effects on γ-globin transcriptional repressors, including components of the NuRD complex (LSD1 and HDACs 2-3), and the downstream repressor BCL11A, in erythroid progenitors from hemoglobinopathy patients. Two HDAC inhibitors (MS-275 and SB939), a short-chain fatty acid derivative (sodium dimethylbutyrate [SDMB]), and an agent identified in high-throughput screening, Benserazide, were studied. These therapeutics induced γ-globin mRNA in progenitors above same subject controls up to 20-fold, and increased F-reticulocytes up to 20%. Cellular protein levels of BCL11A, LSD-1, and KLF1 were suppressed by the compounds. Chromatin immunoprecipitation assays demonstrated a 3.6-fold reduction in LSD1 and HDAC3 occupancy in the γ-globin gene promoter with Benserazide exposure, 3-fold reduction in LSD-1 and HDAC2 occupancy in the γ-globin gene promoter with SDMB exposure, while markers of gene activation (histone H3K9 acetylation and H3K4 demethylation), were enriched 5.7-fold. These findings identify clinical-stage oral therapeutics which inhibit or displace major co-repressors of γ-globin gene transcription and may suggest a rationale for combination therapy to produce enhanced efficacy. Copyright © 2015 Elsevier Inc. All rights reserved.

Therapeutic γ-globin inducers reduce transcriptional repression in hemoglobinopathy erythroid progenitors through distinct mechanisms

PubMed Central

Dai, Yan; Sangerman, Jose; Hong, Yuan Luo; Fuchareon, Suthat; Chui, David H.K.; Faller, Douglas V.; Perrine, Susan P.

2015-01-01

Pharmacologic augmentation of γ-globin expression sufficient to reduce anemia and clinical severity in patients with diverse hemoglobinopathies has been challenging. In studies here, representative molecules from four chemical classes, representing several distinct primary mechanisms of action, were investigated for effects on γ-globin transcriptional repressors, including components of the NuRD complex (LSD1 and HDACs 2-3), and the downstream repressor BCL11A, in erythroid progenitors from hemoglobinopathy patients. Two HDAC inhibitors (MS-275 and SB939), a short-chain fatty acid derivative (sodium dimethylbutyrate [SDMB]), and an agent identified in high-throughput screening, Benserazide, were studied. These therapeutics induced γ globin mRNA in progenitors above same subject controls up to 20-fold, and increased F-reticulocytes up to 20%. Cellular protein levels of BCL11A, LSD-1, and KLF1 were suppressed by the compounds. Chromatin immunoprecipitation assays demonstrated a 3.6-fold reduction in LSD1 and HDAC3 occupancy in the γ-globin gene promoter with Benserazide exposure, 3-fold reduction in LSD-1 and HDAC2 occupancy in the γ-globin gene promoter with SDMB exposure, while markers of gene activation (histone H3K9 acetylation and H3K4 demethylation), were enriched 5.7-fold. These findings identify clinical-stage oral therapeutics which inhibit or displace major co-repressors of γ-globin gene transcription and may suggest a rationale for combination therapy to produce enhanced efficacy. PMID:26603726

Genetic Predictors of Interindividual Variability in Hepatic CYP3A4 ExpressionS⃞

PubMed Central

Lamba, Vishal; Panetta, John C.; Strom, Stephen

2010-01-01

Variability in hepatic CYP3A4 cannot be explained by common CYP3A4 coding variants. We previously identified polymorphisms in pregnane X receptor (PXR) and ATP-binding cassette subfamily B member 1 (ABCB1) associated with CYP3A4 mRNA levels in small cohorts of human livers. However, the relative contributions of these genetic variations or of polymorphisms in other CYP3A4 regulators to variable CYP3A4 expression were not known. We phenotyped livers from white donors (n = 128) by quantitative real-time polymerase chain reaction for expression of CYP3A4, CYP3A5, and CYP3A7 and nine transcriptional regulators, coactivators, and corepressors. We resequenced hepatic nuclear factor-3-β (HNF3β, FoxA2), HNF4α, HNF3γ (FoxA3), nuclear receptor corepressor 2 (NCoR2), and regions of the CYP3A4 promoter and genotyped informative single-nucleotide polymorphisms in PXR and ABCB1 in the same livers. CYP3A4 mRNA was positively correlated with PXR and FoxA2 and negatively correlated with NCoR2 mRNA. A common silent polymorphism and a polymorphic trinucleotide (CCT) repeat in FoxA2 were associated with CYP3A4 expression. The transcriptional activity of the FoxA2 polymorphic CCT repeat alleles (wild-type, n = 14 and variant, n = 13, 15, and 19) when assayed by luciferase reporter transactivation assays was greatest for the wild-type repeat, with deviations from this number having decreased transcriptional activity. This corresponded with higher expression of FoxA2 mRNA and its targets PXR and CYP3A4 in human livers with (CCT) n = 14 genotypes. Multiple linear regression analysis was used to quantify the contributions of selected genetic polymorphisms to variable CYP3A4 expression. This approach identified sex and polymorphisms in FoxA2, HNF4α, FoxA3, PXR, ABCB1, and the CYP3A4 promoter that together explained as much as 24.6% of the variation in hepatic CYP3A4 expression. PMID:19934400

Clarifying the impact of polycomb complex component disruption in human cancers.

PubMed

Yamamoto, Yukiya; Abe, Akihiro; Emi, Nobuhiko

2014-04-01

The dysregulation of proper transcriptional control is a major cause of developmental diseases and cancers. Polycomb proteins form chromatin-modifying complexes that transcriptionally silence genome regions in higher eukaryotes. The BCL6 corepressor (BCOR) complex comprises ring finger protein 1B (RNF2/RING1B), polycomb group ring finger 1 (PCGF1), and lysine-specific demethylase 2B (KDM2B) and is uniquely recruited to nonmethylated CpG islands, where it removes histone H3K36me2 and induces repressive histone H2A monoubiquitylation. Germline BCOR mutations have been detected in patients with oculofaciocardiodental and Lenz microphthalmia syndromes, which are inherited conditions. Recently, several variants of BCOR and BCOR-like 1 (BCORL1) chimeric fusion transcripts were reported in human cancers, including acute promyelocytic leukemia, bone sarcoma, and hepatocellular carcinoma. In addition, massively parallel sequencing has identified inactivating somatic BCOR and BCORL1 mutations in patients with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia, medulloblastoma, and retinoblastoma. More importantly, patients with AML and MDS with BCOR mutations exhibit poor prognosis. This perspective highlights the detection of BCOR mutations and fusion transcripts of BCOR and BCORL1 and discusses their importance for diagnosing cancer subtypes and estimating the treatment responses of patients. Furthermore, this perspective proposes the need for additional functional studies to clarify the oncogenic mechanism by which BCOR and BCORL1 are disrupted in cancers, and how this may lead to the development of novel therapeutics. Mol Cancer Res; 12(4); 479-84. ©2014 AACR.

X-ray magneto-optic KERR effect studies of spring magnet heterostructures.

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

Kortright, J. B.; Kim, S.-K.; Fullerton, E. E.

2000-11-01

The complex 3-dimensional magnetization reversal behavior of Sin-Co/Fe exchange spring films is used to test the sensitivity of different resonant soft x-ray magneto-optical Kerr effect (MOKE) measurements to changes in longitudinal and transverse moments within the SOIIFe layer and to changes in these moments in depth within the Fe layer. As in the visible MOKE, changes in longitudinal and net transverse moments are resolved by measuring both Kerr rotation and intensity loops in the near the Fe 2p core resonance. These x-ray MOKE signals measured using linear incident polarization are more directly interpreted in terms of longitudinal and transverse momentsmore » than are the same signals measured using elliptical polarization. Varying photon energy near the Fe L3line is shown to be an effective means of resolving distinctly different reversal behavior at the top and bottom of the 20 nm thick Fe layer resulting from the strong exchange coupling at the Sin-Co/Fe interface. Measured x-ray MOKE spectra and signals are in qualitative agreement with those calculated using standard magneto-optical formalisms incorporating interference between different layers and measured helicity-dependent magneto-optical constants for Fe.« less

Spine Instability Neoplastic Score: agreement across different medical and surgical specialties.

PubMed

Arana, Estanislao; Kovacs, Francisco M; Royuela, Ana; Asenjo, Beatriz; Pérez-Ramírez, Úrsula; Zamora, Javier

2016-05-01

Spinal instability is an acknowledged complication of spinal metastases; in spite of recent suggested criteria, it is not clearly defined in the literature. This study aimed to assess intra and interobserver agreement when using the Spine Instability Neoplastic Score (SINS) by all physicians involved in its management. Independent multicenter reliability study for the recently created SINS, undertaken with a panel of medical oncologists, neurosurgeons, radiologists, orthopedic surgeons, and radiation oncologists, was carried out. Ninety patients with biopsy-proven spinal metastases and magnetic resonance imaging, reviewed at the multidisciplinary tumor board of our institution, were included. Intraclass correlation coefficient (ICC) was used for SINS score agreement. Fleiss kappa statistic was used to assess agreement on the location of the most affected vertebral level; agreement on the SINS category ("stable," "potentially stable," or "unstable"); and overall agreement with the classification established by tumor board. Clinical data and imaging were provided to 83 specialists in 44 hospitals across 14 Spanish regions. No assessment criteria were pre-established. Each clinician assessed the SINS score twice, with a minimum 6-week interval. Clinicians were blinded to assessments made by other specialists and to their own previous assessment. Subgroup analyses were performed by clinicians' specialty, experience (≤7, 8-13, ≥14 years), and hospital category (four levels according to size and complexity). This study was supported by Kovacs Foundation. Intra and interobserver agreement on the location of the most affected levels was "almost perfect" (κ>0.94). Intra-observer agreement on the SINS score was "excellent" (ICC=0.77), whereas interobserver agreement was "moderate" (ICC=0.55). Intra-observer agreement in SINS category was "substantial" (k=0.61), whereas interobserver agreement was "moderate" (k=0.42). Overall agreement with the tumor board classification was "substantial" (κ=0.61). Results were similar across specialties, years of experience, and hospital category. Agreement on the assessment of metastatic spine instability is moderate. The SINS can help improve communication among clinicians in oncology care. Copyright © 2015 Elsevier Inc. All rights reserved.

Structural and functional analysis of the repressor complex in the Notch signaling pathway of Drosophila melanogaster

PubMed Central

Maier, Dieter; Kurth, Patricia; Schulz, Adriana; Russell, Andrew; Yuan, Zhenyu; Gruber, Kim; Kovall, Rhett A.; Preiss, Anette

2011-01-01

In metazoans, the highly conserved Notch pathway drives cellular specification. On receptor activation, the intracellular domain of Notch assembles a transcriptional activator complex that includes the DNA-binding protein CSL, a composite of human C-promoter binding factor 1, Suppressor of Hairless of Drosophila melanogaster [Su(H)], and lin-12 and Glp-1 phenotype of Caenorhabditis elegans. In the absence of ligand, CSL represses Notch target genes. However, despite the structural similarity of CSL orthologues, repression appears largely diverse between organisms. Here we analyze the Notch repressor complex in Drosophila, consisting of the fly CSL protein, Su(H), and the corepressor Hairless, which recruits general repressor proteins. We show that the C-terminal domain of Su(H) is necessary and sufficient for forming a high-affinity complex with Hairless. Mutations in Su(H) that affect interactions with Notch and Mastermind have no effect on Hairless binding. Nonetheless, we demonstrate that Notch and Hairless compete for CSL in vitro and in cell culture. In addition, we identify a site in Hairless that is crucial for binding Su(H) and subsequently show that this Hairless mutant is strongly impaired, failing to properly assemble the repressor complex in vivo. Finally, we demonstrate Hairless-mediated inhibition of Notch signaling in a cell culture assay, which hints at a potentially similar repression mechanism in mammals that might be exploited for therapeutic purposes. PMID:21737682

The PARP1-Siah1 Axis Controls HIV-1 Transcription and Expression of Siah1 Substrates.

PubMed

Yu, Dan; Liu, Rongdiao; Yang, Geng; Zhou, Qiang

2018-06-26

Recent studies have revealed a key role of PARP1 that catalyzes the poly-ADP-ribosylation (PARylation) of substrates in regulating gene transcription. We show here that HIV-1 transcriptional activation also requires PARP1 activity. Because efficient HIV-1 transactivation is known to depend on the ELL2-containing super elongation complex (SEC), we investigated the functional relationship between PARP1 and ELL2-SEC in HIV-1 transcriptional control. We show that PARP1 elevates ELL2 protein levels to form more ELL2-SEC in cells. This effect is caused by PARP1's suppression of expression of Siah1, an E3 ubiquitin ligase for ELL2, at both mRNA and protein levels. At the mRNA level, PARP1 coordinates with the co-repressor NCoR to suppress Siah1 transcription. At the protein level, PARP1 promotes Siah1 proteolysis, likely through inducing PARylation-dependent ubiquitination (PARdU) of Siah1. Thus, a PARP1-Siah1 axis activates HIV-1 transcription and controls the expression of ELL2 and other Siah1 substrates. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Repurposing Pan-HDAC Inhibitors for ARID1A-Mutated Ovarian Cancer.

PubMed

Fukumoto, Takeshi; Park, Pyoung Hwa; Wu, Shuai; Fatkhutdinov, Nail; Karakashev, Sergey; Nacarelli, Timothy; Kossenkov, Andrew V; Speicher, David W; Jean, Stephanie; Zhang, Lin; Wang, Tian-Li; Shih, Ie-Ming; Conejo-Garcia, Jose R; Bitler, Benjamin G; Zhang, Rugang

2018-03-27

ARID1A, a subunit of the SWI/SNF complex, is among the most frequently mutated genes across cancer types. ARID1A is mutated in more than 50% of ovarian clear cell carcinomas (OCCCs), diseases that have no effective therapy. Here, we show that ARID1A mutation confers sensitivity to pan-HDAC inhibitors such as SAHA in ovarian cancers. This correlated with enhanced growth suppression induced by the inhibition of HDAC2 activity in ARID1A-mutated cells. HDAC2 interacts with EZH2 in an ARID1A status-dependent manner. HDAC2 functions as a co-repressor of EZH2 to suppress the expression of EZH2/ARID1A target tumor suppressor genes such as PIK3IP1 to inhibit proliferation and promote apoptosis. SAHA reduced the growth and ascites of the ARID1A-inactivated OCCCs in both orthotopic and genetic mouse models. This correlated with a significant improvement of survival of mice bearing ARID1A-mutated OCCCs. These findings provided preclinical rationales for repurposing FDA-approved pan-HDAC inhibitors for treating ARID1A-mutated cancers. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Inhibitors for the Vitamin D Receptor–Coregulator Interaction

PubMed Central

Teske, Kelly A.; Yu, Olivia; Arnold, Leggy A.

2016-01-01

The vitamin D receptor (VDR) belongs to the superfamily of nuclear receptors and is activated by the endogenous ligand 1,25-dihydroxyvitamin D3. The genomic effects mediated by VDR consist of the activation and repression of gene transcription, which includes the formation of multi-protein complexes with coregulator proteins. Coregulators bind many nuclear receptors and can be categorized according their role as coactivators (gene activation) or corepressors (gene repression). Herein, different approaches to develop compounds that modulate the interaction between VDR and coregulators are summarized. This include coregulator peptides that were identified by creating phage display libraries. Subsequent modification of these peptides including the introduction of a tether or non-hydrolysable bonds resulted in the first direct VDR–coregulator inhibitors. Later, small molecules that inhibit VDR–coregulator inhibitors were identified using rational drug design and high throughput screening. Early on, allosteric inhibition of VDR–coregulator interactions was achieved with VDR antagonists that change the conformation of VDR and modulate the interactions with coregulators. A detailed discussion of their dual agonist/antagonist effects is given as well as a summary of their biological effects in cell-based assays and in vivo studies. PMID:26827948

Production of pyruvate from mannitol by mannitol-assimilating pyruvate decarboxylase-negative Saccharomyces cerevisiae.

PubMed

Yoshida, Shiori; Tanaka, Hideki; Hirayama, Makoto; Murata, Kousaku; Kawai, Shigeyuki

2015-01-01

Mannitol is contained in brown macroalgae up to 33% (w/w, dry weight), and thus is a promising carbon source for white biotechnology. However, Saccharomyces cerevisiae, a key cell factory, is generally regarded to be unable to assimilate mannitol for growth. We have recently succeeded in producing S. cerevisiae that can assimilate mannitol through spontaneous mutations of Tup1-Cyc8, each of which constitutes a general corepressor complex. In this study, we demonstrate production of pyruvate from mannitol using this mannitol-assimilating S. cerevisiae through deletions of all 3 pyruvate decarboxylase genes. The resultant mannitol-assimilating pyruvate decarboxylase-negative strain produced 0.86 g/L pyruvate without use of acetate after cultivation for 4 days, with an overall yield of 0.77 g of pyruvate per g of mannitol (the theoretical yield was 79%). Although acetate was not needed for growth of this strain in mannitol-containing medium, addition of acetate had a significant beneficial effect on production of pyruvate. This is the first report of production of a valuable compound (other than ethanol) from mannitol using S. cerevisiae, and is an initial platform from which the productivity of pyruvate from mannitol can be improved.

Production of pyruvate from mannitol by mannitol-assimilating pyruvate decarboxylase-negative Saccharomyces cerevisiae

PubMed Central

Yoshida, Shiori; Tanaka, Hideki; Hirayama, Makoto; Murata, Kousaku; Kawai, Shigeyuki

2015-01-01

Mannitol is contained in brown macroalgae up to 33% (w/w, dry weight), and thus is a promising carbon source for white biotechnology. However, Saccharomyces cerevisiae, a key cell factory, is generally regarded to be unable to assimilate mannitol for growth. We have recently succeeded in producing S. cerevisiae that can assimilate mannitol through spontaneous mutations of Tup1-Cyc8, each of which constitutes a general corepressor complex. In this study, we demonstrate production of pyruvate from mannitol using this mannitol-assimilating S. cerevisiae through deletions of all 3 pyruvate decarboxylase genes. The resultant mannitol-assimilating pyruvate decarboxylase-negative strain produced 0.86 g/L pyruvate without use of acetate after cultivation for 4 days, with an overall yield of 0.77 g of pyruvate per g of mannitol (the theoretical yield was 79%). Although acetate was not needed for growth of this strain in mannitol-containing medium, addition of acetate had a significant beneficial effect on production of pyruvate. This is the first report of production of a valuable compound (other than ethanol) from mannitol using S. cerevisiae, and is an initial platform from which the productivity of pyruvate from mannitol can be improved. PMID:26588105

Randomized DNA libraries construction tool: a new 3-bp 'frequent cutter' TthHB27I/sinefungin endonuclease with chemically-induced specificity.

PubMed

Krefft, Daria; Papkov, Aliaksei; Prusinowski, Maciej; Zylicz-Stachula, Agnieszka; Skowron, Piotr M

2018-05-11

Acoustic or hydrodynamic shearing, sonication and enzymatic digestion are used to fragment DNA. However, these methods have several disadvantages, such as DNA damage, difficulties in fragmentation control, irreproducibility and under-representation of some DNA segments. The DNA fragmentation tool would be a gentle enzymatic method, offering cleavage frequency high enough to eliminate DNA fragments distribution bias and allow for easy control of partial digests. Only three such frequently cleaving natural restriction endonucleases (REases) were discovered: CviJI, SetI and FaiI. Therefore, we have previously developed two artificial enzymatic specificities, cleaving DNA approximately every ~ 3-bp: TspGWI/sinefungin (SIN) and TaqII/SIN. In this paper we present the third developed specificity: TthHB27I/SIN(SAM) - a new genomic tool, based on Type IIS/IIC/IIG Thermus-family REases-methyltransferases (MTases). In the presence of dimethyl sulfoxide (DMSO) and S-adenosyl-L-methionine (SAM) or its analogue SIN, the 6-bp cognate TthHB27I recognition sequence 5'-CAARCA-3' is converted into a combined 3.2-3.0-bp 'site' or its statistical equivalent, while a cleavage distance of 11/9 nt is retained. Protocols for various modes of limited DNA digestions were developed. In the presence of DMSO and SAM or SIN, TthHB27I is transformed from rare 6-bp cutter to a very frequent one, approximately 3-bp. Thus, TthHB27I/SIN(SAM) comprises a new tool in the very low-represented segment of such prototype REases specificities. Moreover, this modified TthHB27I enzyme is uniquely suited for controlled DNA fragmentation, due to partial DNA cleavage, which is an inherent feature of the Thermus-family enzymes. Such tool can be used for quasi-random libraries generation as well as for other DNA manipulations, requiring high frequency cleavage and uniform distribution of cuts along DNA.

Expression and localization of components of the histone deacetylases multiprotein repressory complexes in the mouse preimplantation embryo.

PubMed

Kantor, Boris; Makedonski, Kirill; Shemer, Ruth; Razin, Aharon

2003-12-01

DNA methylation had been implicated in the assembly of multiprotein repressory complexes that affect chromatin architecture thereby rendering genes inactive. Proteins containing methyl binding domains (MBDs) are major components of these complexes. MBD3 is a component of the HDAC associated chromatin remodeling complex Mi2/NuRD. The addition of MBD2 to the Mi2/NuRD complex creates MeCP1, a complex that is known to inactivate methylated promoters. The undermethylated state of the mouse preimplantation embryo prompted us to investigate the known repressory complexes at this developmental stage. We found individual components of Mi2/NuRD: MBD3, Mi2, HDAC1 and HDAC2 to be expressed from a very early stage of embryo development and to localize in close proximity with each other and with constitutive heterochromatin by the blastula stage. Expression of MBD2, a component of MeCP1, starts in the blastula stage. Then it is also found to be in proximity with heterochromatin (based on DAPI staining) and with MBD3, Mi2 and HDAC1. In contrast, expression of MeCP2, an MBD containing component of a third repressory complex (MeCP2/Sin3A), is not seen in the preimplantation embryo. Our results suggest that both Mi2/NuRD and MeCP1 complexes are already present at the very early stages of embryo development, while a MeCP2 complex is added to the arsenal of repressory complexes post-implantation at a stage when DNA methylation takes place.

Screening and association testing of common coding variation in steroid hormone receptor co-activator and co-repressor genes in relation to breast cancer risk: the Multiethnic Cohort.

PubMed

Haiman, Christopher A; Garcia, Rachel R; Hsu, Chris; Xia, Lucy; Ha, Helen; Sheng, Xin; Le Marchand, Loic; Kolonel, Laurence N; Henderson, Brian E; Stallcup, Michael R; Greene, Geoffrey L; Press, Michael F

2009-01-30

Only a limited number of studies have performed comprehensive investigations of coding variation in relation to breast cancer risk. Given the established role of estrogens in breast cancer, we hypothesized that coding variation in steroid receptor coactivator and corepressor genes may alter inter-individual response to estrogen and serve as markers of breast cancer risk. We sequenced the coding exons of 17 genes (EP300, CCND1, NME1, NCOA1, NCOA2, NCOA3, SMARCA4, SMARCA2, CARM1, FOXA1, MPG, NCOR1, NCOR2, CALCOCO1, PRMT1, PPARBP and CREBBP) suggested to influence transcriptional activation by steroid hormone receptors in a multiethnic panel of women with advanced breast cancer (n = 95): African Americans, Latinos, Japanese, Native Hawaiians and European Americans. Association testing of validated coding variants was conducted in a breast cancer case-control study (1,612 invasive cases and 1,961 controls) nested in the Multiethnic Cohort. We used logistic regression to estimate odds ratios for allelic effects in ethnic-pooled analyses as well as in subgroups defined by disease stage and steroid hormone receptor status. We also investigated effect modification by established breast cancer risk factors that are associated with steroid hormone exposure. We identified 45 coding variants with frequencies > or = 1% in any one ethnic group (43 non-synonymous variants). We observed nominally significant positive associations with two coding variants in ethnic-pooled analyses (NCOR2: His52Arg, OR = 1.79; 95% CI, 1.05-3.05; CALCOCO1: Arg12His, OR = 2.29; 95% CI, 1.00-5.26). A small number of variants were associated with risk in disease subgroup analyses and we observed no strong evidence of effect modification by breast cancer risk factors. Based on the large number of statistical tests conducted in this study, the nominally significant associations that we observed may be due to chance, and will need to be confirmed in other studies. Our findings suggest that common coding variation in these candidate genes do not make a substantial contribution to breast cancer risk in the general population. Cataloging and testing of coding variants in coactivator and corepressor genes should continue and may serve as a valuable resource for investigations of other hormone-related phenotypes, such as inter-individual response to hormonal therapies used for cancer treatment and prevention.

A Three-Step Atomic Layer Deposition Process for SiN x Using Si2Cl6, CH3NH2, and N2 Plasma.

PubMed

Ovanesyan, Rafaiel A; Hausmann, Dennis M; Agarwal, Sumit

2018-06-06

We report a novel three-step SiN x atomic layer deposition (ALD) process using Si 2 Cl 6 , CH 3 NH 2 , and N 2 plasma. In a two-step process, nonhydrogenated chlorosilanes such as Si 2 Cl 6 with N 2 plasmas lead to poor-quality SiN x films that oxidize rapidly. The intermediate CH 3 NH 2 step was therefore introduced in the ALD cycle to replace the NH 3 plasma step with a N 2 plasma, while using Si 2 Cl 6 as the Si precursor. This three-step process lowers the atomic H content and improves the film conformality on high-aspect-ratio nanostructures as Si-N-Si bonds are formed during a thermal CH 3 NH 2 step in addition to the N 2 plasma step. During ALD, the reactive surface sites were monitored using in situ surface infrared spectroscopy. Our infrared spectra show that, on the post-N 2 plasma-treated SiN x surface, Si 2 Cl 6 reacts primarily with the surface -NH 2 species to form surface -SiCl x ( x = 1, 2, or 3) bonds, which are the reactive sites during the CH 3 NH 2 cycle. In the N 2 plasma step, reactive -NH 2 surface species are created because of the surface H available from the -CH 3 groups. At 400 °C, the SiN x films have a growth per cycle of ∼0.9 Å with ∼12 atomic percent H. The films grown on high-aspect-ratio nanostructures have a conformality of ∼90%.

Optimal Orbital Coverage of Theater Operations and Targets

DTIC Science & Technology

2007-03-01

3.18). (3.18) 1.000140612 .016708617cos( ) .000139589cos(2 )r M= − − M The obliquity of the ecliptic (ε ) was determined using equation (3.19...estimated using equation (3.16). UT1357.5277233 35999.05034M T= + o (3.16) The ecliptic longitude ( eclipticλ ) was determined using equation (3.17...1.914666471 sin( ) .019994643sin(2 ) ecliptic M Mλ λ= + + o M (3.17) The magnitude of the position vector to the sun was solved for using equation

Transcriptional corepressor SMILE recruits SIRT1 to inhibit nuclear receptor estrogen receptor-related receptor gamma transactivation.

PubMed

Xie, Yuan-Bin; Park, Jeong-Hoh; Kim, Don-Kyu; Hwang, Jung Hwan; Oh, Sangmi; Park, Seung Bum; Shong, Minho; Lee, In-Kyu; Choi, Hueng-Sik

2009-10-16

SMILE (small heterodimer partner interacting leucine zipper protein) has been identified as a corepressor of the glucocorticoid receptor, constitutive androstane receptor, and hepatocyte nuclear factor 4alpha. Here we show that SMILE also represses estrogen receptor-related receptor gamma (ERRgamma) transactivation. Knockdown of SMILE gene expression increases ERRgamma activity. SMILE directly interacts with ERRgamma in vitro and in vivo. Domain mapping analysis showed that SMILE binds to the AF2 domain of ERRgamma. SMILE represses ERRgamma transactivation partially through competition with coactivators PGC-1alpha, PGC-1beta, and GRIP1. Interestingly, the repression of SMILE on ERRgamma is released by SIRT1 inhibitors, a catalytically inactive SIRT1 mutant, and SIRT1 small interfering RNA but not by histone protein deacetylase inhibitor. In vivo glutathione S-transferase pulldown and coimmunoprecipitation assays validated that SMILE physically interacts with SIRT1. Furthermore, the ERRgamma inverse agonist GSK5182 enhances the interaction of SMILE with ERRgamma and SMILE-mediated repression. Knockdown of SMILE or SIRT1 blocks the repressive effect of GSK5182. Moreover, chromatin immunoprecipitation assays revealed that GSK5182 augments the association of SMILE and SIRT1 on the promoter of the ERRgamma target PDK4. GSK5182 and adenoviral overexpression of SMILE cooperate to repress ERRgamma-induced PDK4 gene expression, and this repression is released by overexpression of a catalytically defective SIRT1 mutant. Finally, we demonstrated that ERRgamma regulates SMILE gene expression, which in turn inhibits ERRgamma. Overall, these findings implicate SMILE as a novel corepressor of ERRgamma and recruitment of SIRT1 as a novel repressive mechanism for SMILE and ERRgamma inverse agonist.

Functional regulation of Q by microRNA172 and transcriptional co-repressor TOPLESS in controlling bread wheat spikelet density.

PubMed

Liu, Pan; Liu, Jie; Dong, Huixue; Sun, Jiaqiang

2018-02-01

Bread wheat (Triticum aestivum) spike architecture is an important agronomic trait. The Q gene plays a key role in the domestication of bread wheat spike architecture. However, the regulatory mechanisms of Q expression and transcriptional activity remain largely unknown. In this study, we show that overexpression of bread wheat tae-miR172 caused a speltoid-like spike phenotype, reminiscent of that in wheat plants with the q gene. The reduction in Q transcript levels in the tae-miR172 overexpression transgenic bread wheat lines suggests that the Q expression can be suppressed by tae-miR172 in bread wheat. Indeed, our RACE analyses confirmed that the Q mRNA is targeted by tae-miR172 for cleavage. According to our analyses, the Q protein is localized in nucleus and confers transcriptional repression activity. Meanwhile, the Q protein could physically interact with the bread wheat transcriptional co-repressor TOPLESS (TaTPL). Specifically, the N-terminal ethylene-responsive element binding factor-associated amphiphilic repression (EAR) (LDLNVE) motif but not the C-terminal EAR (LDLDLR) motif of Q protein mediates its interaction with the CTLH motif of TaTPL. Moreover, we show that the N-terminal EAR motif of Q protein is also essentially required for the transcriptional repression activity of Q protein. Taken together, we reveal the functional regulation of Q protein by tae-miR172 and transcriptional co-repressor TaTPL in controlling the bread wheat spike architecture. © 2017 The Authors. Plant Biotechnology Journal published by Society for Experimental Biology and The Association of Applied Biologists and John Wiley & Sons Ltd.

Contribution to the search of binaries among Am stars. II. HD 81976 and HD 98880, double-lined spectroscopic binaries

NASA Astrophysics Data System (ADS)

Carquillat, J.-M.; Ginestet, N.; Prieur, J.-L.

2001-04-01

We present the results of the observations of two Am stars of eighth magnitude, the double-lined spectroscopic binaries HD 81976 and HD 98880, carried out with the CORAVEL instrument at the Observatoire de Haute-Provence in order to determine their orbital elements. We found 1) for HD 81976: P = 5.655750 days, T = 2449785.941 HJD, omega = 341.4deg, e = 0.061, K1 = 61.68 km s-1, K2 = 63.84 km s-1, V0 = 19.85 km s-1, a1 sin i = 4.788 Gm, a2 sin i = 4.956 Gm, M1 sin 3 i = 0.5875 Msun, M2 sin 3 i = 0.5676 Msun, and 2) for HD 98880: P = 14.20783 days, T0 = 2448682.883 HJD (ascending node), e = 0., K1 = 42.47 km s-1, K2 = 49.16 km s-1, V0 = 2.40 km s-1, a1 sin i = 8.298 Gm, a2 sin i = 9.604 Gm, M1 sin 3 i = 0.6091 Msun, M2 sin 3 i = 0.5262 Msun. The first of these two systems, HD 81976, is formed by two quasi-identical stars, and the Hipparcos data (MV, B-V) are consistent with late A stars in effective temperature; it is likely that the components rotate synchronised with the orbital motion. A third body may be present in this system since (i) the orbit has a significant eccentricity despite its short period and (ii) the systemic velocity V0 shows a possible drift. For the second system, HD 98880, we give Delta mB 1.25 and we propose a simple model based upon Strömgren photometric indices and the HR theoretical diagram of Schaller et al (1992) in addition to orbital parameters and Hipparcos data: Teff = 7000 K, log 10 g = 4.0, M1 = 1.9 Msun, M2 = 1.6 Msun, log 10(age) = 9.12. The components do not rotate synchronously contrary to HD 81976. Both binaries appear to be detached systems without possibility of eclipses. Based on observations made at the Haute-Provence Observatory, France.

LSD1 dual function in mediating epigenetic corruption of the vitamin D signaling in prostate cancer.

PubMed

Battaglia, Sebastiano; Karasik, Ellen; Gillard, Bryan; Williams, Jennifer; Winchester, Trisha; Moser, Michael T; Smiraglia, Dominic J; Foster, Barbara A

2017-01-01

Lysine-specific demethylase 1A (LSD1) is a key regulator of the androgen (AR) and estrogen receptors (ER), and LSD1 levels correlate with tumor aggressiveness. Here, we demonstrate that LSD1 regulates vitamin D receptor (VDR) activity and is a mediator of 1,25(OH) 2 -D 3 (vitamin D) action in prostate cancer (PCa). Athymic nude mice were xenografted with CWR22 cells and monitored weekly after testosterone pellet removal. Expression of LSD1 and VDR (IHC) were correlated with tumor growth using log-rank test. TRAMP tumors and prostates from wild-type (WT) mice were used to evaluate VDR and LSD1 expression via IHC and western blotting. The presence of VDR and LSD1 in the same transcriptional complex was evaluated via immunoprecipitation (IP) using nuclear cell lysate. The effect of LSD1 and 1,25(OH) 2 -D 3 on cell viability was evaluated in C4-2 and BC1A cells via trypan blue exclusion. The role of LSD1 in VDR-mediated gene transcription was evaluated for Cdkn1a , E2f1 , Cyp24a1 , and S100g via qRT-PCR-TaqMan and via chromatin immunoprecipitation assay. Methylation of Cdkn1a TSS was measured via bisulfite sequencing, and methylation of a panel of cancer-related genes was quantified using methyl arrays. The Cancer Genome Atlas data were retrieved to identify genes whose status correlates with LSD1 and DNA methyltransferase 1 (DNMT1). Results were correlated with patients' survival data from two separate cohorts of primary and metastatic PCa. LSD1 and VDR protein levels are elevated in PCa tumors and correlate with faster tumor growth in xenograft mouse models. Knockdown of LSD1 reduces PCa cell viability, and gene expression data suggest a dual coregulatory role of LSD1 for VDR, acting as a coactivator and corepressor in a locus-specific manner. LSD1 modulates VDR-dependent transcription by mediating the recruitment of VDR and DNMT1 at the TSS of VDR-targeted genes and modulates the epigenetic status of transcribed genes by altering H3K4me2 and H3K9Ac and DNA methylation. Lastly, LSD1 and DNMT1 belong to a genome-wide signature whose expression correlates with shorter progression-free survival and overall survival in primary and metastatic patients' samples, respectively. Results demonstrate that LSD1 has a dual coregulatory role as corepressor and coactivator for VDR and defines a genomic signature whose targeting might have clinical relevance for PCa patients.

Low Thermal Conductance Transition Edge Sensor (TES) for SPICA

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

Khosropanah, P.; Dirks, B.; Kuur, J. van der

2009-12-16

We fabricated and characterized low thermal conductance transition edge sensors (TES) for SAFARI instrument on SPICA. The device is based on a superconducting Ti/Au bilayer deposited on suspended SiN membrane. The critical temperature of the device is 113 mK. The low thermal conductance is realized by using long and narrow SiN supporting legs. All measurements were performed having the device in a light-tight box, which to a great extent eliminates the loading of the background radiation. We measured the current-voltage (IV) characteristics of the device in different bath temperatures and determine the thermal conductance (G) to be equal to 320more » fW/K. This value corresponds to a noise equivalent power (NEP) of 3x10{sup -19} W/{radical}(Hz). The current noise and complex impedance is also measured at different bias points at 55 mK bath temperature. The measured electrical (dark) NEP is 1x10{sup -18} W/{radical}(Hz), which is about a factor of 3 higher than what we expect from the thermal conductance that comes out of the IV curves. Despite using a light-tight box, the photon noise might still be the source of this excess noise. We also measured the complex impedance of the same device at several bias points. Fitting a simple first order thermal-electrical model to the measured data, we find an effective time constant of about 2.7 ms and a thermal capacity of 13 fJ/K in the middle of the transition.« less

Administration of SIN-1 induces guinea pig airway hyperresponsiveness through inactivation of airway neutral endopeptidase.

PubMed

Kanazawa, H; Hirata, K; Yoshikawa, J

1999-12-01

Peroxynitrite plays an important role in the pathogenesis of airway inflammation. We have already found that peroxynitrite may contribute to decreased beta(2)-adrenoceptor responses in airway smooth muscle. However, it is not known whether peroxynitrite can alter neutral endopeptidase (EC 3.4.24.11; NEP) activity in the airways. This study was designed to determine whether peroxynitrite induces airway hyperresponsiveness to substance P (SP) and endothelin-1 (ET-1) through the inactivation of airway NEP. We examined whether the administration of S-morpholinosydnonimine (SIN-1), a compound that releases peroxynitrite, increased bronchoconstrictor responses to SP and ET-1 in anesthetized guinea pigs. In addition, we assayed NEP activity in the airways of SIN-1-exposed guinea pigs. Though SIN-1 (10(-7) M) alone had no effect on pulmonary resistance, pretreatment with SIN-1 significantly enhanced SP- and ET-1-induced bronchoconstriction. Pretreatment with phosphoramidon, an NEP inhibitor, also enhanced SP- and ET-1-induced bronchoconstriction. However, simultaneous administration of phosphoramidon and SIN-1 had no additive effect on SP- and ET-1-induced bronchoconstriction. Peroxynitrite formation by SIN-1 was completely inhibited by N-acetylcysteine (NAC) and glutathione (GSH) in vitro, and pretreatment with NAC and GSH significantly reversed the potentiation by SIN-1 of SP-induced bronchoconstriction. In addition, the NEP activity of the trachea after SIN-1 exposure was significantly reduced compared to the level in control guinea pigs (solvent for SIN-1: 30.0+/-4.2 fmol.min(-1).mg tissue(-1); 10(-7) M SIN-1; 15.5+/-4.5 fmol.min(-1).mg tissue(-1), p<0.05). These findings suggest that peroxynitrite induces airway hyperresponsiveness to SP and ET-1 through the inactivation of airway NEP, and that peroxynitrite is an important mediator of the alterations in airway functions.

TaC-coated graphite prepared via a wet ceramic process: Application to CVD susceptors for epitaxial growth of wide-bandgap semiconductors

NASA Astrophysics Data System (ADS)

Nakamura, Daisuke; Kimura, Taishi; Narita, Tetsuo; Suzumura, Akitoshi; Kimoto, Tsunenobu; Nakashima, Kenji

2017-11-01

A novel sintered tantalum carbide coating (SinTaC) prepared via a wet ceramic process is proposed as an approach to reducing the production cost and improving the crystal quality of bulk-grown crystals and epitaxially grown films of wide-bandgap semiconductors. Here, we verify the applicability of the SinTaC components as susceptors for chemical vapor deposition (CVD)-SiC and metal-organic chemical vapor deposition (MOCVD)-GaN epitaxial growth in terms of impurity incorporation from the SinTaC layers and also clarify the surface-roughness controllability of SinTaC layers and its advantage in CVD applications. The residual impurity elements in the SinTaC layers were confirmed to not severely incorporate into the CVD-SiC and MOCVD-GaN epilayers grown using the SinTaC susceptors. The quality of the epilayers was also confirmed to be equivalent to that of epilayers grown using conventional susceptors. Furthermore, the surface roughness of the SinTaC components was controllable over a wide range of average roughness (0.4 ≤ Ra ≤ 5 μm) and maximum height roughness (3 ≤ Rz ≤ 36 μm) through simple additional surface treatment procedures, and the surface-roughened SinTaC susceptor fabricated using these procedures was predicted to effectively reduce thermal stress on epi-wafers. These results confirm that SinTaC susceptors are applicable to epitaxial growth processes and are advantageous over conventional susceptor materials for reducing the epi-cost and improving the quality of epi-wafers.

Somatic mutations in the transcriptional corepressor gene BCORL1 in adult acute myelogenous leukemia

PubMed Central

Li, Meng; Collins, Roxane; Jiao, Yuchen; Ouillette, Peter; Bixby, Dale; Erba, Harry; Vogelstein, Bert; Kinzler, Kenneth W.

2011-01-01

To further our understanding of the genetic basis of acute myelogenous leukemia (AML), we determined the coding exon sequences of ∼ 18 000 protein-encoding genes in 8 patients with secondary AML. Here we report the discovery of novel somatic mutations in the transcriptional corepressor gene BCORL1 that is located on the X-chromosome. Analysis of BCORL1 in an unselected cohort of 173 AML patients identified a total of 10 mutated cases (6%) with BCORL1 mutations, whereas analysis of 19 AML cell lines uncovered 4 (21%) BCORL1 mutated cell lines. The majority (87%) of the mutations in BCORL1 were predicted to inactivate the gene product as a result of nonsense mutations, splice site mutation, or out-of-frame insertions or deletions. These results indicate that BCORL1 by genetic criteria is a novel candidate tumor suppressor gene, joining the growing list of genes recurrently mutated in AML. PMID:21989985

Dimerization-induced corepressor binding and relaxed DNA-binding specificity are critical for PML/RARA-induced immortalization

PubMed Central

Zhou, Jun; Pérès, Laurent; Honoré, Nicole; Nasr, Rihab; Zhu, Jun; de Thé, Hugues

2006-01-01

The pathogenesis of acute promyelocytic leukemia involves the transcriptional repression of master genes of myeloid differentiation by the promyelocytic leukemia–retinoic acid receptor α (PML/RARA) oncogene. PML-enforced RARA homodimerization allows the tighter binding of corepressors, silencing RARA target genes. In addition, homodimerization dramatically extends the spectrum of DNA-binding sites of the fusion protein compared with those of normal RARA. Yet, any contribution of these two properties of PML/RARA to differentiation arrest and immortalization of primary mouse hematopoietic progenitors was unknown. We demonstrate that dimerization-induced silencing mediator of retinoid and thyroid receptors (SMRT)-enhanced binding and relaxed DNA-binding site specificity are both required for efficient immortalization. Thus, enforced RARA dimerization is critical not only for triggering transcriptional repression but also for extending the repertoire of target genes. Our studies exemplify how dimerization-induced gain of functions converts an unessential transcription factor into a dominant oncogenic protein. PMID:16757557

BCL6 interacting corepressor contributes to germinal center T follicular helper cell formation and B cell helper function

PubMed Central

Yang, Jessica A.; Tubo, Noah J.; Gearhart, Micah D.; Bardwell, Vivian J.; Jenkins, Marc K.

2015-01-01

CD4+ germinal center (GC) T follicular helper (GC-Tfh) cells help B cells become long-lived plasma cells and memory cells. The transcriptional repressor BCL6 plays a key role in GC-Tfh formation by inhibiting the expression of genes that promote differentiation into other lineages. We determined whether BCOR, a component of a Polycomb repressive complex that interacts with the BCL6 BTB domain, influences GC-Tfh differentiation. T cell-targeted BCOR deficiency led to a substantial loss of peptide:MHCII-specific GC-Tfh cells following Listeria monocytogenes infection and a 2-fold decrease following immunization with a peptide in CFA. The reduction in GC-Tfh cells was associated with diminished plasma cell and GC B cell formation. Thus, T cell-expressed BCOR is critical for optimal GC-Tfh differentiation and humoral immunity. PMID:25964495

The co-existence of transcriptional activator and transcriptional repressor MEF2 complexes influences tumor aggressiveness

PubMed Central

Di Giorgio, Eros; Franforte, Elisa; Cefalù, Sebastiano; Rossi, Sabrina; Dei Tos, Angelo Paolo; Polano, Maurizio; Maestro, Roberta; Paluvai, Harikrishnareddy

2017-01-01

The contribution of MEF2 TFs to the tumorigenic process is still mysterious. Here we clarify that MEF2 can support both pro-oncogenic or tumor suppressive activities depending on the interaction with co-activators or co-repressors partners. Through these interactions MEF2 supervise histone modifications associated with gene activation/repression, such as H3K4 methylation and H3K27 acetylation. Critical switches for the generation of a MEF2 repressive environment are class IIa HDACs. In leiomyosarcomas (LMS), this two-faced trait of MEF2 is relevant for tumor aggressiveness. Class IIa HDACs are overexpressed in 22% of LMS, where high levels of MEF2, HDAC4 and HDAC9 inversely correlate with overall survival. The knock out of HDAC9 suppresses the transformed phenotype of LMS cells, by restoring the transcriptional proficiency of some MEF2-target loci. HDAC9 coordinates also the demethylation of H3K4me3 at the promoters of MEF2-target genes. Moreover, we show that class IIa HDACs do not bind all the regulative elements bound by MEF2. Hence, in a cell MEF2-target genes actively transcribed and strongly repressed can coexist. However, these repressed MEF2-targets are poised in terms of chromatin signature. Overall our results candidate class IIa HDACs and HDAC9 in particular, as druggable targets for a therapeutic intervention in LMS. PMID:28419090

Silencing the epigenetic silencer KDM4A for TRAIL and DR5 simultaneous induction and antitumor therapy.

PubMed

Wang, Junjian; Wang, Haibin; Wang, Ling-Yu; Cai, Demin; Duan, Zhijian; Zhang, Yanhong; Chen, Peng; Zou, June X; Xu, Jianzhen; Chen, Xinbin; Kung, Hsing-Jien; Chen, Hong-Wu

2016-11-01

Recombinant TRAIL and agonistic antibodies to death receptors (DRs) have been in clinical trial but displayed limited anti-cancer efficacy. Lack of functional DR expression in tumors is a major limiting factor. We report here that chromatin regulator KDM4A/JMJD2A, not KDM4B, has a pivotal role in silencing tumor cell expression of both TRAIL and its receptor DR5. In TRAIL-sensitive and -resistant cancer cells of lung, breast and prostate, KDM4A small-molecule inhibitor compound-4 (C-4) or gene silencing strongly induces TRAIL and DR5 expression, and causes TRAIL-dependent apoptotic cell death. KDM4A inhibition also strongly sensitizes cells to TRAIL. C-4 alone potently inhibits tumor growth with marked induction of TRAIL and DR5 expression in the treated tumors and effectively sensitizes them to the newly developed TRAIL-inducer ONC201. Mechanistically, C-4 does not appear to act through the Akt-ERK-FOXO3a pathway. Instead, it switches histone modifying enzyme complexes at promoters of TRAIL and DR5 transcriptional activator CHOP gene by dissociating KDM4A and nuclear receptor corepressor (NCoR)-HDAC complex and inducing the recruitment of histone acetylase CBP. Thus, our results reveal KDM4A as a key epigenetic silencer of TRAIL and DR5 in tumors and establish inhibitors of KDM4A as a novel strategy for effectively sensitizing tumors to TRAIL pathway-based therapeutics.

Silencing the epigenetic silencer KDM4A for TRAIL and DR5 simultaneous induction and antitumor therapy

PubMed Central

Wang, Junjian; Wang, Haibin; Wang, Ling-Yu; Cai, Demin; Duan, Zhijian; Zhang, Yanhong; Chen, Peng; Zou, June X; Xu, Jianzhen; Chen, Xinbin; Kung, Hsing-Jien; Chen, Hong-Wu

2016-01-01

Recombinant TRAIL and agonistic antibodies to death receptors (DRs) have been in clinical trial but displayed limited anti-cancer efficacy. Lack of functional DR expression in tumors is a major limiting factor. We report here that chromatin regulator KDM4A/JMJD2A, not KDM4B, has a pivotal role in silencing tumor cell expression of both TRAIL and its receptor DR5. In TRAIL-sensitive and -resistant cancer cells of lung, breast and prostate, KDM4A small-molecule inhibitor compound-4 (C-4) or gene silencing strongly induces TRAIL and DR5 expression, and causes TRAIL-dependent apoptotic cell death. KDM4A inhibition also strongly sensitizes cells to TRAIL. C-4 alone potently inhibits tumor growth with marked induction of TRAIL and DR5 expression in the treated tumors and effectively sensitizes them to the newly developed TRAIL-inducer ONC201. Mechanistically, C-4 does not appear to act through the Akt-ERK-FOXO3a pathway. Instead, it switches histone modifying enzyme complexes at promoters of TRAIL and DR5 transcriptional activator CHOP gene by dissociating KDM4A and nuclear receptor corepressor (NCoR)-HDAC complex and inducing the recruitment of histone acetylase CBP. Thus, our results reveal KDM4A as a key epigenetic silencer of TRAIL and DR5 in tumors and establish inhibitors of KDM4A as a novel strategy for effectively sensitizing tumors to TRAIL pathway-based therapeutics. PMID:27612013

Maximum Correntropy Unscented Kalman Filter for Ballistic Missile Navigation System based on SINS/CNS Deeply Integrated Mode.

PubMed

Hou, Bowen; He, Zhangming; Li, Dong; Zhou, Haiyin; Wang, Jiongqi

2018-05-27

Strap-down inertial navigation system/celestial navigation system ( SINS/CNS) integrated navigation is a high precision navigation technique for ballistic missiles. The traditional navigation method has a divergence in the position error. A deeply integrated mode for SINS/CNS navigation system is proposed to improve the navigation accuracy of ballistic missile. The deeply integrated navigation principle is described and the observability of the navigation system is analyzed. The nonlinearity, as well as the large outliers and the Gaussian mixture noises, often exists during the actual navigation process, leading to the divergence phenomenon of the navigation filter. The new nonlinear Kalman filter on the basis of the maximum correntropy theory and unscented transformation, named the maximum correntropy unscented Kalman filter, is deduced, and the computational complexity is analyzed. The unscented transformation is used for restricting the nonlinearity of the system equation, and the maximum correntropy theory is used to deal with the non-Gaussian noises. Finally, numerical simulation illustrates the superiority of the proposed filter compared with the traditional unscented Kalman filter. The comparison results show that the large outliers and the influence of non-Gaussian noises for SINS/CNS deeply integrated navigation is significantly reduced through the proposed filter.

Piecewise compensation for the nonlinear error of fiber-optic gyroscope scale factor

NASA Astrophysics Data System (ADS)

Zhang, Yonggang; Wu, Xunfeng; Yuan, Shun; Wu, Lei

2013-08-01

Fiber-Optic Gyroscope (FOG) scale factor nonlinear error will result in errors in Strapdown Inertial Navigation System (SINS). In order to reduce nonlinear error of FOG scale factor in SINS, a compensation method is proposed in this paper based on curve piecewise fitting of FOG output. Firstly, reasons which can result in FOG scale factor error are introduced and the definition of nonlinear degree is provided. Then we introduce the method to divide the output range of FOG into several small pieces, and curve fitting is performed in each output range of FOG to obtain scale factor parameter. Different scale factor parameters of FOG are used in different pieces to improve FOG output precision. These parameters are identified by using three-axis turntable, and nonlinear error of FOG scale factor can be reduced. Finally, three-axis swing experiment of SINS verifies that the proposed method can reduce attitude output errors of SINS by compensating the nonlinear error of FOG scale factor and improve the precision of navigation. The results of experiments also demonstrate that the compensation scheme is easy to implement. It can effectively compensate the nonlinear error of FOG scale factor with slightly increased computation complexity. This method can be used in inertial technology based on FOG to improve precision.

Sinomenine Hydrochloride Attenuates Renal Fibrosis by Inhibiting Excessive Autophagy Induced by Adriamycin: An Experimental Study

PubMed Central

Zhao, Ming-ming

2017-01-01

The objective of this study is to investigate if sinomenine hydrochloride (SIN-HCl) could be effective against adriamycin-induced renal fibrosis by regulating autophagy in a rat model. Forty male Sprague-Dawley (SD) rats were randomly divided into control group, model group, telmisartan group, and SIN-HCl group; rat model was induced by adriamycin; all rats were given intragastric administration for 6 weeks. Urine was collected from rats in metabolic cages to determine 24 h protein level. This was done after intragastric administration for the first two weeks and then once for every two weeks. Renal pathological changes were examined by the staining of HE, Masson, and PASM. Expressions and distributions of fibronectin (FN), laminin (LN), light chain 3 (LC3), and Beclin-1 were observed by immunohistochemistry. SIN-HCl ameliorates proteinuria, meanwhile attenuating the renal pathological changes in adriamycin-induced rats and also attenuating renal fibrosis and excessive autophagy by reducing the expression of FN, LN, LC3, and Beclin-1. SIN-HCl attenuates renal fibrosis by inhibiting excessive autophagy induced by adriamycin and upregulates the basal autophagy. PMID:28798804

Molecular characterization of the pSinB plasmid of the arsenite oxidizing, metallotolerant Sinorhizobium sp. M14 - insight into the heavy metal resistome of sinorhizobial extrachromosomal replicons.

PubMed

Romaniuk, Krzysztof; Dziewit, Lukasz; Decewicz, Przemyslaw; Mielnicki, Sebastian; Radlinska, Monika; Drewniak, Lukasz

2017-01-01

Sinorhizobium sp. M14 is an As(III)-oxidizing, psychrotolerant strain, capable of growth in the presence of extremely high concentrations of arsenic and many other heavy metals. Metallotolerant abilities of the M14 strain depend upon the presence of two extrachromosomal replicons: pSinA (∼ 109 kb) and pSinB (∼ 300 kb). The latter was subjected to complex analysis. The performed analysis demonstrated that the plasmid pSinB is a narrow-host-range repABC-type replicon, which is fully stabilized by the phd-vapC-like toxin-antitoxin stabilizing system. In silico analysis showed that among the phenotypic gene clusters of the plasmid pSinB, eight modules are potentially involved in heavy metals resistance (HMR). These modules carry genes encoding efflux pumps, permeases, transporters and copper oxidases, which provide resistance to arsenic, cadmium, cobalt, copper, iron, mercury, nickel, silver and zinc. The functional analysis revealed that the HMR modules are active and have an effect on the minimal inhibitory concentration (MIC) values observed for the heterological host cells. The phenotype was manifested by an increase or decrease of the MICs of heavy metals and it was strain specific. The analysis of distribution of the heavy metal resistance genes, i.e. resistome, in Sinorhizobium spp. plasmids, revealed that the HMR modules are common in these replicons. © FEMS 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

APACK, A Combined Antenna and Propagation Model.

DTIC Science & Technology

1981-07-01

sin6 [-e- klUl1 + R e-j2kHcose 1- eck " 2 v’s 6 - -j k£l3 (1-R) Fe ei Hcose (sin 2 -case) l- 3 J n3 Ee 30 1 e-jkr cas ja( + 8) -2 Me~ cs -ea os o + 1...IPE DISTRIBUTION LIST FOR ESD-TR-80-102 CoQntinued)I Defense Technical Information (Bnter 12 Cameron Station Alexandria, VA 22314 AFGL

A Simple Auxin Transcriptional Response System Regulates Multiple Morphogenetic Processes in the Liverwort Marchantia polymorpha

PubMed Central

Flores-Sandoval, Eduardo; Eklund, D. Magnus; Bowman, John L.

2015-01-01

In land plants comparative genomics has revealed that members of basal lineages share a common set of transcription factors with the derived flowering plants, despite sharing few homologous structures. The plant hormone auxin has been implicated in many facets of development in both basal and derived lineages of land plants. We functionally characterized the auxin transcriptional response machinery in the liverwort Marchantia polymorpha, a member of the basal lineage of extant land plants. All components known from flowering plant systems are present in M. polymorpha, but they exist as single orthologs: a single MpTOPLESS (TPL) corepressor, a single MpTRANSPORT INHIBITOR RESPONSE 1 auxin receptor, single orthologs of each class of AUXIN RESPONSE FACTOR (ARF; MpARF1, MpARF2, MpARF3), and a single negative regulator AUXIN/INDOLE-3-ACETIC ACID (MpIAA). Phylogenetic analyses suggest this simple system is the ancestral condition for land plants. We experimentally demonstrate that these genes act in an auxin response pathway — chimeric fusions of the MpTPL corepressor with heterodimerization domains of MpARF1, MpARF2, or their negative regulator, MpIAA, generate auxin insensitive plants that lack the capacity to pattern and transition into mature stages of development. Our results indicate auxin mediated transcriptional regulation acts as a facilitator of branching, differentiation and growth, rather than acting to determine or specify tissues during the haploid stage of the M. polymorpha life cycle. We hypothesize that the ancestral role of auxin is to modulate a balance of differentiated and pluri- or totipotent cell states, whose fates are determined by interactions with combinations of unrelated transcription factors. PMID:26020649

The peroxynitrite donor 3-morpholinosydnonimine induces reversible changes in electrophysiological properties of neurons of the guinea-pig spinal cord.

PubMed

Ashki, N; Hayes, K C; Bao, F

2008-09-22

Elevated concentrations of nitric oxide (NO) and peroxynitrite (ONOO(-)) are present within the CNS following neurotrauma and are implicated in the pathogenesis of the accompanying neurologic deficits. We tested the hypothesis that elevated extracellular concentrations of ONOO(-), introduced by the donor 3-morpholinosydnonimine (SIN-1), induce reversible axonal conduction deficits in neurons of the guinea-pig spinal cord. The compound action potential (CAP) and compound membrane potential (CMP) of excised ventral cord white matter were recorded before, during, and after, bathing the tissue (30 min) in varying concentrations (0.125-2.0 mM) of SIN-1 (3.75-60 microM ONOO(-)). The principal results were rapid onset, concentration-dependent, reductions in amplitude of the CAP (P<0.05). At a concentration of 0.25 mM of SIN-1 the reduction in CAP amplitude was fully reversible and was not accompanied by any changes in CMP. At higher concentrations of SIN-1 (> or =0.5 mM) the reversibility was incomplete and there was concurrent depolarization of the CMP. These electrophysiological changes were not evident when the donor had been a priori depleted of ONOO(-) by uric acid or was co-administered with the ONOO(-) scavenger ebselen (3 mM). Immuno-fluorescence staining for nitrotyrosine (Ntyr) revealed extensive nitration of tyrosine residues in neurons exposed to higher concentrations of SIN-1. These results are the first to demonstrate that ONOO(-) induces reversible conduction deficits within axons of the spinal cord. The dissociation of CAP and CMP changes at low concentrations of SIN-1, when the CAP changes were reversible and there was no evidence of nitration of tyrosine residues, is consistent with ONOO(-)-induced alteration in Na+ channel conductance in the axolemma. The results support the view that ONOO(-) contributes to both reversible and non-reversible neurologic deficits following neurotrauma. The reversal of immune-mediated conduction deficits may contribute to spontaneous neurologic deficits following neurotrauma.

G-quadruplex RNA binding and recognition by the lysine-specific histone demethylase-1 enzyme.

PubMed

Hirschi, Alexander; Martin, William J; Luka, Zigmund; Loukachevitch, Lioudmila V; Reiter, Nicholas J

2016-08-01

Lysine-specific histone demethylase 1 (LSD1) is an essential epigenetic regulator in metazoans and requires the co-repressor element-1 silencing transcription factor (CoREST) to efficiently catalyze the removal of mono- and dimethyl functional groups from histone 3 at lysine positions 4 and 9 (H3K4/9). LSD1 interacts with over 60 regulatory proteins and also associates with lncRNAs (TERRA, HOTAIR), suggesting a regulatory role for RNA in LSD1 function. We report that a stacked, intramolecular G-quadruplex (GQ) forming TERRA RNA (GG[UUAGGG]8UUA) binds tightly to the functional LSD1-CoREST complex (Kd ≈ 96 nM), in contrast to a single GQ RNA unit ([UUAGGG]4U), a GQ DNA ([TTAGGG]4T), or an unstructured single-stranded RNA. Stabilization of a parallel-stranded GQ RNA structure by monovalent potassium ions (K(+)) is required for high affinity binding to the LSD1-CoREST complex. These data indicate that LSD1 can distinguish between RNA and DNA as well as structured versus unstructured nucleotide motifs. Further, cross-linking mass spectrometry identified the primary location of GQ RNA binding within the SWIRM/amine oxidase domain (AOD) of LSD1. An ssRNA binding region adjacent to this GQ binding site was also identified via X-ray crystallography. This RNA binding interface is consistent with kinetic assays, demonstrating that a GQ-forming RNA can serve as a noncompetitive inhibitor of LSD1-catalyzed demethylation. The identification of a GQ RNA binding site coupled with kinetic data suggests that structured RNAs can function as regulatory molecules in LSD1-mediated mechanisms. © 2016 Hirschi et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society.

G-quadruplex RNA binding and recognition by the lysine-specific histone demethylase-1 enzyme

PubMed Central

Hirschi, Alexander; Martin, William J.; Luka, Zigmund; Loukachevitch, Lioudmila V.; Reiter, Nicholas J.

2016-01-01

Lysine-specific histone demethylase 1 (LSD1) is an essential epigenetic regulator in metazoans and requires the co-repressor element-1 silencing transcription factor (CoREST) to efficiently catalyze the removal of mono- and dimethyl functional groups from histone 3 at lysine positions 4 and 9 (H3K4/9). LSD1 interacts with over 60 regulatory proteins and also associates with lncRNAs (TERRA, HOTAIR), suggesting a regulatory role for RNA in LSD1 function. We report that a stacked, intramolecular G-quadruplex (GQ) forming TERRA RNA (GG[UUAGGG]8UUA) binds tightly to the functional LSD1–CoREST complex (Kd ≈ 96 nM), in contrast to a single GQ RNA unit ([UUAGGG]4U), a GQ DNA ([TTAGGG]4T), or an unstructured single-stranded RNA. Stabilization of a parallel-stranded GQ RNA structure by monovalent potassium ions (K+) is required for high affinity binding to the LSD1–CoREST complex. These data indicate that LSD1 can distinguish between RNA and DNA as well as structured versus unstructured nucleotide motifs. Further, cross-linking mass spectrometry identified the primary location of GQ RNA binding within the SWIRM/amine oxidase domain (AOD) of LSD1. An ssRNA binding region adjacent to this GQ binding site was also identified via X-ray crystallography. This RNA binding interface is consistent with kinetic assays, demonstrating that a GQ-forming RNA can serve as a noncompetitive inhibitor of LSD1-catalyzed demethylation. The identification of a GQ RNA binding site coupled with kinetic data suggests that structured RNAs can function as regulatory molecules in LSD1-mediated mechanisms. PMID:27277658

Dopamine Dysfunction in DYT1 Dystonia

DTIC Science & Technology

2015-07-01

20mM Tris-Cl (pH 7.6), 137 mM NaCl, 0.1% Tween 20, the membranes were incubated overnight at 4°C with rabbit anti-tor- sinA antibody (1:500; Abcam...during the juvenile period to changes in tor- sinA expression or function. Another consideration is the potential compensatory effects of torsinB, which...Buckley AC, Burdette AJ, et al. (2010) Chemical enhancement of tor- sinA function in cell and animal models of torsion dystonia. Dis Model Mech 3: 386–396

Influence of barrier absorption properties on laser patterning thin organic films

NASA Astrophysics Data System (ADS)

Naithani, Sanjeev; Mandamparambil, Rajesh; van Assche, Ferdie; Schaubroeck, David; Fledderus, Henri; Prenen, An; Van Steenberge, Geert; Vanfleteren, Jan

2012-06-01

This paper presents a study of selective ablation of thin organic films (LEP- Light Emitting Polymer, PEDOT:PSS- Poly 3,4-ethylenedioxythiophene: polystyrene sulfonate) by using 248 nm Excimer laser, on various kinds of multilayered SiN barrier foils for the development of Organic Light Emitting Diodes (OLED). Different Silicon Nitride (SiN) barrier foils with dedicated absorption spectra are taken into account for this purpose. The drive for looking into different types of SiN originates from the fact that the laser selective removal of a polymer without damage to the barrier layer underneath is challenging in the dynamic laser processing of thin films. The barrier is solely responsible for the proper encapsulation of the OLED stack. The main limitation of current OLED design is its shorter life span, which is directly related to the moisture or water permeation into the stack, leading to black spots. An optimization of laser parameters like fluence and number of shots has been carried out for the various types of SiN barrier foils. We are able to obtain a wider working process window for the selective removal of LEP and PEDOT:PSS from SiN barrier, by variation of the different types of SiN.

Silicon Nitride Deposition for Flexible Organic Electronic Devices by VHF (162 MHz)-PECVD Using a Multi-Tile Push-Pull Plasma Source.

PubMed

Kim, Ki Seok; Kim, Ki Hyun; Ji, You Jin; Park, Jin Woo; Shin, Jae Hee; Ellingboe, Albert Rogers; Yeom, Geun Young

2017-10-19

Depositing a barrier film for moisture protection without damage at a low temperature is one of the most important steps for organic-based electronic devices. In this study, the authors investigated depositing thin, high-quality SiN x film on organic-based electronic devices, specifically, very high-frequency (162 MHz) plasma-enhanced chemical vapor deposition (VHF-PECVD) using a multi-tile push-pull plasma source with a gas mixture of NH 3 /SiH 4 at a low temperature of 80 °C. The thin deposited SiN x film exhibited excellent properties in the stoichiometry, chemical bonding, stress, and step coverage. Thin film quality and plasma damage were investigated by the water vapor transmission rate (WVTR) and by electrical characteristics of organic light-emitting diode (OLED) devices deposited with SiN x , respectively. The thin deposited SiN x film exhibited a low WVTR of 4.39 × 10 -4  g (m 2 · day) -1 for a single thin (430 nm thick) film SiN x and the electrical characteristics of OLED devices before and after the thin SiN x film deposition on the devices did not change, which indicated no electrical damage during the deposition of SiN x on the OLED device.

Stress engineering in GaN structures grown on Si(111) substrates by SiN masking layer application

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

Szymański, Tomasz, E-mail: tomasz.szymanski@pwr.edu.pl; Wośko, Mateusz; Paszkiewicz, Bogdan

2015-07-15

GaN layers without and with an in-situ SiN mask were grown by using metal organic vapor phase epitaxy for three different approaches used in GaN on silicon(111) growth, and the physical and optical properties of the GaN layers were studied. For each approach applied, GaN layers of 1.4 μm total thickness were grown, using silan SiH{sub 4} as Si source in order to grow Si{sub x}N{sub x} masking layer. The optical micrographs, scanning electron microscope images, and atomic force microscope images of the grown samples revealed cracks for samples without SiN mask, and micropits, which were characteristic for the samples grownmore » with SiN mask. In situ reflectance signal traces were studied showing a decrease of layer coalescence time and higher degree of 3D growth mode for samples with SiN masking layer. Stress measurements were conducted by two methods—by recording micro-Raman spectra and ex-situ curvature radius measurement—additionally PLs spectra were obtained revealing blueshift of PL peak positions with increasing stress. The authors have shown that a SiN mask significantly improves physical and optical properties of GaN multilayer systems reducing stress in comparison to samples grown applying the same approaches but without SiN masking layer.« less

Reducing Line Edge Roughness in Si and SiN through plasma etch chemistry optimization for photonic waveguide applications

NASA Astrophysics Data System (ADS)

Marchack, Nathan; Khater, Marwan; Orcutt, Jason; Chang, Josephine; Holmes, Steven; Barwicz, Tymon; Kamlapurkar, Swetha; Green, William; Engelmann, Sebastian

2017-03-01

The LER and LWR of subtractively patterned Si and SiN waveguides was calculated after each step in the process. It was found for Si waveguides that adjusting the ratio of CF4:CHF3 during the hard mask open step produced reductions in LER of 26 and 43% from the initial lithography for isolated waveguides patterned with partial and full etches, respectively. However for final LER values of 3.0 and 2.5 nm on fully etched Si waveguides, the corresponding optical loss measurements were indistinguishable. For SiN waveguides, introduction of C4H9F to the conventional CF4/CHF3 measurement was able to reduce the mask height budget by a factor of 5, while reducing LER from the initial lithography by 26%.

Proto-oncogene FBI-1 (Pokemon/ZBTB7A) represses transcription of the tumor suppressor Rb gene via binding competition with Sp1 and recruitment of co-repressors.

PubMed

Jeon, Bu-Nam; Yoo, Jung-Yoon; Choi, Won-Il; Lee, Choong-Eun; Yoon, Ho-Geun; Hur, Man-Wook

2008-11-28

FBI-1 (also called Pokemon/ZBTB7A) is a BTB/POZ-domain Krüppel-like zinc-finger transcription factor. Recently, FBI-1 was characterized as a proto-oncogenic protein, which represses tumor suppressor ARF gene transcription. The expression of FBI-1 is increased in many cancer tissues. We found that FBI-1 potently represses transcription of the Rb gene, a tumor suppressor gene important in cell cycle arrest. FBI-1 binds to four GC-rich promoter elements (FREs) located at bp -308 to -188 of the Rb promoter region. The Rb promoter also contains two Sp1 binding sites: GC-box 1 (bp -65 to -56) and GC-box 2 (bp -18 to -9), the latter of which is also bound by FBI-1. We found that FRE3 (bp -244 to -236) is also a Sp1 binding element. FBI-1 represses transcription of the Rb gene not only by binding to the FREs, but also by competing with Sp1 at the GC-box 2 and the FRE3. By binding to the FREs and/or the GC-box, FBI-1 represses transcription of the Rb gene through its POZ-domain, which recruits a co-repressor-histone deacetylase complex and deacetylates histones H3 and H4 at the Rb gene promoter. FBI-1 inhibits C2C12 myoblast cell differentiation by repressing Rb gene expression.

New Precision Orbits of Bright Double-lined Spectroscopic Binaries. X. HD 96511, HR 7578, and KZ Andromedae

NASA Astrophysics Data System (ADS)

Fekel, Francis C.; Henry, Gregory W.; Tomkin, Jocelyn

2017-09-01

From an extensive number of newly acquired radial velocities we determine the orbital elements for three late-type dwarf systems, HD 96511, HR 7578, and KZ And. The orbital periods are 18.89737 ± 0.00002, 46.81610 ± 0.00006, and 3.0329113 ± 0.0000005 days, respectively, and all three systems are eccentric, although KZ And is just barely so. We have detected lines of the secondary of HD 96511 for the first time. The orbital dimensions (a 1 sin I and a 2 sin I) and minimum masses (m 1 sin3 I and m 2 sin3 I) of the binary components all have accuracies of 0.2% or better. Extensive photometry of the chromospherically active binary HR 7578 confirms a rather long rotation period of 16.446 ± 0.002 days and that the K3 V components do not eclipse. We have estimated the basic properties of the stars in the three systems and compared those results with evolutionary tracks. The results for KZ And that we computed with the revised Hipparcos parallax of van Leeuwen produce inconsistencies. That parallax appears to be too large, and so, instead, we used the original Hipparcos parallax of the common proper motion primary, which improves the results, although some problems remain.

--No Title--

Science.gov Websites

sin(2*pi*T) - 0.012 cos(2*pi*T) - 0.006 sin(4*pi*T) + 0.007 cos(4*pi*T) where pi = 3.14159265... and T 2018 6 2 58271 0.1170 0.4482 0.07673 2018 6 3 58272 0.1187 0.4480 0.07651 2018 6 4 58273 0.1203 0.4478 2018 7 2 58301 0.1626 0.4344 0.07174 2018 7 3 58302 0.1639 0.4336 0.07210 2018 7 4 58303 0.1652 0.4328

Signaling coupled epigenomic regulation of gene expression.

PubMed

Kumar, R; Deivendran, S; Santhoshkumar, T R; Pillai, M R

2017-10-26

Inheritance of genomic information independent of the DNA sequence, the epigenetics, as well as gene transcription are profoundly shaped by serine/threonine and tyrosine signaling kinases and components of the chromatin remodeling complexes. To precisely respond to a changing external milieu, human cells efficiently translate upstream signals into post-translational modifications (PTMs) on histones and coregulators such as corepressors, coactivators, DNA-binding factors and PTM modifying enzymes. Because a protein with multiple residues for putative PTMs is expected to undergo more than one PTM in cells stimulated with growth factors, the outcome of combinational PTM codes on histones and coregulators is profoundly shaped by regulatory interplays between PTMs. The genomic functions of signaling kinases in cancer cells are manifested by the downstream effectors of cytoplasmic signaling cascades as well as translocation of the cytoplasmic signaling kinases to the nucleus. Signaling-mediated phosphorylation of histones serves as a regulatory switch for other PTMs, and connects chromatin remodeling complexes into gene transcription and gene activity. Here, we will discuss the recent advances in signaling-dependent epigenomic regulation of gene transcription using a few representative cancer-relevant serine/threonine and tyrosine kinases and their interplay with chromatin remodeling factors in cancer cells.

miR-1271 inhibits ERα expression and confers letrozole resistance in breast cancer.

PubMed

Yu, Tao; Yu, Hai-Ru; Sun, Jia-Yi; Zhao, Zhao; Li, Shuang; Zhang, Xin-Feng; Liao, Zhi-Xuan; Cui, Ming-Ke; Li, Juan; Li, Chan; Zhang, Qiang

2017-12-05

Attenuation of estrogen receptor α (ERα) expression via unknown mechanism(s) is a hallmark of endocrine-resistant breast cancer (BCa) progression. Here, we report that miR-1271 was significantly down-regulated in letrozole-resistant BCa tissues and in letrozole-resistant BCa cells. miR-1271 directly targeted the chromatin of DNA damage-inducible transcript 3 (DDIT3) gene. miR-1271 expression level was inversely correlated to DDIT3 mRNA level in BCa biopsies. Form a mechanistic standpoint, reintroduction of exogenous miR-1271 could effectively restore ERα level via inhibiting DDIT3 expression, thereby potentiating letrozole sensitivity in BCa cells. Moreover, DDIT3 deregulation promoted letrozole-resistance by acting as a potent corepressor of ESR1 transcription. Taken together, we have identified that disruption of the miR-1271/DDIT3/ERα cascade plays a causative role in the pathogenesis of letrozole resistance in BCa.

Pleiotropic roles of Clostridium difficile sin locus

PubMed Central

Ou, Junjun; Dupuy, Bruno

2018-01-01

Clostridium difficile is the primary cause of nosocomial diarrhea and pseudomembranous colitis. It produces dormant spores, which serve as an infectious vehicle responsible for transmission of the disease and persistence of the organism in the environment. In Bacillus subtilis, the sin locus coding SinR (113 aa) and SinI (57 aa) is responsible for sporulation inhibition. In B. subtilis, SinR mainly acts as a repressor of its target genes to control sporulation, biofilm formation, and autolysis. SinI is an inhibitor of SinR, so their interaction determines whether SinR can inhibit its target gene expression. The C. difficile genome carries two sinR homologs in the operon that we named sinR and sinR’, coding for SinR (112 aa) and SinR’ (105 aa), respectively. In this study, we constructed and characterized sin locus mutants in two different C. difficile strains R20291 and JIR8094, to decipher the locus’s role in C. difficile physiology. Transcriptome analysis of the sinRR’ mutants revealed their pleiotropic roles in controlling several pathways including sporulation, toxin production, and motility in C. difficile. Through various genetic and biochemical experiments, we have shown that SinR can regulate transcription of key regulators in these pathways, which includes sigD, spo0A, and codY. We have found that SinR’ acts as an antagonist to SinR by blocking its repressor activity. Using a hamster model, we have also demonstrated that the sin locus is needed for successful C. difficile infection. This study reveals the sin locus as a central link that connects the gene regulatory networks of sporulation, toxin production, and motility; three key pathways that are important for C. difficile pathogenesis. PMID:29529083

Surface Second Harmonic Generation Studies of Stepped Ag(111) Electrode Surfaces

DTIC Science & Technology

1993-05-27

Surface Warfare Center China Lake, CA 93555-6001 Carderock Division Detachment Annapolis, MD 21402-1198 Dr. Elek Lindner (1) Naval Command, Contrl and...polarized pump beam at frequency (t. (2,W) (,( d) sin(3)p)qS’ , ,si ,p Eq. 3 with dj" =FXzf f, 10 d3 sin(3(p) Eq.4 with d = F1z)fkfk where the...electrodes at an applied potential of -0.5 V as a function of azimuthal angle for s-polarized SHG and s-polarized pump beam. Shown are measurements on

Nuclear receptor TLX prevents retinal dystrophy and recruits the corepressor atrophin1.

PubMed

Zhang, Chun-Li; Zou, Yuhua; Yu, Ruth T; Gage, Fred H; Evans, Ronald M

2006-05-15

During mammalian embryogenesis, precise coordination of progenitor cell proliferation and differentiation is essential for proper organ size and function. The involvement of TLX (NR2E1), an orphan nuclear receptor, has been implicated in ocular development, as Tlx-/- mice exhibit visual impairment. Using genetic and biochemical approaches, we show that TLX modulates retinal progenitor cell proliferation and cell cycle re-entry by directly regulating the expression of Pten and its target cyclin D1. Additionally, TLX finely tunes the progenitor differentiation program by modulating the phospholipase C and mitogen-activated protein kinase (MAPK) pathways and the expression of an array of cell type-specific transcriptional regulators. Consequently, Tlx-/- mice have a dramatic reduction in retina thickness and enhanced generation of S-cones, and develop severe early onset retinal dystrophy. Furthermore, TLX interacts with atrophin1 (Atn1), a corepressor that is involved in human neurodegenerative dentatorubral-pallidoluysian atrophy (DRPLA) and that is essential for development of multiple tissues. Together, these results reveal a molecular strategy by which an orphan nuclear receptor can precisely orchestrate tissue-specific proliferation and differentiation programs to prevent retinal malformation and degeneration.

AES/GRG5: more than just a dominant-negative TLE/GRG family member.

PubMed

Beagle, Brandon; Johnson, Gail V W

2010-11-01

The human Transducin-like Enhancer of Split (TLE) and mouse homologue, Groucho gene-related protein (GRG), represent a family of conserved non-DNA binding transcriptional modulatory proteins divided into two subgroups based upon size. The long TLE/GRGs consist of four pentadomain proteins that are dedicated co-repressors for multiple transcription factors (TF). The second TLE/GRG subgroup is composed of the Amino-terminal Enhancer of Split (AES) in humans and its mouse homolog GRG5 (AES/GRG5). In contrast to the dedicated co-repressor function of long TLE/GRGs, AES/GRG5 can both positively or negatively modulate various TF as well as non-TF proteins in a long TLE/GRG-dependent or -independent manner. Therefore, AES/GRG5 is a functionally dynamic protein that is not exclusively defined by its role as a long TLE/GRG antagonist. AES/GRG5 may function in various developmental and pathological processes but the functional characteristics of endogenous AES/GRG5 in a physiologically relevant context remains to be determined. © 2010 Wiley-Liss, Inc.

Protective effects of Lagerstroemia speciosa on 3-morpholinosydnonimine (SIN-1)-induced oxidative stress in HIT-T15 pancreatic β cells.

PubMed

Song, Jia-Le; Zhao, Xin; Wang, Qiang; Zhang, Ting

2013-05-01

Reactive oxygen species (ROS)-induced pancreatic β cell death affects insulin secretion and is important in the pathogenesis of diabetes. Lagerstroemia speciosa, a traditional folk medicine, has been used for t he prevention and treatment of diabetes. However, whether Lagerstroemia speciosa has a cytoprotective effect on pancreatic β cells remains to be elucidated. The present study aimed to investigate the cytoprotective effects of hot water extracts from Lagerstroemia speciosa leaves (LWE) on 3-morpholinosydnonimine (SIN-1)-induced oxidative damage in Syrian hamster pancreatic insulinoma HIT-T15 cells. The HIT-T15 cells were first treated with SIN-1 (50 µM) for 24 h and then co-incubated with LWE for 48 h. SIN-1 significantly decreased HIT-T15 cell viability (P<0.05); however, LWE did not exert a significant cytotoxic effect and increased the viability of HIT-T15 cells in a dose‑dependent manner. To further investigate the protective effects of LWE on SIN-1‑induced oxidative stress in HIT-T15 cells, the cellular levels of ROS, lipid peroxidation and endogenous antioxidant enzymes, including superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-px), were determined. LWE decreased the intracellular levels of ROS and lipid peroxidation, and increased the activities of antioxidant enzymes. These results suggest that LWE has a cytoprotective effect against SIN-1‑induced oxidative stress in HIT-T15 cells through the inhibition of lipid peroxidation, a decrease in ROS levels and an increase in antioxidant enzyme activity. In addition, LWE increased insulin secretion in SIN-1-treated HIT-T15 cells. Our results suggested that LWE were effective in the treatment of diabetes. Further studies are required to study the anti-diabetic molecular mechanism in a cell model.

Verification of a Micro-Thrusting Model to Maintain Satellites in Low Orbit.

DTIC Science & Technology

1987-06-01

RND*DT*DT CL2PzAMOD(CL2P,6 .283185307179600) IF(CL2P)520, 530,530 520 CLZP=CL2P+6.Z831853071796D0 530 GZP =G1ZPm0T+GoZP H2PzHl2P*DT+H0ZP SINEG=SIN...EDLz.500NE2P*CLZIP*SIN (2.* GZP )+C8*CDSING+E2P*Cl*COS (S.*OZP)- 1 ETA3*D2 AID14.:SIN(CL2P) AID15zCOS(CLZP) ESLCE *AID14+EDL*AI0l5 ECLsC! *AID15

Isotropic plasma etching of Ge Si and SiN x films

DOE PAGES

Henry, Michael David; Douglas, Erica Ann

2016-08-31

This study reports on selective isotropic dry etching of chemically vapor deposited (CVD) Ge thin film, release layers using a Shibaura chemical downstream etcher (CDE) with NF 3 and Ar based plasma chemistry. Relative etch rates between Ge, Si and SiN x are described with etch rate reductions achieved by adjusting plasma chemistry with O 2. Formation of oxides reducing etch rates were measured for both Ge and Si, but nitrides or oxy-nitrides created using direct injection of NO into the process chamber were measured to increase Si and SiN x etch rates while retarding Ge etching.

Diffraction Effects in Directed Radiation Beams

DTIC Science & Technology

1990-04-03

cosP acosO )/sin a sinJ], 0 / ’V< a , and Oga cos’ j (a-ct)/Yj, ()< 13 a < Rt/2, and where (r, t) is ident ical to t (I- t ) e:.:cep• that a i1 IepIac ed...Toraldo di Francia , NuoVo Cimento, Suppl. 9, 426 (1952)> 3. W T. Welford, Qptics, (Onfordi University Press, New York, 1981), chap. 3. 4. C.. J. Bouwkarnp

Recent Results from the Daya Bay Reactor Neutrino Experiment

NASA Astrophysics Data System (ADS)

Huang, En-Chuan

2016-11-01

The Daya Bay Reactor Neutrino Experiment is designed to precisely measure the mixing parameter sin2 2θ13 via relative measurements with eight functionally identical antineutrino detectors (ADs). In 2012, Daya Bay has first measured a non-zero sin2 2θ13 value with a significance larger than 5σ with the first six ADs. With the installation of two new ADs to complete the full configuration, Daya Bay has continued to increase statistics and lower systematic uncertainties for better precision of sin2 2θ13 and for the exploration of other physics topics. In this proceeding, the latest analysis results of sin2 2θ13 and |Δm 2 ee|, including a measurement made with neutron capture on Gadolinium and an independent measurement made with neutron capture on hydrogen are presented. The latest results of the search for sterile neutrino in the mass splitting range of 10-3 eV2 < |Δm 2 41| < 0.3 eV2 and the absolute measurement of the rate and energy spectrum of reactor antineutrinos will also be presented.

Low-temperature SiON films deposited by plasma-enhanced atomic layer deposition method using activated silicon precursor

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

Suh, Sungin; Kim, Jun-Rae; Kim, Seongkyung

2016-01-15

It has not been an easy task to deposit SiN at low temperature by conventional plasma-enhanced atomic layer deposition (PE-ALD) since Si organic precursors generally have high activation energy for adsorption of the Si atoms on the Si-N networks. In this work, in order to achieve successful deposition of SiN film at low temperature, the plasma processing steps in the PE-ALD have been modified for easier activation of Si precursors. In this modification, the efficiency of chemisorption of Si precursor has been improved by additional plasma steps after purging of the Si precursor. As the result, the SiN films preparedmore » by the modified PE-ALD processes demonstrated higher purity of Si and N atoms with unwanted impurities such as C and O having below 10 at. % and Si-rich films could be formed consequently. Also, a very high step coverage ratio of 97% was obtained. Furthermore, the process-optimized SiN film showed a permissible charge-trapping capability with a wide memory window of 3.1 V when a capacitor structure was fabricated and measured with an insertion of the SiN film as the charge-trap layer. The modified PE-ALD process using the activated Si precursor would be one of the most practical and promising solutions for SiN deposition with lower thermal budget and higher cost-effectiveness.« less

Photoluminescence properties of arsenic and boron doped Si3N4 nanocrystal embedded in SiN x O y matrix

NASA Astrophysics Data System (ADS)

Puglia, Denise; Sombrio, Guilherme; dos Reis, Roberto; Boudinov, Henri

2018-03-01

Photoluminescence emission of Si3N4 nanocrystals embedded in SiN x O y matrices was investigated. Nanocrystals were grown by annealing of silicon oxynitride films deposited by sputtering, passivated in forming gas atmosphere and implanted with boron and arsenic. Emission energy was tuned from green to ultraviolet by changing the composition of SiN x O y matrices. Structural characterization of the nanocrystals was performed by Transmission Electron Microscopy. Photoluminescence at room and low temperatures was analyzed and the results suggest that light emission originates in the interface between the nanocrystals and the matrix. The highest photoluminescence intensity at room temperature was achieved by arsenic doped silicon oxynitride films deposited with an excess of nitrogen.

Low temperature ECR-CVD of SiN X for III-V device passivation

NASA Astrophysics Data System (ADS)

Lee, J. W.; MacKenzie, K.; Johnson, D.; Shul, R. J.; Pearton, S. J.; Ren, F.

1998-06-01

Electron Cyclotron Resonance SiH 4/N 2 and SiH 4/NH 3 discharges have been employed for deposition of SiN X over a range of temperatures (25-120°C), source powers (200-700 W), pressures (15-40 mTorr), SiH 4 percentages (20-50%) and additional Ar flow rates (0-30 sccm). Deposition rates were in the range 100-700 Å min -1, with refractive indices of 1.7-2.3. The SiH 4/N 2 chemistry allowed a wider process window for tailoring the stress in the SiN X films, with chuck temperature, ECR source power, chamber pressure, SiH 4 composition and Ar addition all producing a transition from compressive to tensile stress, or vice-versa.

New simple A{sub 4} neutrino model for nonzero {theta}{sub 13} and large {delta}{sub CP}

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

Ishimori, Hajime

In a new simple application of the non-Abelian discrete symmetry A{sub 4} to charged-lepton and neutrino mass matrices, we show that for the current experimental central value of sin{sup 2} 2{theta}{sub 13} Asymptotically-Equal-To 0.1, leptonic CP violation is necessarily large, i.e. Double-Vertical-Line tan{delta}{sub CP} Double-Vertical-Line > 1.3. We also consider T{sub 7} model with one parameter to be complex, thus allowing for one Dirac CP phase {delta}{sub CP} and two Majorana CP phases {alpha}{sub 1,2}. We find a slight modification to this correlation as a function of {delta}{sub CP}. For a given set of input values of {Delta}m{sup 2}{sub 21},more » {Delta}m{sup 2}{sub 32}, {theta}{sub 12}, and {theta}{sub 13}, we obtain sin{sup 2} 2{theta}{sub 23} and m{sub ee} (the effective Majorana neutrino mass in neutrinoless double beta decay) as functions of tan {delta}{sub CP}. We find that the structure of this model always yields small Double-Vertical-Line tan {delta}{sub CP} Double-Vertical-Line .« less

Increased expression of c-Ski as a co-repressor in transforming growth factor-beta signaling correlates with progression of esophageal squamous cell carcinoma.

PubMed

Fukuchi, Minoru; Nakajima, Masanobu; Fukai, Yasuyuki; Miyazaki, Tatsuya; Masuda, Norihiro; Sohda, Makoto; Manda, Ryokuhei; Tsukada, Katsuhiko; Kato, Hiroyuki; Kuwano, Hiroyuki

2004-03-01

Transforming growth factor-beta (TGF-beta) regulates cell growth inhibition, and inactivation of the TGF-beta signaling pathway contributes to tumor development. In our previous study, altered expression of TGF-beta, TGF-beta-specific receptors and Smad4 was shown to correlate with tumor progression in esophageal squamous cell carcinoma (SCC). These components, however, were maintained normally in some patients with esophageal SCC. In our study, the mechanism by which aggressive esophageal SCC maintains these components was investigated, with particular emphasis on the participation of c-Ski and SnoN as transcriptional co-repressors in TGF-beta signaling. Immunohistochemistry for c-Ski and SnoN was carried out on surgical specimens obtained from 80 patients with esophageal SCC. The expression of c-Ski and SnoN was also studied in 6 established cell lines derived from esophageal SCC and compared to an immortalized human esophageal cell line by Western blotting. High levels of expression of c-Ski, detected immunohistologically, were found to correlate with depth of invasion (p = 0.0080) and pathologic stage (p = 0.0447). There was, however, no significant correlation between expression of SnoN and clinicopathologic characteristics. A significant correlation between c-Ski and TGF-beta expression was observed. Moreover, in patients with TGF-beta negative expression, the survival rates of patients with c-Ski positive expression were significantly lower than those of patients with c-Ski negative expression (p = 0.0486). c-Ski was expressed at a high level in 5 of 6 cell lines derived from esophageal SCC compared to immortalized esophageal keratinocytes. Furthermore, the cyclin-dependent kinase (CDK) inhibitor, p21 that was up-regulated by TGF-beta signaling was expressed at a low level in the 5 cell lines. The expression of c-Ski protein as a transcriptional co-repressor in TGF-beta signaling seems to be correlated with tumor progression of esophageal SCC. Copyright 2003 Wiley-Liss, Inc.

A selective peroxisome proliferator-activated receptor-gamma modulator, telmisartan, binds to the receptor in a different fashion from thiazolidinediones.

PubMed

Tagami, Tetsuya; Yamamoto, Hiroyuki; Moriyama, Kenji; Sawai, Kuniko; Usui, Takeshi; Shimatsu, Akira; Naruse, Mitsuhide

2009-02-01

Angiotensin type 1 receptor blockers are widely used for the treatment of hypertension, and one angiotensin type 1 receptor blocker, telmisartan, specifically activates the peroxisome proliferator-activated receptor (PPAR)-gamma. We studied the impact of PPARgamma mutants on transcriptional control and interaction with cofactors to elucidate differences in the molecular mechanism between telmisartan and other PPARgamma agonists, thiazolidinediones (TZDs). We created several amino acid substitutions in the ligand binding domain of PPARgamma that, based on molecular modeling, may affect the binding of these agents. In transient expression experiments, wild-type PPARgamma-mediated transcription stimulated by telmisartan was more than one third of that stimulated by TZDs. The activation stimulated by TZDs was impaired, whereas activation stimulated by telmisartan was retained, in the H323Y, S342A, and H449A mutants. In the Y473A mutant, the TZD-induced activation was further impaired and lower than that of telmisartan-induced activation. Coexpression of coactivators enhanced the activation by both telmisartan and TZDs, but activation by telmisartan always exceeded that of TZDs in the Y473A mutant. Based on a mammalian two-hybrid assay, the interaction with corepressors was retained in Y473A. Telmisartan and TZDs, but not 9cis retinoic acid, dissociated corepressors from the wild-type PPARgamma. Telmisartan most effectively dissociated corepressors from Y473A. The interaction with coactivators was enhanced by TZD activation of wild-type PPARgamma and both telmisartan and TZD activation of Y473A. Thus, the Y473A mutant is selectively stimulated by telmisartan but not TZDs, suggesting that telmisartan and TZDs have differential effects on the transcriptional control. In conclusion, these PPARgamma mutants could be powerful tools for developing novel therapeutic agents that retain the metabolic efficacy of PPARgamma activation with fewer adverse effects, such as the increase in body weight associated with TZDs.

High resolution in-beam γ-ray spectroscopy

NASA Astrophysics Data System (ADS)

Kern, J.; Dousse, J.-Cl.; Gasser, M.; Perny, B.; Rhême, Ch.

1985-01-01

An in-beam curved crystal facility has been installed at the SIN variable energy cyclotron. Using the (110) planes of a 3.0 mm thick quartz lamina bent at 3.15 m, diffraction peaks typically 6 arcsec wide (FWHM) are obtained. The energy resolution is thus, for instance, 110 eV at 170 keV in 3rd order. Due to a sophisticated detector system and heavy shielding, the sensitivity of the instrument is quite good. The facility proves quite useful in (p,xnγ) reaction studies whenever the γ-ray spectrum is very complex, e.g. in the study of odd-odd deformed nuclei. Complicated multiplets appearing in the 176Yb(p,3nγ)174Lu spectrum could be successfully resolved. From the results we derive that the g-factors of the 142 d, Jπ=6- isomer, take anomalous values.

New technological developments provide deep-sea sediment density flow insights: the Monterey Coordinated Canyon Experiment

NASA Astrophysics Data System (ADS)

O'Reilly, T. C.; Kieft, B.; Chaffey, M. R.; Wolfson-Schwehr, M.; Herlien, R.; Bird, L.; Klimov, D.; Paull, C. K.; Gwiazda, R.; Lundsten, E. M.; Anderson, K.; Caress, D. W.; Sumner, E. J.; Simmons, S.; Parsons, D. R.; Talling, P.; Rosenberger, K. J.; Xu, J.; Maier, K. L.; Gales, J. A.

2017-12-01

The Monterey Coordinated Canyon Experiment (CCE) deployed an array of instruments along the Monterey Canyon floor to characterize the structure, velocity and frequency of sediment flows. CCE utilized novel technologies developed at MBARI to capture sediment flow data in unprecedented detail. 1. The Seafloor Instrument Node (SIN) at 1850 meters depth housed 3 ADCPs at 3 different frequencies, CTD, current meter, oxygen optode, fluorometer/backscatter sensor, and logged data at 10 second intervals or faster. The SIN included an acoustic modem for communication with shore through a Wave Glider relay, and provided high-resolution measurements of three flow events during three successive deployments over 1.5 years. 2. Beachball-sized Benthic Event Detectors (BEDs) were deployed on or under the seafloor to measure the characteristics of sediment density flows. Each BED recorded data from a pressure sensor and a 3-axis accelerometer and gyro to characterize motions during transport events (e.g. tumble vs rotation). An acoustic modem capable of operating through more than a meter of sediment enabled communications with a ship or autonomous surface vehicle. Multiple BEDs were deployed at various depths in the canyon during CCE, detecting and measuring many transport events; one BED moved 9 km down canyon in 50 minutes during one event. 3. Wave Glider Hot Spot (HS), equipped with acoustic and RF modems, acted as data relay between SIN, BEDs and shore, and acoustically located BEDs after sediment density flows.. In some cases HS relayed BED motion data to shore within a few hours of the event. HS provided an acoustic console to the SIN, allowing shore-based users to check SIN health and status, perform maintenance, etc. 4. Mapping operations were conducted 4 times at the SIN site to quantify depositional and erosional patterns, utilizing a prototype ultra-high-resolution mapping system on the ROV Doc Ricketts. The system consists of a 400-kHz Reson 7125 multibeam sonar, a 3DatDepth SL1 subsea LiIDAR, two stereo color cameras, and a Kearfott SeaDevil INS. At a survey altitude of 3 m above the bed, the mapping system provides 5-cm resolution multibeam bathymetry, 1-cm resolution lidar bathymetry, and 2-mm resolution photomosaics. We will describe the design and full capabilities of these novel systems.

[Mangrove dynamics in the Cispata lagoon system (Colombian Caribbean) during last 900 years].

PubMed

Castaño, Ana; Urrego, Ligia; Bernal, Gladys

2010-12-01

The lagoon complex of Cispatá (old Sinú river delta) located at the Northwestern coast of the Colombian Caribbean, encloses one of the biggest mangrove areas in this region. This area has changed during the last 330 years because of several environmental and climatic causes, mainly changes in the position of the delta (Sinú River), which is the main freshwater source in this area, and sea level rise. We hypothesized that the climatic and geomorphologic dynamics has caused changes in the extension and composition of mangrove vegetation, especially during last 150 years. The dynamics of mangroves during the last 900 years was reconstructed based on the changes in the stratigraphy, pollen record, calcite concentrations (CaCO3) and C/N ratio, along two sediment cores from La Flotante and Navio lagoons, located in Cispatá complex. The age model was built based on lineal interpolation of 210Pb ages and changes in granulometry. Establishment and expansion of mangrove forests during the last 900 years were related to fluviomarine dynamics in the area and the lagoon formation. During the period encompassed between 1064 and 1762 A.D., the Mestizos spit was formed when marine conditions predominated in the surroundings of La Flotante Lagoon. At the site of Navío, a river dominated lagoon, terrigenous conditions dominated since 1830. Although the colonization of herbaceous pioneer vegetation started between 1142 and 1331 A.D., mangrove colonization only took place since 1717 A.D. Mangrove colonization was a result of the delta progradation. In 1849 A.D. the Sinú river delta migrated to the Cispatá bay. The eustatic sea level rise, the increase in river discharges and sedimentation rates produced the establishment of mangrove forests dominated by Rhizophora since 1849. Since 1900 a marine intrusion was recorded in both lagoons. In 1938, the migration of the delta toward its actual location in Tinajones gave place to the formation of the present lagoon system and to the expansion of mangrove forests, which reflects the balance between the high alluvial sediment input and the current sea level rise as has been recorded in similar ecosystems.

MicroRNA-876-5p inhibits epithelial-mesenchymal transition and metastasis of hepatocellular carcinoma by targeting BCL6 corepressor like 1.

PubMed

Xu, Qiuran; Zhu, Qiaojuan; Zhou, Zhenyu; Wang, Yufeng; Liu, Xin; Yin, Guozhi; Tong, Xiangmin; Tu, Kangsheng

2018-07-01

Our previous study has reported that BCL6 corepressor like 1 (BCORL1) plays an oncogenic role in hepatocellular carcinoma (HCC) via promoting epithelial-mesenchymal transition (EMT) and tumor metastasis. However, the regulation of BCORL1 mediated by microRNAs (miRNAs) remains poorly known. The analysis of our clinical samples indicated that BCORL1 expression was markedly higher in HCC tissues than that in tumor-adjacent normal tissues. The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets revealed that high BCORL1 expression associated with high tumor grade, advanced tumor stage and poor survival of HCC patients. miR-875-5p expression was down-regulated and negatively correlated with BCORL1 mRNA expression in HCC tissues. Furthermore, miR-876-5p inversely regulated BCORL1 abundance in HCC cells by directly targeting the 3'-untranslated region (3'-UTR) of BCORL1. Ectopic expression of miR-876-5p suppressed cell migration and invasion in both HCCLM3 and MHCC97H cells. In accordance, miR-876-5p knockdown promoted the metastatic behaviors of Hep3B cells. Mechanistically, miR-876-5p suppressed the EMT progression of HCC cells. HCC tissues with high miR-876-5p level showed a higher E-cadherin staining compared to cases with low miR-876-5p level. Moreover, the repression of cell metastasis mediated by miR-876-5p was rescued by BCORL1 restoration in HCCLM3 cells. Notably, low miR-876-5p expression associated with venous infiltration, high tumor grade and advanced tumor stage. HCC patients with low miR-876-5p expression had a significant poorer overall survival and disease-free survival. To conclude, miR-876-5p inhibits EMT progression, migration and invasion of HCC cells by targeting BCORL1. Therefore, miR-876-5p/BCORL1 axis may represent as a novel therapeutic target for HCC treatment. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Ten Sins Challenging Education in the Contemporary Global Era: A Philosophical Essay

ERIC Educational Resources Information Center

Sinagatullin, Ilghiz M.

2004-01-01

According to this author, the modern epoch is characterized by a decrease of vital spirituality and an increase of materialistic values and virtues. This article discusses what the author views as the ten sins challenging education in the contemporary global era. These are: (1) the shrinking of spiritual values; (2) corruption; (3) sexual…

Analysis of mammalian proteins involved in chromatin modification reveals new metaphase centromeric proteins and distinct chromosomal distribution patterns.

PubMed

Craig, Jeffrey M; Earle, Elizabeth; Canham, Paul; Wong, Lee H; Anderson, Melissa; Choo, K H Andy

2003-12-01

We have examined the metaphase chromosomal localization of 15 proteins that have previously been described as involved in mammalian chromatin modification and/or transcriptional modulation. Immunofluorescence data indicate that all the proteins localize to human and mouse centromeres, a neocentromere, and the active centromere of a dicentric chromosome, with six of these proteins (Sin3A, PCAF, MYST, MBD2, ORC2, P300/CBP) being demonstrated at mammalian centromeres for the first time. Most of these proteins fall into two distinct chromosomal distribution patterns: (a) kinetochore-associated proteins (Sin3A, PCAF, MYST and BAF180), which colocalize with metaphase kinetochores, but not any of the pericentric and other major heterochromatic regions; and (b) heterochromatin-associated proteins (MeCP2, MBD1, MBD2, ATRX, HP1alpha, HDAC1, HDAC2, DNMT1 and DNMT3b), which colocalize with centromeric/pericentric heterochromatin and all other major heterochromatic sites. A heterogeneous third group (c) consists of the origin recognition complex subunit ORC2 and the histone acetyltransferase P300/CBP, which associate generally with kinetochores in humans and centromeric/pericentric heterochromatin in mouse, with some minor differences in localization. These observations indicate an extensive sharing of protein components involved in chromatin modification at gene loci, centromeres and various chromosomal heterochromatic landmarks. The definition of distinct patterns of chromosomal distribution for these proteins provides a useful basis for the further investigation of the broad-ranging roles of these proteins.

Ultra-low noise TES bolometer arrays for SAFARI instrument on SPICA

NASA Astrophysics Data System (ADS)

Khosropanah, P.; Suzuki, T.; Ridder, M. L.; Hijmering, R. A.; Akamatsu, H.; Gottardi, L.; van der Kuur, J.; Gao, J. R.; Jackson, B. D.

2016-07-01

SRON is developing ultra-low noise Transition Edge Sensors (TESs) based on a superconducting Ti/Au bilayer on a suspended SiN island with SiN legs for the SAFARI instrument aboard the SPICA mission. We successfully fabricated TESs with very narrow (0.5-0.7 μm) and thin (0.25 μm) SiN legs on different sizes of SiN islands using deep reactiveion etching process. The pixel size is 840x840 μm2 and there are variety of designs with and without optical absorbers. For TESs without absorbers, we measured electrical NEPs as low as <1x10-19 W/√Hz with response time of 0.3 ms and reached the phonon noise limit. Using TESs with absorbers, we quantified the darkness of our setup and confirmed a photon noise level of 2x10-19 W/√Hz.

Competition between Ski and CREB-binding protein for binding to Smad proteins in transforming growth factor-beta signaling.

PubMed

Chen, Weijun; Lam, Suvana S; Srinath, Hema; Schiffer, Celia A; Royer, William E; Lin, Kai

2007-04-13

The family of Smad proteins mediates transforming growth factor-beta (TGF-beta) signaling in cell growth and differentiation. Smads repress or activate TGF-beta signaling by interacting with corepressors (e.g. Ski) or coactivators (e.g. CREB-binding protein (CBP)), respectively. Specifically, Ski has been shown to interfere with the interaction between Smad3 and CBP. However, it is unclear whether Ski competes with CBP for binding to Smads and whether they can interact with Smad3 at the same binding surface on Smad3. We investigated the interactions among purified constructs of Smad, Ski, and CBP in vitro by size-exclusion chromatography, isothermal titration calorimetry, and mutational studies. Here, we show that Ski-(16-192) interacted directly with a homotrimer of receptor-regulated Smad protein (R-Smad), e.g. Smad2 or Smad3, to form a hexamer; Ski-(16-192) interacted with an R-Smad.Smad4 heterotrimer to form a pentamer. CBP-(1941-1992) was also found to interact directly with an R-Smad homotrimer to form a hexamer and with an R-Smad.Smad4 heterotrimer to form a pentamer. Moreover, these domains of Ski and CBP competed with each other for binding to Smad3. Our mutational studies revealed that domains of Ski and CBP interacted with Smad3 at a portion of the binding surface of the Smad anchor for receptor activation. Our results suggest that Ski negatively regulates TGF-beta signaling by replacing CBP in R-Smad complexes. Our working model suggests that Smad protein activity is delicately balanced by Ski and CBP in the TGF-beta pathway.

Elemental abundance analyses with DAO spectrograms: XXXII. HR 6455 (A3 III), δ Aqr (A3 V), η Lep (F2 V), and 1 Boo (A1 V)

NASA Astrophysics Data System (ADS)

Yüce, K.; Adelman, S. J.; Gulliver, A. F.; Hill, G.

2011-08-01

We examine the sharp-lined stars HR 6455 (A3 III, v sin i = 8.7 km s-1) and η Lep (F2 V, v sin i = 13.5 km s-1) as well as δ Aqr (A3 V, v sin i = 81 km s-1) and 1 Boo (A1 V, v sin i = 59 km s-1) to increase the number consistently analyzed A and F stars using high dispersion and high S/N (≥200) spectrograms obtained with CCD detectors at the long Coudé camera of the 1.22-m telescope of the Dominion Astrophysical Observatory. Such studies contribute to understanding systematic abundance differences between normal and non-magnetic main-sequence band chemically peculiar A and early F stars. LTE fine analyses of HR 6455, δ Aqr, and 1 Boo using Kurucz's ATLAS suite programs show the same general elemental abundance trends with differences in the metal richness. Light and iron-peak element abundances are generally solar or overabundant while heavy element and rare earth element abundances are overabundant. HR 6455 is an evolved Am star while δ Aqr and 1 Boo show the phenomenon to different extents. Most derived abundances of η Lep are solar. Table 3 is available at the CDS via http://cdsarc.u-strasbg.fr/cgi-bin/qcat?J/AN/332/681

Axisymmetric Optical Membrane Modeling Based on Experimental Results

DTIC Science & Technology

2004-03-01

polymers; one such was NASA’s Inflatable Antenna Experiment (IAE), which is a pressurized lenticular about 14 meters in diameter. It was designed...2cos2θ Astigmatism with axis at +/- 45 deg 5 ρ 2sin2θ Astigmatism with axis at +/- 0 or 90 deg 6 (3 ρ 2-2) ρ cosθ Primary coma along y axis...7 (3 ρ 2-2) ρ sinθ Primary coma along x axis 51 8 6 ρ 4-6 ρ 2+1 Primary spherical aberration 9 ρ 3cos(3θ ) Triangular astigmatism , base on y axis

Phosphorylation status determines the opposing functions of Smad2/Smad3 as STAT3 cofactors in TH17 differentiation

PubMed Central

Yoon, Jeong-Hwan; Sudo, Katsuko; Kuroda, Masahiko; Kato, Mitsuyasu; Lee, In-Kyu; Han, Jin Soo; Nakae, Susumu; Imamura, Takeshi; Kim, Juryun; Ju, Ji Hyeon; Kim, Dae-Kee; Matsuzaki, Koichi; Weinstein, Michael; Matsumoto, Isao; Sumida, Takayuki; Mamura, Mizuko

2015-01-01

Transforming growth factor-β (TGF-β) and interleukin-6 (IL-6) are the pivotal cytokines to induce IL-17-producing CD4+ T helper cells (TH17); yet their signalling network remains largely unknown. Here we show that the highly homologous TGF-β receptor-regulated Smads (R-Smads): Smad2 and Smad3 oppositely modify STAT3-induced transcription of IL-17A and retinoic acid receptor-related orphan nuclear receptor, RORγt encoded by Rorc, by acting as a co-activator and co-repressor of STAT3, respectively. Smad2 linker phosphorylated by extracellular signal-regulated kinase (ERK) at the serine 255 residue interacts with STAT3 and p300 to transactivate, whereas carboxy-terminal unphosphorylated Smad3 interacts with STAT3 and protein inhibitor of activated STAT3 (PIAS3) to repress the Rorc and Il17a genes. Our work uncovers carboxy-terminal phosphorylation-independent noncanonical R-Smad–STAT3 signalling network in TH17 differentiation. PMID:26194464

Phosphorylation status determines the opposing functions of Smad2/Smad3 as STAT3 cofactors in TH17 differentiation.

PubMed

Yoon, Jeong-Hwan; Sudo, Katsuko; Kuroda, Masahiko; Kato, Mitsuyasu; Lee, In-Kyu; Han, Jin Soo; Nakae, Susumu; Imamura, Takeshi; Kim, Juryun; Ju, Ji Hyeon; Kim, Dae-Kee; Matsuzaki, Koichi; Weinstein, Michael; Matsumoto, Isao; Sumida, Takayuki; Mamura, Mizuko

2015-07-21

Transforming growth factor-β (TGF-β) and interleukin-6 (IL-6) are the pivotal cytokines to induce IL-17-producing CD4(+) T helper cells (TH17); yet their signalling network remains largely unknown. Here we show that the highly homologous TGF-β receptor-regulated Smads (R-Smads): Smad2 and Smad3 oppositely modify STAT3-induced transcription of IL-17A and retinoic acid receptor-related orphan nuclear receptor, RORγt encoded by Rorc, by acting as a co-activator and co-repressor of STAT3, respectively. Smad2 linker phosphorylated by extracellular signal-regulated kinase (ERK) at the serine 255 residue interacts with STAT3 and p300 to transactivate, whereas carboxy-terminal unphosphorylated Smad3 interacts with STAT3 and protein inhibitor of activated STAT3 (PIAS3) to repress the Rorc and Il17a genes. Our work uncovers carboxy-terminal phosphorylation-independent noncanonical R-Smad-STAT3 signalling network in TH17 differentiation.

XIAP as a Molecular Target for Therapeutic Intervention in Prostate Cancer

DTIC Science & Technology

2007-10-01

receptor corepressor Clara Hwang Æ Veda N. Giri Æ John C. Wilkinson Æ Casey W. Wright Æ Amanda S. Wilkinson Æ Kathleen A. Cooney Æ Colin S. Duckett Received...including BRCA1, histone deacetylases (HDAC), and members of the polycomb group (PcG) of proteins. Clara Hwang and Veda N. Giri contributed equally to

How Good Is Good Enough?

ERIC Educational Resources Information Center

Wiggins, Grant

2014-01-01

Education has a long-standing practice of turning worthwhile learning goals into lists of bits. One might even say that this practice is the original sin in curriculum design: take a complex whole, divide it into small pieces, string those together in a rigid sequence of instruction and testing, and call completion of this sequence…

Airborne Pointing and Tracking Systems Open Port Design and Modification Analysis

DTIC Science & Technology

1976-04-01

into 1 gives n 2: FX = S Ujk co8 2G + k. sin2G.) + 6v(k -kJslnG. cosG. - G, kt R sinG.] i=l n ZFy = ^ [ ^^r"^) 8inei co8ei + 6y...sinei cos6. = 0 Ul i=l i^l (4) and n n 1 Sin2ei 1 2 cos e. 1=1 And Equation 3 reduces to i=l n^ 2 (5) ! £ Fx - f (kr + V...Bornhorst) AFAPL (CC/D. Cheatom, Jr.) CINCSAC (INEP) ARL (AP/Lt Col Duggins) AFFDL ( FX /Dr. VanKuren) AFFTD (PDTR/Lt Faehl) AFFTC (ETEO/R. Buxton) AF

Optimization and evaluation of pluronic lecithin organogels as a transdermal delivery vehicle for sinomenine.

PubMed

Ba, Wenqiang; Li, Zhou; Wang, Lisheng; Wang, Ding; Liao, Weiguo; Fan, Wentao; Wu, Yinai; Liao, Fengyun; Yu, Jianye

2016-08-01

The purpose of the present study was to prepare and optimize sinomenine (SIN) pluronic lecithin organogels system (PLO), and to evaluate the permeability of the optimized PLO in vitro and in vivo. Box-Behnken design was used to optimize the PLO and the optimized formulation was pluronic F127 of 19.61%, lecithin of 3.60% and SIN of 1.27%. The formulation was evaluated its skin permeation and drug deposition both in vitro and in vivo compared with gel. Permeation and deposition studies of PLO were carried out with Franz diffusion cells in vitro and with microdialysis in vivo. In vitro studies, permeation rate (Jss) of SIN from PLO was 146.55 ± 2.93 μg/cm(2)/h, significantly higher than that of gel (120.39 μg/cm(2)/h) and the amount of SIN deposited in skin from the PLO was 10.08 ± 0.86 μg/cm(2), significantly larger than that from gel (6.01 ± 0.04 μg/cm(2)). In vivo skin microdialysis studies showed that the maximum concentration (Cmax) of SIN from PLO in "permeation study" and "drug-deposition study" were 150.27 ± 20.85 μg/ml and 67.95 μg/ml, respectively, both significantly higher than that of SIN from gel (29.66 and 6.73 μg/ml). The results recommend that PLO can be used as an advantageous transdermal delivery vehicle to enhance the permeation and skin deposition of SIN.

The Expanding Complexity of Estrogen Receptor Signaling in the Cardiovascular System

PubMed Central

Menazza, Sara; Murphy, Elizabeth

2016-01-01

Estrogen has important effects on cardiovascular function including regulation of vascular function, blood pressure, endothelial relaxation, the development of hypertrophy and cardioprotection. However, the mechanisms by which estrogen mediates these effects are still poorly understood. As detailed in this review, estrogen can regulate transcription by binding to two nuclear receptors, ERα and ERβ, which differentially regulate gene transcription. ERα and ERβ regulation of gene transcription is further modulated by tissue specific co-activators and co-repressors. Estrogen can bind to ERα and ERβ localized at the plasma membrane as well as GPER to initiate membrane delimited signaling, which enhances kinase signaling pathways that can have acute and long term effects. The kinase signaling pathways can also mediate transcriptional changes, and can synergize with the estrogen receptor to regulate cell function. This review will summarize the beneficial effects of estrogen in protecting the cardiovascular system through ER-dependent mechanisms with an emphasis on the role of the recently described ER-membrane signaling mechanisms. PMID:26838792

AML1/ETO accelerates cell migration and impairs cell-to-cell adhesion and homing of hematopoietic stem/progenitor cells

PubMed Central

Saia, Marco; Termanini, Alberto; Rizzi, Nicoletta; Mazza, Massimiliano; Barbieri, Elisa; Valli, Debora; Ciana, Paolo; Gruszka, Alicja M.; Alcalay, Myriam

2016-01-01

The AML1/ETO fusion protein found in acute myeloid leukemias functions as a transcriptional regulator by recruiting co-repressor complexes to its DNA binding site. In order to extend the understanding of its role in preleukemia, we expressed AML1/ETO in a murine immortalized pluripotent hematopoietic stem/progenitor cell line, EML C1, and found that genes involved in functions such as cell-to-cell adhesion and cell motility were among the most significantly regulated as determined by RNA sequencing. In functional assays, AML1/ETO-expressing cells showed a decrease in adhesion to stromal cells, an increase of cell migration rate in vitro, and displayed an impairment in homing and engraftment in vivo upon transplantation into recipient mice. Our results suggest that AML1/ETO expression determines a more mobile and less adherent phenotype in preleukemic cells, therefore altering the interaction with the hematopoietic niche, potentially leading to the migration across the bone marrow barrier and to disease progression. PMID:27713544

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

Li, Qun-Yi; Zhang, Meng; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai

Selective antagonists of the glucocorticoid receptor (GR) are desirable for the treatment of hypercortisolemia associated with Cushing's syndrome, psychic depression, obesity, diabetes, neurodegenerative diseases, and glaucoma. NC3327, a non-steroidal small molecule with potent binding affinity to GR (K{sub i} = 13.2 nM), was identified in a high-throughput screening effort. As a full GR antagonist, NC3327 greatly inhibits the dexamethasone (Dex) induction of marker genes involved in hepatic gluconeogenesis, but has a minimal effect on matrix metalloproteinase 9 (MMP-9), a GR responsive pro-inflammatory gene. Interestingly, the compound recruits neither coactivators nor corepressors to the GR complex but competes with glucocorticoids formore » the interaction between GR and a coactivator peptide. Moreover, NC3327 does not trigger GR nuclear translocation, but significantly blocks Dex-induced GR transportation to the nucleus, and thus appears to be a 'competitive' GR antagonist. Therefore, the non-steroidal compound, NC3327, may represent a new class of GR antagonists as potential therapeutics for a variety of cortisol-related endocrine disorders.« less

Identification of zinc finger transcription factor EGR2 as a novel acetylated protein.

PubMed

Noritsugu, Kota; Ito, Akihiro; Nakao, Yoichi; Yoshida, Minoru

2017-08-05

EGR2 is a zinc finger transcription factor that regulates myelination in the peripheral nervous system and T cell anergy. The transcriptional activity of EGR2 is known to be regulated by its co-activators and/or co-repressors. Although the activity of transcription factors is generally regulated not only by interactions with co-regulators but also posttranslational modifications including acetylation, little is known about posttranslational modifications of EGR2. Here we show that EGR2 is a novel acetylated protein. Through immunoblotting analyses using an antibody that specifically recognizes the acetylated form of EGR2, CBP and p300 were identified as acetyltransferases, while HDAC6, 10 and SIRT1 were identified as deacetylases of EGR2. Although the NuRD complex containing HDAC1 and HDAC2 is known to associate with EGR2, the present study suggests that acetylation of EGR2 is regulated independently of NuRD. Copyright © 2017 Elsevier Inc. All rights reserved.

High-performance Thin-layer Chromatography Method Development, Validation, and Simultaneous Quantification of Four Compounds Identified in Standardized Extracts of Orthosiphon stamineus.

PubMed

Hashim, Suzana; Beh, Hooi Kheng; Hamil, Mohamad Shahrul Ridzuan; Ismail, Zhari; Majid, Amin Malik Shah Abdul

2016-01-01

Orthosiphon stamineus is a medicinal herb widely grown in Southeast Asia and tropical countries. It has been used traditionally as a diuretic, abdominal pain, kidney and bladder inflammation, gout, and hypertension. This study aims to develop and validate the high-performance thin layer chromatography (HPTLC) method for quantification of rosmarinic acid (RA), 3'-hydroxy-5,6,7,4'-tetramethoxyflavone (TMF), sinensitin (SIN) and eupatorin (EUP) found in ethanol, 50% ethanol and water extract of O. stamineus leaves. HPTLC method was conducted using an HPTLC system with a developed mobile phase system of toluene: ethyl acetate: formic acid (3:7:0.1) performed on precoated silica gel 60 F254 TLC plates. The method was validated based on linearity, accuracy, precision, limit of detection, limit of quantification (LOQ), and specificity, respectively. The detection of spots was observed at ultraviolet 254 nm and 366 nm. The linearity of RA, TMF, SIN, and EUP were obtained between 10 and 100 ng/spot with high correlation coefficient value (R 2 ) of more than 0.986. The limit of detection was found to be 122.47 ± 3.95 (RA), 43.38 ± 0.79 (SIN), 17.26 ± 1.16 (TMF), and 46.80 ± 1.33 ng/spot (EUP), respectively. Whereas the LOQ was found to be 376.44 ± 6.70 (RA), 131.45 ± 2.39 (SIN), 52.30 ± 2.01 (TMF), and 141.82 ± 1.58 ng/spot (EUP), respectively. The proposed method showed good linearity, precision, accuracy, and high sensitivity. Hence, it may be applied in a routine quantification of RA, SIN, TMF, and EUP found in ethanol, 50% of ethanol and water extract of O. stamineus leaves. HPTLC method provides rapid estimation of the marker compound for routine quality control analysis.The established HPTLC method is rapid for qualitative and quantitative fingerprinting of Orthosiphon stamineus extract used for commercial product.Four identified markers (RA, SIN, EUP and TMF) found in three a different type of O. stamineus extracts specifically ethanol, 50% ethanol and water extract were successfully quantified using HPTLC method. Abbreviations Used : HPTLC: High-performance thin layer chromatography; RA: Rosmarinic acid; TMF: 3'-hydroxy-5,6,7,4'-tetramethoxyflavone; SIN: Sinensitin; EUP: Eupatorin; E: Ethanol; EW: 50% ethanol; W: Water; BK: Batu Kurau; KB: Kepala Batas; S: Sik; CJ: Changkat Jering; SB: Sungai Buloh.

Measurements of neutrino oscillation in appearance and disappearance channels by the T2K experiment with 6.6 ×1 020 protons on target

NASA Astrophysics Data System (ADS)

Abe, K.; Adam, J.; Aihara, H.; Akiri, T.; Andreopoulos, C.; Aoki, S.; Ariga, A.; Assylbekov, S.; Autiero, D.; Barbi, M.; Barker, G. J.; Barr, G.; Bartet-Friburg, P.; Bass, M.; Batkiewicz, M.; Bay, F.; Berardi, V.; Berger, B. E.; Berkman, S.; Bhadra, S.; Blaszczyk, F. d. M.; Blondel, A.; Bolognesi, S.; Bordoni, S.; Boyd, S. B.; Brailsford, D.; Bravar, A.; Bronner, C.; Buchanan, N.; Calland, R. G.; Caravaca Rodríguez, J.; Cartwright, S. L.; Castillo, R.; Catanesi, M. G.; Cervera, A.; Cherdack, D.; Chikuma, N.; Christodoulou, G.; Clifton, A.; Coleman, J.; Coleman, S. J.; Collazuol, G.; Connolly, K.; Cremonesi, L.; Dabrowska, A.; Danko, I.; Das, R.; Davis, S.; de Perio, P.; De Rosa, G.; Dealtry, T.; Dennis, S. R.; Densham, C.; Dewhurst, D.; Di Lodovico, F.; Di Luise, S.; Dolan, S.; Drapier, O.; Duboyski, T.; Duffy, K.; Dumarchez, J.; Dytman, S.; Dziewiecki, M.; Emery-Schrenk, S.; Ereditato, A.; Escudero, L.; Ferchichi, C.; Feusels, T.; Finch, A. J.; Fiorentini, G. A.; Friend, M.; Fujii, Y.; Fukuda, Y.; Furmanski, A. P.; Galymov, V.; Garcia, A.; Giffin, S.; Giganti, C.; Gilje, K.; Goeldi, D.; Golan, T.; Gonin, M.; Grant, N.; Gudin, D.; Hadley, D. R.; Haegel, L.; Haesler, A.; Haigh, M. D.; Hamilton, P.; Hansen, D.; Hara, T.; Hartz, M.; Hasegawa, T.; Hastings, N. C.; Hayashino, T.; Hayato, Y.; Hearty, C.; Helmer, R. L.; Hierholzer, M.; Hignight, J.; Hillairet, A.; Himmel, A.; Hiraki, T.; Hirota, S.; Holeczek, J.; Horikawa, S.; Hosomi, F.; Huang, K.; Ichikawa, A. K.; Ieki, K.; Ieva, M.; Ikeda, M.; Imber, J.; Insler, J.; Irvine, T. J.; Ishida, T.; Ishii, T.; Iwai, E.; Iwamoto, K.; Iyogi, K.; Izmaylov, A.; Jacob, A.; Jamieson, B.; Jiang, M.; Johnson, S.; Jo, J. H.; Jonsson, P.; Jung, C. K.; Kabirnezhad, M.; Kaboth, A. C.; Kajita, T.; Kakuno, H.; Kameda, J.; Kanazawa, Y.; Karlen, D.; Karpikov, I.; Katori, T.; Kearns, E.; Khabibullin, M.; Khotjantsev, A.; Kielczewska, D.; Kikawa, T.; Kilinski, A.; Kim, J.; King, S.; Kisiel, J.; Kitching, P.; Kobayashi, T.; Koch, L.; Koga, T.; Kolaceke, A.; Konaka, A.; Kopylov, A.; Kormos, L. L.; Korzenev, A.; Koshio, Y.; Kropp, W.; Kubo, H.; Kudenko, Y.; Kurjata, R.; Kutter, T.; Lagoda, J.; Lamont, I.; Larkin, E.; Laveder, M.; Lawe, M.; Lazos, M.; Lindner, T.; Lister, C.; Litchfield, R. P.; Longhin, A.; Lopez, J. P.; Ludovici, L.; Magaletti, L.; Mahn, K.; Malek, M.; Manly, S.; Marino, A. D.; Marteau, J.; Martin, J. F.; Martins, P.; Martynenko, S.; Maruyama, T.; Matveev, V.; Mavrokoridis, K.; Mazzucato, E.; McCarthy, M.; McCauley, N.; McFarland, K. S.; McGrew, C.; Mefodiev, A.; Metelko, C.; Mezzetto, M.; Mijakowski, P.; Miller, C. A.; Minamino, A.; Mineev, O.; Missert, A.; Miura, M.; Moriyama, S.; Mueller, Th. A.; Murakami, A.; Murdoch, M.; Murphy, S.; Myslik, J.; Nakadaira, T.; Nakahata, M.; Nakamura, K. G.; Nakamura, K.; Nakayama, S.; Nakaya, T.; Nakayoshi, K.; Nantais, C.; Nielsen, C.; Nirkko, M.; Nishikawa, K.; Nishimura, Y.; Nowak, J.; O'Keeffe, H. M.; Ohta, R.; Okumura, K.; Okusawa, T.; Oryszczak, W.; Oser, S. M.; Ovsyannikova, T.; Owen, R. A.; Oyama, Y.; Palladino, V.; Palomino, J. L.; Paolone, V.; Payne, D.; Perevozchikov, O.; Perkin, J. D.; Petrov, Y.; Pickard, L.; Pinzon Guerra, E. S.; Pistillo, C.; Plonski, P.; Poplawska, E.; Popov, B.; Posiadala-Zezula, M.; Poutissou, J.-M.; Poutissou, R.; Przewlocki, P.; Quilain, B.; Radicioni, E.; Ratoff, P. N.; Ravonel, M.; Rayner, M. A. M.; Redij, A.; Reeves, M.; Reinherz-Aronis, E.; Riccio, C.; Rodrigues, P. A.; Rojas, P.; Rondio, E.; Roth, S.; Rubbia, A.; Ruterbories, D.; Rychter, A.; Sacco, R.; Sakashita, K.; Sánchez, F.; Sato, F.; Scantamburlo, E.; Scholberg, K.; Schoppmann, S.; Schwehr, J. D.; Scott, M.; Seiya, Y.; Sekiguchi, T.; Sekiya, H.; Sgalaberna, D.; Shah, R.; Shaker, F.; Shaw, D.; Shiozawa, M.; Short, S.; Shustrov, Y.; Sinclair, P.; Smith, B.; Smy, M.; Sobczyk, J. T.; Sobel, H.; Sorel, M.; Southwell, L.; Stamoulis, P.; Steinmann, J.; Still, B.; Suda, Y.; Suzuki, A.; Suzuki, K.; Suzuki, S. Y.; Suzuki, Y.; Tacik, R.; Tada, M.; Takahashi, S.; Takeda, A.; Takeuchi, Y.; Tanaka, H. K.; Tanaka, H. A.; Tanaka, M. M.; Terhorst, D.; Terri, R.; Thompson, L. F.; Thorley, A.; Tobayama, S.; Toki, W.; Tomura, T.; Touramanis, C.; Tsukamoto, T.; Tzanov, M.; Uchida, Y.; Vacheret, A.; Vagins, M.; Vasseur, G.; Wachala, T.; Wakamatsu, K.; Walter, C. W.; Wark, D.; Warzycha, W.; Wascko, M. O.; Weber, A.; Wendell, R.; Wilkes, R. J.; Wilking, M. J.; Wilkinson, C.; Williamson, Z.; Wilson, J. R.; Wilson, R. J.; Wongjirad, T.; Yamada, Y.; Yamamoto, K.; Yanagisawa, C.; Yano, T.; Yen, S.; Yershov, N.; Yokoyama, M.; Yoo, J.; Yoshida, K.; Yuan, T.; Yu, M.; Zalewska, A.; Zalipska, J.; Zambelli, L.; Zaremba, K.; Ziembicki, M.; Zimmerman, E. D.; Zito, M.; Żmuda, J.; T2K Collaboration

2015-04-01

We report on measurements of neutrino oscillation using data from the T2K long-baseline neutrino experiment collected between 2010 and 2013. In an analysis of muon neutrino disappearance alone, we find the following estimates and 68% confidence intervals for the two possible mass hierarchies: normal hierarchy: sin2θ23=0.51 4-0.056+0.055 and Δ m322=(2.51 ±0.10 )×1 0-3 eV2/c4 and inverted hierarchy: sin2θ23=0.511 ±0.055 and Δ m132=(2.48 ±0.10 )×1 0-3 eV2/c4 . The analysis accounts for multinucleon mechanisms in neutrino interactions which were found to introduce negligible bias. We describe our first analyses that combine measurements of muon neutrino disappearance and electron neutrino appearance to estimate four oscillation parameters, |Δ m2|, sin2θ23, sin2θ13, δC P, and the mass hierarchy. Frequentist and Bayesian intervals are presented for combinations of these parameters, with and without including recent reactor measurements. At 90% confidence level and including reactor measurements, we exclude the region δC P=[0.15 ,0.83 ]π for normal hierarchy and δC P=[-0.08 ,1.09 ]π for inverted hierarchy. The T2K and reactor data weakly favor the normal hierarchy with a Bayes factor of 2.2. The most probable values and 68% one-dimensional credible intervals for the other oscillation parameters, when reactor data are included, are sin2θ23=0.52 8-0.038+0.055 and |Δ m322 |=(2.51 ±0.11 )×1 0-3 eV2/c4 .

Erratum: The Growth Rate of Tidally Excited Waves in Accretion Disks

NASA Astrophysics Data System (ADS)

Vishniac, Ethan T.; Zhang, Changsong

1997-03-01

In the paper ``The Growth Rate of Tidally Excited Waves in Accretion Disks'' by Ethan T. Vishniac and Changsong Zhang (ApJ, 461, 307 [1996]), the original formulae for the Eulerian velocities in terms of the Lagrangian displacements were in error. The correct formulae are (equation numbers here match those in the original paper) Δvr=-2ω¯ξr sin (2ω¯t+2θ) (33)and Δvθ=(3/2Ωξr+2ω¯ξθ) cos (2ω¯t+2θ) . (34) This changes the matrix elements used in calculating the wave growth rates to <ṽr|ΔL|A>=sin (2ψ)/8 -∞∞ṽr[vr(-(∂rΔvr)/2-(Δvθ)/r)-Δvz∂zvr-((2Δvθ)/r-(2Δvr)/r)vθ-χkr Δρ/ρ S]dz=sin (2ψ)/8 -∞∞ṽr{vr(ω¯∂rξr-2ω¯ (ξθ)/r-3Ω (ξr)/r)+∂zvr2ω¯ξz-(2vθ)/r [ξr(3Ω/2+2ω¯)+2ω¯ξθ]+χkrS[(ξr)/r+∂rξr+2/r ξθ+∂zξz(1+z∂zlnρ)]}dz ,<ṽθ|ΔL|A>=sin (2ψ)/8 -∞∞ṽθ[vr(∂rΔvθ+(Δvθ)/r)+vθ(-1/2 ∂rΔvr+(Δvr)/r-(Δvθ)/r)+Δvz∂zvθ]dz=sin (2ψ)/8 -∞∞ṽθ{vr[3Ω/2 ∂rξr+2ω¯∂rξθ-3Ω/4 (ξr)/r+(2ω¯-3Ω) (ξθ)/r]+vθ[ω¯∂rξr-2ω¯ (ξθ)/r-(3Ω+2ω¯) (ξr)/r]-2ω¯ξz∂zvθ}dz ,<ṽz|ΔL|A>=(sin(2ψ))/8-∞∞ṽz[vz(-∂zΔvz+1/2∂rΔvr-(Δvθ)/r)-Δvz∂zvz-Δρ/ρS(-(zΩ2)/(c2s)+∂z)χ-δ(1/ρ∂zΔP+2Δρ/ρzΩ2)]dz=sin (2ψ)/8 -∞∞ṽz{vz(-ω¯∂rξr-2ω¯ (ξθ)/r+2ω¯∂zξz)+2ω¯ξz∂zvz-Δρ/ρ S(-(zΩ2)/(c2s)+∂z)χ+zΩ2[(γ-2) Δρ/ρ+γ ΔS/S-∂zξz(2+z∂zlnρ+(γz2Ω2)/(c2s))]δ}dz , (44) (46) (48)<χ˜|ΔL|A>=sin (2ψ)/8 -∞∞χ˜[[-(c2s)/S ΔP/P krvr+(c2s)/S ((∂zΔP)/γP+ΔP/P ∂z)vz×{(γ-1/2)[(∂r(rΔvr))/r-(2Δvθ)/r]+Δvz(-(zΩ2)/(c2s)+∂z)+γ∂z(Δvz)}χ

Influence of Surface Passivation on AlN Barrier Stress and Scattering Mechanism in Ultra-thin AlN/GaN Heterostructure Field-Effect Transistors.

PubMed

Lv, Y J; Song, X B; Wang, Y G; Fang, Y L; Feng, Z H

2016-12-01

Ultra-thin AlN/GaN heterostructure field-effect transistors (HFETs) with, and without, SiN passivation were fabricated by the same growth and device processes. Based on the measured DC characteristics, including the capacitance-voltage (C-V) and output current-voltage (I-V) curves, the variation of electron mobility with gate bias was found to be quite different for devices with, and without, SiN passivation. Although the AlN barrier layer is ultra thin (c. 3 nm), it was proved that SiN passivation induces no additional tensile stress and has no significant influence on the piezoelectric polarization of the AlN layer using Hall and Raman measurements. The SiN passivation was found to affect the surface properties, thereby increasing the electron density of the two-dimensional electron gas (2DEG) under the access region. The higher electron density in the access region after SiN passivation enhanced the electrostatic screening for the non-uniform distributed polarization charges, meaning that the polarization Coulomb field scattering has a weaker effect on the electron drift mobility in AlN/GaN-based devices.

Molecular characterization of human thyroid hormone receptor β isoform 4.

PubMed

Moriyama, Kenji; Yamamoto, Hiroyuki; Futawaka, Kumi; Atake, Asami; Kasahara, Masato; Tagami, Tetsuya

2016-01-01

Thyroid hormone exerts a pleiotropic effect on development, differentiation, and metabolism through thyroid hormone receptor (TR). A novel thyroid hormone receptor β isoform (TRβ4) was cloned using PCR from a human pituitary cDNA library as a template. We report here the characterization of TRβ4 from a molecular basis. Temporal expression of TRβ4 during the fetal period is abundant in the brain and kidney, comparable with the adult pattern. Western blot analysis revealed that TRs are ubiquitination labile proteins, while TRβ1 is potentially stable. TRβ1, peroxisome proliferator-activated receptors (PPAR), and vitamin D receptor (VDR), which belong to class II transcription factors that function via the formation of heterodimeric complexes with retinoid X receptor (RXR), were suppressed by TRβ4 in a dose-dependent manner. Thus, TRβ4 exhibits ligand-independent transcriptional silencing, possibly as a substitute for dimerized RXR. In this study, TRβ1 and TRβ4 transcripts were detected in several cell lines. Quantitative RT-PCR assay showed that the expression of TRβ4 in human embryonic carcinoma cells of the testis was suppressed by sex hormone in a reciprocal manner to TRβ1. In contrast, TRβ4 was expressed under a high dose of triiodothyronine (T3) in a reciprocal manner to TRβ1. Finally, in transiently transfected NIH-3T3 cells, green fluorescence protein (GFP)-tagged TRβ4 was mostly nuclear in both the absence and the presence of T3. By mutating defined regions of both TRβs, we found that both TRβ1 and TRβ4 had altered nuclear/cytoplasmic distribution as compared with wild-type, and different to T3 and the nuclear receptor corepressor (NCoR). Thus, site-specific DNA binding is not essential for maintaining TRβs within the nucleus.

Silicon nitride and silicon etching by CH{sub 3}F/O{sub 2} and CH{sub 3}F/CO{sub 2} plasma beams

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

Kaler, Sanbir S.; Lou, Qiaowei; Donnelly, Vincent M., E-mail: vmdonnelly@uh.edu

2016-07-15

Silicon nitride (SiN, where Si:N ≠ 1:1) films low pressure-chemical vapor deposited on Si substrates, Si films on Ge on Si substrates, and p-Si samples were exposed to plasma beams emanating from CH{sub 3}F/O{sub 2} or CH{sub 3}F/CO{sub 2} inductively coupled plasmas. Conditions within the plasma beam source were maintained at power of 300 W (1.9 W/cm{sup 3}), pressure of 10 mTorr, and total gas flow rate of 10 sccm. X-ray photoelectron spectroscopy was used to determine the thicknesses of Si/Ge in addition to hydrofluorocarbon polymer films formed at low %O{sub 2} or %CO{sub 2} addition on p-Si and SiN. Polymer film thickness decreasedmore » sharply as a function of increasing %O{sub 2} or %CO{sub 2} addition and dropped to monolayer thickness above the transition point (∼48% O{sub 2} or ∼75% CO{sub 2}) at which the polymer etchants (O and F) number densities in the plasma increased abruptly. The C(1s) spectra for the polymer films deposited on p-Si substrates appeared similar to those on SiN. Spectroscopic ellipsometry was used to measure the thickness of SiN films etched using the CH{sub 3}F/O{sub 2} and CH{sub 3}F/CO{sub 2} plasma beams. SiN etching rates peaked near 50% O{sub 2} addition and 73% CO{sub 2} addition. Faster etching rates were measured in CH{sub 3}F/CO{sub 2} than CH{sub 3}F/O{sub 2} plasmas above 70% O{sub 2} or CO{sub 2} addition. The etching of Si stopped after a loss of ∼3 nm, regardless of beam exposure time and %O{sub 2} or %CO{sub 2} addition, apparently due to plasma assisted oxidation of Si. An additional GeO{sub x}F{sub y} peak was observed at 32.5 eV in the Ge(3d) region, suggesting deep penetration of F into Si, under the conditions investigated.« less

New Precision Orbits of Bright Double-lined Spectroscopic Binaries. X. HD 96511, HR 7578, and KZ Andromedae

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

Fekel, Francis C.; Henry, Gregory W.; Tomkin, Jocelyn, E-mail: fekel@evans.tsuniv.edu, E-mail: gregory.w.henry@gmail.com

2017-09-01

From an extensive number of newly acquired radial velocities we determine the orbital elements for three late-type dwarf systems, HD 96511, HR 7578, and KZ And. The orbital periods are 18.89737 ± 0.00002, 46.81610 ± 0.00006, and 3.0329113 ± 0.0000005 days, respectively, and all three systems are eccentric, although KZ And is just barely so. We have detected lines of the secondary of HD 96511 for the first time. The orbital dimensions ( a {sub 1} sin i and a {sub 2} sin i ) and minimum masses ( m {sub 1} sin{sup 3} i and m {sub 2} sin{sup 3} i ) of the binary components all have accuracies ofmore » 0.2% or better. Extensive photometry of the chromospherically active binary HR 7578 confirms a rather long rotation period of 16.446 ± 0.002 days and that the K3 V components do not eclipse. We have estimated the basic properties of the stars in the three systems and compared those results with evolutionary tracks. The results for KZ And that we computed with the revised Hipparcos parallax of van Leeuwen produce inconsistencies. That parallax appears to be too large, and so, instead, we used the original Hipparcos parallax of the common proper motion primary, which improves the results, although some problems remain.« less

VLSI Implementation of Stray Insensitive Switched Capacitor Composite Operational Amplifiers

DTIC Science & Technology

1993-12-01

ENDS SWITCH *Power Supplies VIN 3 0 SIN(0 0. 1 10OKHz) VCLK 8 0 PULSE(5 -5 O.Ous 2ns 2ns 0.O5us Ol1us) III X1 0 45 OPAMPI X2 5 67 OPAMPI X3 8 9 10 11...105 46F C13 305 105 68F C14 304 105 68F C15 300 105 120F C16 102 105 390F 116 C17 301 105 121F .ENDS CLOCK *Power Supplies VIN 3 0 SIN(O 0.1 400KHz

Nuclear receptor TLX prevents retinal dystrophy and recruits the corepressor atrophin1

PubMed Central

Zhang, Chun-Li; Zou, Yuhua; Yu, Ruth T.; Gage, Fred H.; Evans, Ronald M.

2006-01-01

During mammalian embryogenesis, precise coordination of progenitor cell proliferation and differentiation is essential for proper organ size and function. The involvement of TLX (NR2E1), an orphan nuclear receptor, has been implicated in ocular development, as Tlx−/− mice exhibit visual impairment. Using genetic and biochemical approaches, we show that TLX modulates retinal progenitor cell proliferation and cell cycle re-entry by directly regulating the expression of Pten and its target cyclin D1. Additionally, TLX finely tunes the progenitor differentiation program by modulating the phospholipase C and mitogen-activated protein kinase (MAPK) pathways and the expression of an array of cell type-specific transcriptional regulators. Consequently, Tlx−/− mice have a dramatic reduction in retina thickness and enhanced generation of S-cones, and develop severe early onset retinal dystrophy. Furthermore, TLX interacts with atrophin1 (Atn1), a corepressor that is involved in human neurodegenerative dentatorubral-pallidoluysian atrophy (DRPLA) and that is essential for development of multiple tissues. Together, these results reveal a molecular strategy by which an orphan nuclear receptor can precisely orchestrate tissue-specific proliferation and differentiation programs to prevent retinal malformation and degeneration. PMID:16702404

Cntnap2 expression in the cerebellum of Foxp2(R552H) mice, with a mutation related to speech-language disorder.

PubMed

Fujita, Eriko; Tanabe, Yuko; Momoi, Mariko Y; Momoi, Takashi

2012-01-11

Foxp2(R552H) knock-in (KI) mice carrying a mutation related to human speech-language disorder exhibit impaired ultrasonic vocalization and poor Purkinje cell development. Foxp2 is a forkhead domain-containing transcriptional repressor that associates with its co-repressor CtBP; Foxp2(R552H) displays reduced DNA binding activity. A genetic connection between FOXP2 and CNTNAP2 has been demonstrated in vitro, but not in vivo. Here we show that Cntnap2 mRNA levels significantly increased in the cerebellum of Foxp2(R552H) KI pups, although the cerebellar population of Foxp2-positive Purkinje cells was very small. Furthermore, Cntnap2 immunofluorescence did not decrease in the poorly developed Purkinje cells of Foxp2(R552H) KI pups, although synaptophysin immunofluorescence decreased. Cntnap2 and CtBP were ubiquitously expressed, while Foxp2 co-localized with CtBP only in Purkinje cells. Taken together, these observations suggest that Foxp2 may regulate ultrasonic vocalization by associating with CtBP in Purkinje cells; Cntnap2 may be a target of this co-repressor. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Constraints on the Obliquities of Kepler Planet-hosting Stars

NASA Astrophysics Data System (ADS)

Winn, Joshua N.; Petigura, Erik A.; Morton, Timothy D.; Weiss, Lauren M.; Dai, Fei; Schlaufman, Kevin C.; Howard, Andrew W.; Isaacson, Howard; Marcy, Geoffrey W.; Justesen, Anders Bo; Albrecht, Simon

2017-12-01

Stars with hot Jupiters have obliquities ranging from 0° to 180°, but relatively little is known about the obliquities of stars with smaller planets. Using data from the California-Kepler Survey, we investigate the obliquities of stars with planets spanning a wide range of sizes, most of which are smaller than Neptune. First, we identify 156 planet hosts for which measurements of the projected rotation velocity (v\\sin i) and rotation period are both available. By combining estimates of v and v\\sin i, we find nearly all the stars to be compatible with high inclination, and hence, low obliquity (≲20°). Second, we focus on a sample of 159 hot stars ({T}{eff}> 6000 K) for which v\\sin i is available but not necessarily the rotation period. We find six stars for which v\\sin i is anomalously low, an indicator of high obliquity. Half of these have hot Jupiters, even though only 3% of the stars that were searched have hot Jupiters. We also compare the v\\sin i distribution of the hot stars with planets to that of 83 control stars selected without prior knowledge of planets. The mean v\\sin i of the control stars is lower than that of the planet hosts by a factor of approximately π /4, as one would expect if the planet hosts have low obliquities. All these findings suggest that the Kepler planet-hosting stars generally have low obliquities, with the exception of hot stars with hot Jupiters.

Geometric and electronic structures of silicon-sodium binary clusters. I. Ionization energy of SinNam

NASA Astrophysics Data System (ADS)

Kishi, Reiko; Iwata, Suehiro; Nakajima, Atsushi; Kaya, Koji

1997-08-01

Sodium doped silicon clusters (SinNam; 1⩽n⩽14, 1⩽m⩽5) produced by two types of laser vaporization were studied. The adsorption of Na atoms on the Sin clusters leads the substantial lowering of the ionization energy, Ei, of SinNam clusters. Their reactivity toward NO molecules was measured with a fast flow reactor, and the anticorrelation between the Eis and the reactivity was clearly observed; species having low Ei exhibit high reactivity and vice versa. Moreover, the clear parallelism between the Eis of SinNa and the EAs of Sin is found. This is consistent with the fact that the structure of SinNa clusters keeps the frame of the corresponding Sin cluster unchanged and that the electronic structure of SinNa is similar to that of the corresponding negative ion Sin-. In addition to the experimental studies, the geometries, adsorption energies, and vertical ionization energies of SinNa (n=1-7) were investigated with ab initio MO calculations including electron correlation; The Møller-Plesset perturbation theory was used and the configuration interaction (CI) calculation was carried out, particularly for a diatomic molecule, SiNa.

Structure-activity relationships of neoechinulin A analogues with cytoprotection against peroxynitrite-induced PC12 cell death.

PubMed

Kimoto, Kuniaki; Aoki, Toshiaki; Shibata, Yasushi; Kamisuki, Shinji; Sugawara, Fumio; Kuramochi, Kouji; Nakazaki, Atsuo; Kobayashi, Susumu; Kuroiwa, Kenji; Watanabe, Nobuo; Arai, Takao

2007-10-01

Neoechinulin A, an alkaloid from Eurotium rubrum Hiji025, protected neuronal PC12 cells against cell death induced by peroxynitrite derived from SIN-1 (3-(4-morpholinyl)sydnonimine hydrochloride). In this study, we investigated the structure-activity relationships of neoechinulin A and a set of its analogues by using assays to measure anti-nitration and antioxidant activities and cytoprotection against SIN-1-induced PC12 cell death. The presence of the diketopiperazine ring was essential for both the antioxidant and anti-nitration activities of neoechinulin A derivatives. Nevertheless, a derivative lacking the diketopiperazine ring could still protect PC12 cells against SIN-1 cytotoxicity. An acyclic analogue completely lost the cytoprotective effect while retaining its antioxidant/anti-nitration activities. Pre-incubation of the cells with neoechinulin A for at least 12 hours was essential for the cells to gain SIN-1 resistance. These results suggest that neoechinulin A endows the cells with cytoprotection through a biological effect different from the apparent antioxidant/anti-nitration activities.

The Seismic Design of Waterfront Retaining Structures

DTIC Science & Technology

1992-11-01

a higher posi- tion along the back of the wall than the static active earth pressure force due to the concentration of soil mass comprising the...inertia force k.’W acting downward). = tan-1 [. ] (by eq 35) - 5.35- KAB = CO2 (30-5. 35)cos (5.35)cosZ(0)cos(5.35+3)f1 + /sin(30+3)sin(30-5. 35-6...distance between the anchor and the sheet pile. Two anchored bulkheads were in place in the harbor of San Antonio, Chile , during the very large earthquake

Characterization of a JAZ7 activation-tagged Arabidopsis mutant with increased susceptibility to the fungal pathogen Fusarium oxysporum

PubMed Central

Thatcher, Louise F.; Cevik, Volkan; Grant, Murray; Zhai, Bing; Jones, Jonathan D.G.; Manners, John M.; Kazan, Kemal

2016-01-01

In Arabidopsis, jasmonate (JA)-signaling plays a key role in mediating Fusarium oxysporum disease outcome. However, the roles of JASMONATE ZIM-domain (JAZ) proteins that repress JA-signaling have not been characterized in host resistance or susceptibility to this pathogen. Here, we found most JAZ genes are induced following F. oxysporum challenge, and screening T-DNA insertion lines in Arabidopsis JAZ family members identified a highly disease-susceptible JAZ7 mutant (jaz7-1D). This mutant exhibited constitutive JAZ7 expression and conferred increased JA-sensitivity, suggesting activation of JA-signaling. Unlike jaz7 loss-of-function alleles, jaz7-1D also had enhanced JA-responsive gene expression, altered development and increased susceptibility to the bacterial pathogen Pst DC3000 that also disrupts host JA-responses. We also demonstrate that JAZ7 interacts with transcription factors functioning as activators (MYC3, MYC4) or repressors (JAM1) of JA-signaling and contains a functional EAR repressor motif mediating transcriptional repression via the co-repressor TOPLESS (TPL). We propose through direct TPL recruitment, in wild-type plants JAZ7 functions as a repressor within the JA-response network and that in jaz7-1D plants, misregulated ectopic JAZ7 expression hyper-activates JA-signaling in part by disturbing finely-tuned COI1-JAZ-TPL-TF complexes. PMID:26896849

The dependency of different stress-level SiN capping films and the optimization of D-SMT process for the device performance booster in Ge n-FinFETs

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

Liao, M.-H., E-mail: mhliaoa@ntu.edu.tw; Chen, P.-G.

The capping stressed SiN film is one of the most important process steps for the dislocation stress memorization technique (D-SMT), which has been used widely in the current industry, for the electron mobility booster in the n-type transistor beyond the 32/28 nm technology node. In this work, we found that the different stress-level SiN capping films influence the crystal re-growth velocities along different directions including [100] and [110] directions in Ge a lot. It can be further used to optimize the dislocation angle in the transistor during the D-SMT process and then results in the largest channel stress distribution to boostmore » the device performance in the Ge n-FinFETs. Based on the theoretical calculation and experimental demonstration, it shows that the Ge three dimensional (3D) n-FinFETs device performance is improved ∼55% with the usage of +3 GPa tensile stressed SiN capping film. The channel stress and dislocation angle is ∼2.5 GPa and 30°, measured by the atomic force microscope-Raman technique and transmission electron microscopy, respectively.« less

New precision orbits of bright double-lined spectroscopic binaries. IX. HD 54371, HR 2692, and 16 ursa majoris

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

Fekel, Francis C.; Williamson, Michael H.; Muterspaugh, Matthew W.

2015-02-01

With extensive sets of new radial velocities we have determined orbital elements for three previously known spectroscopic binaries, HD 54371, HR 2692, and 16 UMa. All three systems have had the lines of their secondaries detected for the first time. The orbital periods range from 16.24 to 113.23 days, and the three binaries have modestly or moderately eccentric orbits. The secondary to primary mass ratios range from 0.50 to 0.64. The orbital dimensions (a{sub 1} sin i and a{sub 2} sin i) and minimum masses (m{sub 1} sin{sup 3} i and m{sub 2} sin{sup 3} i) of the binary componentsmore » all have accuracies of ⩽1%. With our spectroscopic results and the Hipparcos data, we also have determined astrometric orbits for two of the three systems, HR 2692 and 16 UMa. The primaries of HD 54371 and 16 UMa are solar-type stars, and their secondaries are likely K or M dwarfs. The primary of HR 2692 is a late-type subgiant and its secondary is a G or K dwarf. The primaries of both HR 2692 and 16 UMa may be pseudosynchronously rotating, while that of HD 54371 is rotating faster than its pseudosynchronous velocity.« less

Transforming Growth Factor-β/SMAD Target Gene SKIL Is Negatively Regulated by the Transcriptional Cofactor Complex SNON-SMAD4*

PubMed Central

Tecalco-Cruz, Angeles C.; Sosa-Garrocho, Marcela; Vázquez-Victorio, Genaro; Ortiz-García, Layla; Domínguez-Hüttinger, Elisa; Macías-Silva, Marina

2012-01-01

The human SKI-like (SKIL) gene encodes the SMAD transcriptional corepressor SNON that antagonizes TGF-β signaling. SNON protein levels are tightly regulated by the TGF-β pathway: whereas a short stimulation with TGF-β decreases SNON levels by its degradation via the proteasome, longer TGF-β treatment increases SNON levels by inducing SKIL gene expression. Here, we investigated the molecular mechanisms involved in the self-regulation of SKIL gene expression by SNON. Bioinformatics analysis showed that the human SKIL gene proximal promoter contains a TGF-β response element (TRE) bearing four groups of SMAD-binding elements that are also conserved in mouse. Two regions of 408 and 648 bp of the human SKIL gene (∼2.4 kb upstream of the ATG initiation codon) containing the core promoter, transcription start site, and the TRE were cloned for functional analysis. Binding of SMAD and SNON proteins to the TRE region of the SKIL gene promoter after TGF-β treatment was demonstrated by ChIP and sequential ChIP assays. Interestingly, the SNON-SMAD4 complex negatively regulated basal SKIL gene expression through binding the promoter and recruiting histone deacetylases. In response to TGF-β signal, SNON is removed from the SKIL gene promoter, and then the activated SMAD complexes bind the promoter to induce SKIL gene expression. Subsequently, the up-regulated SNON protein in complex with SMAD4 represses its own expression as part of the negative feedback loop regulating the TGF-β pathway. Accordingly, when the SNON-SMAD4 complex is absent as in some cancer cells lacking SMAD4 the regulation of some TGF-β target genes is modified. PMID:22674574

Transforming growth factor-β/SMAD Target gene SKIL is negatively regulated by the transcriptional cofactor complex SNON-SMAD4.

PubMed

Tecalco-Cruz, Angeles C; Sosa-Garrocho, Marcela; Vázquez-Victorio, Genaro; Ortiz-García, Layla; Domínguez-Hüttinger, Elisa; Macías-Silva, Marina

2012-08-03

The human SKI-like (SKIL) gene encodes the SMAD transcriptional corepressor SNON that antagonizes TGF-β signaling. SNON protein levels are tightly regulated by the TGF-β pathway: whereas a short stimulation with TGF-β decreases SNON levels by its degradation via the proteasome, longer TGF-β treatment increases SNON levels by inducing SKIL gene expression. Here, we investigated the molecular mechanisms involved in the self-regulation of SKIL gene expression by SNON. Bioinformatics analysis showed that the human SKIL gene proximal promoter contains a TGF-β response element (TRE) bearing four groups of SMAD-binding elements that are also conserved in mouse. Two regions of 408 and 648 bp of the human SKIL gene (∼2.4 kb upstream of the ATG initiation codon) containing the core promoter, transcription start site, and the TRE were cloned for functional analysis. Binding of SMAD and SNON proteins to the TRE region of the SKIL gene promoter after TGF-β treatment was demonstrated by ChIP and sequential ChIP assays. Interestingly, the SNON-SMAD4 complex negatively regulated basal SKIL gene expression through binding the promoter and recruiting histone deacetylases. In response to TGF-β signal, SNON is removed from the SKIL gene promoter, and then the activated SMAD complexes bind the promoter to induce SKIL gene expression. Subsequently, the up-regulated SNON protein in complex with SMAD4 represses its own expression as part of the negative feedback loop regulating the TGF-β pathway. Accordingly, when the SNON-SMAD4 complex is absent as in some cancer cells lacking SMAD4 the regulation of some TGF-β target genes is modified.

A novel role of BELL1-like homeobox genes, PENNYWISE and POUND-FOOLISH, in floral patterning.

PubMed

Yu, Lifeng; Patibanda, Varun; Smith, Harley M S

2009-02-01

Flowers are determinate shoots comprised of perianth and reproductive organs displayed in a whorled phyllotactic pattern. Floral organ identity genes display region-specific expression patterns in the developing flower. In Arabidopsis, floral organ identity genes are activated by LEAFY (LFY), which functions with region-specific co-regulators, UNUSUAL FLORAL ORGANS (UFO) and WUSCHEL (WUS), to up-regulate homeotic genes in specific whorls of the flower. PENNYWISE (PNY) and POUND-FOOLISH (PNF) are redundant functioning BELL1-like homeodomain proteins that are expressed in shoot and floral meristems. During flower development, PNY functions with a co-repressor complex to down-regulate the homeotic gene, AGAMOUS (AG), in the outer whorls of the flower. However, the function of PNY as well as PNF in regulating floral organ identity in the central whorls of the flower is not known. In this report, we show that combining mutations in PNY and PNF enhance the floral patterning phenotypes of weak and strong alleles of lfy, indicating that these BELL1-like homeodomain proteins play a role in the specification of petals, stamens and carpels during flower development. Expression studies show that PNY and PNF positively regulate the homeotic genes, APETALA3 and AG, in the inner whorls of the flower. Moreover, PNY and PNF function in parallel with LFY, UFO and WUS to regulate homeotic gene expression. Since PNY and PNF interact with the KNOTTED1-like homeodomain proteins, SHOOTMERISTEMLESS (STM) and KNOTTED-LIKE from ARABIDOPSIS THALIANA2 (KNAT2) that regulate floral development, we propose that PNY/PNF-STM and PNY/PNF-KNAT2 complexes function in the inner whorls to regulate flower patterning events.

A 2D/3D image analysis system to track fluorescently labeled structures in rod-shaped cells: application to measure spindle pole asymmetry during mitosis.

PubMed

Schmitter, Daniel; Wachowicz, Paulina; Sage, Daniel; Chasapi, Anastasia; Xenarios, Ioannis; Simanis; Unser, Michael

2013-01-01

The yeast Schizosaccharomyces pombe is frequently used as a model for studying the cell cycle. The cells are rod-shaped and divide by medial fission. The process of cell division, or cytokinesis, is controlled by a network of signaling proteins called the Septation Initiation Network (SIN); SIN proteins associate with the SPBs during nuclear division (mitosis). Some SIN proteins associate with both SPBs early in mitosis, and then display strongly asymmetric signal intensity at the SPBs in late mitosis, just before cytokinesis. This asymmetry is thought to be important for correct regulation of SIN signaling, and coordination of cytokinesis and mitosis. In order to study the dynamics of organelles or large protein complexes such as the spindle pole body (SPB), which have been labeled with a fluorescent protein tag in living cells, a number of the image analysis problems must be solved; the cell outline must be detected automatically, and the position and signal intensity associated with the structures of interest within the cell must be determined. We present a new 2D and 3D image analysis system that permits versatile and robust analysis of motile, fluorescently labeled structures in rod-shaped cells. We have designed an image analysis system that we have implemented as a user-friendly software package allowing the fast and robust image-analysis of large numbers of rod-shaped cells. We have developed new robust algorithms, which we combined with existing methodologies to facilitate fast and accurate analysis. Our software permits the detection and segmentation of rod-shaped cells in either static or dynamic (i.e. time lapse) multi-channel images. It enables tracking of two structures (for example SPBs) in two different image channels. For 2D or 3D static images, the locations of the structures are identified, and then intensity values are extracted together with several quantitative parameters, such as length, width, cell orientation, background fluorescence and the distance between the structures of interest. Furthermore, two kinds of kymographs of the tracked structures can be established, one representing the migration with respect to their relative position, the other representing their individual trajectories inside the cell. This software package, called "RodCellJ", allowed us to analyze a large number of S. pombe cells to understand the rules that govern SIN protein asymmetry. (Continued on next page) (Continued from previous page). "RodCellJ" is freely available to the community as a package of several ImageJ plugins to simultaneously analyze the behavior of a large number of rod-shaped cells in an extensive manner. The integration of different image-processing techniques in a single package, as well as the development of novel algorithms does not only allow to speed up the analysis with respect to the usage of existing tools, but also accounts for higher accuracy. Its utility was demonstrated on both 2D and 3D static and dynamic images to study the septation initiation network of the yeast Schizosaccharomyces pombe. More generally, it can be used in any kind of biological context where fluorescent-protein labeled structures need to be analyzed in rod-shaped cells. RodCellJ is freely available under http://bigwww.epfl.ch/algorithms.html.

SYVN1, NEDD8, and FBXO2 Proteins Regulate ΔF508 Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Ubiquitin-mediated Proteasomal Degradation.

PubMed

Ramachandran, Shyam; Osterhaus, Samantha R; Parekh, Kalpaj R; Jacobi, Ashley M; Behlke, Mark A; McCray, Paul B

2016-12-02

We previously reported that delivery of a microRNA-138 mimic or siRNA against SIN3A to cultured cystic fibrosis (ΔF508/ΔF508) airway epithelia partially restored ΔF508-cystic fibrosis transmembrane conductance regulator (CFTR)-mediated cAMP-stimulated Cl - conductance. We hypothesized that dissecting this microRNA-138/SIN3A-regulated gene network would identify individual proteins contributing to the rescue of ΔF508-CFTR function. Among the genes in the network, we rigorously validated candidates using functional CFTR maturation and electrolyte transport assays in polarized airway epithelia. We found that depletion of the ubiquitin ligase SYVN1, the ubiquitin/proteasome system regulator NEDD8, or the F-box protein FBXO2 partially restored ΔF508-CFTR-mediated Cl - transport in primary cultures of human cystic fibrosis airway epithelia. Moreover, knockdown of SYVN1, NEDD8, or FBXO2 in combination with corrector compound 18 further potentiated rescue of ΔF508-CFTR-mediated Cl - conductance. This study provides new knowledge of the CFTR biosynthetic pathway. It suggests that SYVN1 and FBXO2 represent two distinct multiprotein complexes that may degrade ΔF508-CFTR in airway epithelia and identifies a new role for NEDD8 in regulating ΔF508-CFTR ubiquitination. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Development and Application of Decision Aid for Tactical Control of Battlefield Operations: Bibliographic Sort of the Decision Aiding Literature

DTIC Science & Technology

1973-12-01

THEORY GAML THE’RY GROUP PROb SQL= U tIC PMLTRIC3b 63 C.LARKSON G a DEC MAK IN SMALL GROUPS A SIM STUDY bLHt SCI 6t0 13 2081 bRUNER J b STUDIES IN...MAK IN SMALL GROUPS A SIN STUDY : BLH 5(1 6d 13 2861 DODSON j 0 AS SIN RES FACILITYz SIN SYS DGN FOR TE AkCRL 111 PRI9I4• FLEEING R ASKS PROC.CONFLICTING...POU315IC HF. 66 MAR 7-1 SHURL ( H NNUAtCENTER FOR COMP BASED BEH STUDIES UCLA SEMIA NTIS-AD 731059 713 CLARKSON b DEC MAK IN SMALL GROUPS A SIM STUDY

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

Kamitani, Shinya; Ohbayashi, Norihiko; Ikeda, Osamu

Signal transducers and activators of transcription (STATs) mediate cell proliferation, differentiation, and survival in immune responses, hematopoiesis, neurogenesis, and other biological processes. Recently, we showed that KAP1 is a novel STAT-binding partner that regulates STAT3-mediated transactivation. KAP1 is a universal co-repressor protein for the KRAB zinc finger protein superfamily of transcriptional repressors. In this study, we found KAP1-dependent repression of interferon (IFN)/STAT1-mediated signaling. We also demonstrated that endogenous KAP1 associates with endogenous STAT1 in vivo. Importantly, a small-interfering RNA-mediated reduction in KAP1 expression enhanced IFN-induced STAT1-dependent IRF-1 gene expression. These results indicate that KAP1 may act as an endogenous regulatormore » of the IFN/STAT1 signaling pathway.« less

Negative feedback regulation of TGF-beta signaling by the SnoN oncoprotein.

PubMed

Stroschein, S L; Wang, W; Zhou, S; Zhou, Q; Luo, K

1999-10-22

Smad proteins mediate transforming growth factor-beta (TGF-beta) signaling to regulate cell growth and differentiation. The SnoN oncoprotein was found to interact with Smad2 and Smad4 and to repress their abilities to activate transcription through recruitment of the transcriptional corepressor N-CoR. Immediately after TGF-beta stimulation, SnoN is rapidly degraded by the nuclear accumulation of Smad3, allowing the activation of TGF-beta target genes. By 2 hours, TGF-beta induces a marked increase in SnoN expression, resulting in termination of Smad-mediated transactivation. Thus, SnoN maintains the repressed state of TGF-beta-responsive genes in the absence of ligand and participates in negative feedback regulation of TGF-beta signaling.

Low RNA Polymerase III activity results in up regulation of HXT2 glucose transporter independently of glucose signaling and despite changing environment

PubMed Central

Szatkowska, Roza

2017-01-01

Background Saccharomyces cerevisiae responds to glucose availability in the environment, inducing the expression of the low-affinity transporters and high-affinity transporters in a concentration dependent manner. This cellular decision making is controlled through finely tuned communication between multiple glucose sensing pathways including the Snf1-Mig1, Snf3/Rgt2-Rgt1 (SRR) and cAMP-PKA pathways. Results We demonstrate the first evidence that RNA Polymerase III (RNAP III) activity affects the expression of the glucose transporter HXT2 (RNA Polymerase II dependent—RNAP II) at the level of transcription. Down-regulation of RNAP III activity in an rpc128-1007 mutant results in a significant increase in HXT2 mRNA, which is considered to respond only to low extracellular glucose concentrations. HXT2 expression is induced in the mutant regardless of the growth conditions either at high glucose concentration or in the presence of a non-fermentable carbon source such as glycerol. Using chromatin immunoprecipitation (ChIP), we found an increased association of Rgt1 and Tup1 transcription factors with the highly activated HXT2 promoter in the rpc128-1007 strain. Furthermore, by measuring cellular abundance of Mth1 corepressor, we found that in rpc128-1007, HXT2 gene expression was independent from Snf3/Rgt2-Rgt1 (SRR) signaling. The Snf1 protein kinase complex, which needs to be active for the release from glucose repression, also did not appear perturbed in the mutated strain. Conclusions/Significance These findings suggest that the general activity of RNAP III can indirectly affect the RNAP II transcriptional machinery on the HXT2 promoter when cellular perception transduced via the major signaling pathways, broadly recognized as on/off switch essential to either positive or negative HXT gene regulation, remain entirely intact. Further, Rgt1/Ssn6-Tup1 complex, which has a dual function in gene transcription as a repressor-activator complex, contributes to HXT2 transcriptional activation. PMID:28961268

"Faith of Our Fathers" -- Lesbian, Gay and Bisexual Teachers' Attitudes towards the Teaching of Religion in Irish Denominational Primary Schools

ERIC Educational Resources Information Center

Fahie, Declan

2017-01-01

Owing to a variety of complex historical and socio-cultural factors, the Irish education system remains heavily influenced by denominational mores and values [Ferriter, D. 2012. "Occasions of Sin: Sex & Society in Modern Ireland." London: Profile Books], particularly those of the Roman Catholic Church [O'Toole, B. 2015.…

Microbiologically Influenced Corrosion: Causative Organisms and Mechanisms

DTIC Science & Technology

2012-01-31

corrosion is both predictable and complex. In aquatic environments and under some atmospheric conditions . microorganisms settle on surfaces and alter the...some atmospheric conditions , microorganisms settle on sin laces and alter the surface chemistry controlling the rates of corrosion or shifting the...pitting corrosion of some allO) S continues under deposits of iron-oxidizing bacteria independent of bacterial activity. Similarly, microbiologicall

A comparison of companion matrix methods to find roots of a trigonometric polynomial

NASA Astrophysics Data System (ADS)

Boyd, John P.

2013-08-01

A trigonometric polynomial is a truncated Fourier series of the form fN(t)≡∑j=0Naj cos(jt)+∑j=1N bj sin(jt). It has been previously shown by the author that zeros of such a polynomial can be computed as the eigenvalues of a companion matrix with elements which are complex valued combinations of the Fourier coefficients, the "CCM" method. However, previous work provided no examples, so one goal of this new work is to experimentally test the CCM method. A second goal is introduce a new alternative, the elimination/Chebyshev algorithm, and experimentally compare it with the CCM scheme. The elimination/Chebyshev matrix (ECM) algorithm yields a companion matrix with real-valued elements, albeit at the price of usefulness only for real roots. The new elimination scheme first converts the trigonometric rootfinding problem to a pair of polynomial equations in the variables (c,s) where c≡cos(t) and s≡sin(t). The elimination method next reduces the system to a single univariate polynomial P(c). We show that this same polynomial is the resultant of the system and is also a generator of the Groebner basis with lexicographic ordering for the system. Both methods give very high numerical accuracy for real-valued roots, typically at least 11 decimal places in Matlab/IEEE 754 16 digit floating point arithmetic. The CCM algorithm is typically one or two decimal places more accurate, though these differences disappear if the roots are "Newton-polished" by a single Newton's iteration. The complex-valued matrix is accurate for complex-valued roots, too, though accuracy decreases with the magnitude of the imaginary part of the root. The cost of both methods scales as O(N3) floating point operations. In spite of intimate connections of the elimination/Chebyshev scheme to two well-established technologies for solving systems of equations, resultants and Groebner bases, and the advantages of using only real-valued arithmetic to obtain a companion matrix with real-valued elements, the ECM algorithm is noticeably inferior to the complex-valued companion matrix in simplicity, ease of programming, and accuracy.

The Putzig-NURF nucleosome remodeling complex is required for ecdysone receptor signaling and innate immunity in Drosophila melanogaster.

PubMed

Kugler, Sabrina J; Gehring, Eva-Maria; Wallkamm, Veronika; Krüger, Victoria; Nagel, Anja C

2011-05-01

Putzig (Pzg) was originally identified as being an integral component of the TRF2/DREF complex in Drosophila melanogaster, thereby regulating the transcriptional activation of replication-related genes. In a DREF-independent manner, Pzg was shown to mediate Notch target gene activation. This function of Pzg entails an association with the nucleosome remodeling factor complex NURF, which directly binds the ecdysone receptor EcR and coregulates targets of the EcR via the NURF-specific subunit Nurf-301. In contrast, Nurf-301 acts as a negative regulator of JAK/STAT signaling. Here, we provide evidence to show that Pzg is fundamental for these functions of NURF, apart from the regulation of Notch signaling activity. A jump-out mutagenesis provided us with a pzg null mutant displaying early larval lethality, defects in growth, and molting accompanied by aberrant feeding behavior. We show that Pzg is associated with EcR in vivo and required for the transcriptional induction of EcR target genes, whereas reduced ecdysteroid levels imply a NURF-independent function of Pzg. Moreover, pzg interferes with JAK/STAT-signaling activity by acting as a corepressor of Ken. Lamellocyte differentiation was consistently affected in a JAK/STAT mutant background and the expression level of defense response genes was elevated in pzg mutants, leading to the formation of melanotic tumors. Our results suggest that Pzg acts as an important partner of NURF in the regulation of EcR and JAK/STAT signaling.

Imprinting regulator DNMT3L is a transcriptional repressor associated with histone deacetylase activity.

PubMed

Aapola, Ulla; Liiv, Ingrid; Peterson, Pärt

2002-08-15

DNMT3L is a regulator of imprint establishment of normally methylated maternal genomic sequences. DNMT3L shows high similarity to the de novo DNA methyltransferases, DNMT3A and DNMT3B, however, the amino acid residues needed for DNA cytosine methyltransferase activity have been lost from the DNMT3L protein sequence. Apart from methyltransferase activity, Dnmt3a and Dnmt3b serve as transcriptional repressors associating with histone deacetylase (HDAC) activity. Here we show that DNMT3L can also repress transcription by binding directly to HDAC1 protein. We have identified the PHD-like zinc finger of the ATRX domain as a main repression motif of DNMT3L, through which DNMT3L recruits the HDAC activity needed for transcriptional silencing. Furthermore, we show that DNMT3L protein contains an active nuclear localisation signal at amino acids 156-159. These results describe DNMT3L as a co-repressor protein and suggest that a transcriptionally repressed chromatin organisation through HDAC activity is needed for establishment of genomic imprints.

NEW PRECISION ORBITS OF BRIGHT DOUBLE-LINED SPECTROSCOPIC BINARIES. V. THE AM STARS HD 434 AND 41 SEXTANTIS

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

Fekel, Francis C.; Williamson, Michael H., E-mail: fekel@evans.tsuniv.ed

We have detected the secondary component in two previously known spectroscopic binaries, HD 434 and 41 Sex, and for the first time determined double-lined orbits for them. Despite the relatively long period of 34.26 days and a moderate eccentricity of 0.32, combined with the components' rotationally broadened lines, measurement of the primary and secondary radial velocities of HD 434 has enabled us to obtain significantly improved orbital elements. While the 41 Sex system has a much shorter period of 6.167 days and a circular orbit, the estimated V mag difference of 3.2 between its components also makes this a challengingmore » system. The new orbital dimensions (a{sub 1} sin i and a{sub 2} sin i) and minimum masses (m{sub 1} sin{sup 3} i and m{sub 2} sin{sup 3} i) of HD 434 have accuracies of 0.8% or better, while the same quantities for 41 Sex are good to 0.5% or better. Both components of HD 434 are Am stars while the Am star primary of 41 Sex has a late-F or early-G companion. All four stars are on the main sequence. The two components of HD 434 are rotating much faster than their predicted pseudosynchronous velocities, while both components of 41 Sex are synchronously rotating. For the primary of 41 Sex, the spectrum line depth changes noted by Sreedhar Rao et al. were not detected.« less

Mooring Mechanics. A Comprehensive Computer Study. Volume II. Three Dimensional Dynamic Analysis of Moored and Drifting Buoy Systems

DTIC Science & Technology

1976-12-01

If point p and w are overlapping then: [Rpw]E R pw]B VBw VEw Ec - EB x Rcp -2.2- Here; VEw i (V +t + i (0 + ) + *w x ox x y 1, y 1i ( Voz + Cz) and...VBw =ix[Vox + 4x -x - Z’cose] + +i z[ Voz + (D - Zc + z’Osinf] = x [ (Vox + Ox - C)cose A - ( Voz + 0z - zo )Sin6 - z’g] + iz’[(Vox + ox " )sinO + ( Voz ...3pr3. Following representation is used in this analysis for this force (AM). S.*.’ I.-; , . ’x.:, I A -3C- 3 L 1rAM = C ip 1 AEt{ z’=-. .. r- L 3

Evidence of early disk-locking among low-mass members of the Orion Nebula Cluster

NASA Astrophysics Data System (ADS)

Biazzo, K.; Melo, C. H. F.; Pasquini, L.; Randich, S.; Bouvier, J.; Delfosse, X.

2009-12-01

Context: We present new high-resolution spectroscopic observations for 91 pre-main sequence stars in the Orion Nebular Cluster (ONC) with masses in the range 0.10-0.25~M_⊙ carried out with the multi-fiber spectrograph flames attached to the UT2 at the Paranal Observatory. Aims: Our aim is to better understand the disk-locking scenario in very low-mass stars. Methods: We have derived radial velocities, projected rotational velocities, and full width at 10% of the Hα emission peak. Using published measurements of infrared excess (Δ(I_C-K)), as disk tracer and equivalent width of the nead-infrared Ca II line λ8542, mid-infrared difference [3.6]-[8.0] μm derived by Spitzer data, and 10% Hα width as diagnostic of the level of accretion, we looked for any correlation between projected angular rotational velocity divided by the radius (v sin i/R) and presence of disk and accretion. Results: For 4 low-mass stars, the cross-correlation function is clearly double-lined, indicating that the stars are SB2 systems. The distribution of rotation periods derived from our v sin i measurements is unimodal with a peak of a few days, in agreement with previous results for M<0.25~M_⊙. The photometric periods were combined with our v sin i to derive the equatorial velocity and the distribution of rotational axes. Our < sin i> is lower than the one expected for a random distribution, as previously found. We find no evidence of a population of fast rotators close to the break-up velocity. A clear correlation between v sin i/R and Δ(I_C-K) has been found. While a spread in the rotation rates is seen for stars with no circumstellar disk (Δ(I_C-K)<0.3), stars with a circumstellar disk (Δ(I_C-K)>0.3) show an abrupt drop in their rotation rates by a factor of ~5. On the other hand, only a partial correlation between v sin i and accretion is observed when other indicators are used. The X-ray coronal activity level (log L_X/L_bol) shows no dependence on v sin i/R, suggesting that all stars are in a saturated regime limit. The critical velocity is probably below our v sin i detection limit of 9 km s-1. Conclusions: The ONC low-mass stars in our sample, close to the hydrogen burning limit, at present do not seem to be locked, but the clear correlation we find between rotation and infrared color excess suggests that they were locked once. In addition, the percentage of accretors seems to scale inversely to the stellar mass. Based on the flames Science Verification proposal 60.A-9145(A) and the flames proposal 76.C-0524(A). Table [see full textsee full textsee full textsee full text] is only available in electronic form at http://www.aanda.org

Theoretical study of the electronic states of newly detected dications. Case of MgS2+ AND SiN2+

NASA Astrophysics Data System (ADS)

Khairat, Toufik; Salah, Mohammed; Marakchi, Khadija; Komiha, Najia

2017-08-01

The dications MgS2+ and SiN2+, experimentally observed by mass spectroscopy, are theoretically studied here. The potential energy curves of the electronic states of the two dications MgS2+ and SiN2+ are mapped and their spectroscopic parameters determined by analysis of the electronic, vibrational and rotational wave functions obtained by using complete active space self-consistent field (CASSCF) calculations, followed by the internally contracted multi-reference configuration interaction (MRCI)+Q associated with the AV5Z correlation consistent atomic orbitals basis sets. In the following, besides the characterization of the potential energy curves, excitation and dissociation energies, spectroscopic constants and a double-ionization spectra of MgS and SiN are determined using the transition moments values and Franck-Condon factors. The electronic ground states of the two dications appear to be of X3∑-nature for MgS2+ and X4∑- for SiN2+ and shows potential wells of about 1.20 eV and 1.40 eV, respectively. Several excited states of these doubly charged molecules also depicted here are slightly bound. The adiabatic double-ionization energies were deduced, at 21.4 eV and 18.4 eV, respectively, from the potential energy curves of the electronic ground states of the neutral and charged species. The neutral molecules, since involved, are also investigated here. From all these results, the experimental lines of the mass spectra of MgS and SiN could be partly assigned.

Outbreaks of health care-associated influenza-like illness in France: Impact of electronic notification.

PubMed

Munier-Marion, Elodie; Bénet, Thomas; Dananché, Cédric; Soing-Altach, Sophan; Maugat, Sylvie; Vaux, Sophie; Vanhems, Philippe

2017-11-01

Mandatory notification of health care-associated (HA) infections, including influenza-like illness (ILI) outbreaks, has been implemented in France since 2001. In 2012, the system moved to online electronic notification of HA infections (e-SIN). The objectives of this study are to describe ILI outbreak notifications to Santé publique France (SPF), the French national public health agency, and to evaluate the impact of notification dematerialization. All notifications of HA ILI outbreaks between July 2001 and June 2015 were included. Notifications before and after e-SIN implementation were compared regarding notification delay and information exhaustiveness. Overall, 506 HA ILI outbreaks were reported, accounting for 7,861 patients and health care professionals. Median delay between occurrence of the first case and notification was, respectively, 32 and 13 days before and after e-SIN utilization (P < .001). Information exhaustiveness was improved by electronic notification regarding HA status (8.5% of missing data before and 2.3% after e-SIN, P = .003), hypotheses of cause (25.4% of missing data before vs 8.0% after e-SIN, P < .001), and level of event control (23.7% of missing data before vs 7.5% after e-SIN, P < .001). HA influenza notifications, including HA ILI or influenza, to health authorities are essential to guide decisional instances and health care practices. Electronic notifications have improved the timeliness and quality of information transmitted. Copyright © 2017 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.

High S/N Echelle spectroscopy in young stellar groups. II. Rotational velocities of early-type stars in SCO OB2.

NASA Astrophysics Data System (ADS)

Brown, A. G. A.; Verschueren, W.

1997-03-01

We investigate the rotational velocities of early-type stars in the Sco OB2 association. We measure v.sin(i) for 156 established and probable members of the association. The measurements are performed with three different techniques, which are in increasing order of expected v.sin(i): 1) converting the widths of spectral lines directly to v.sin(i), 2) comparing artificially broadened spectra of low v.sin(i) stars to the target spectrum, 3) comparing the HeI λ4026 line profile to theoretical models. The sample is extended with literature data for 47 established members of Sco OB2. Analysis of the v.sin(i) distributions shows that there are no significant differences between the subgroups of Sco OB2. We find that members of the binary population of Sco OB2 on the whole rotate more slowly than the single stars. In addition, we find that the B7-B9 single star members rotate significantly faster than their B0-B6 counterparts. We test various hypotheses for the distribution of v.sin(i) in the association. The results show that we cannot clearly exclude any form of random distribution of the direction and/or magnitude of the intrinsic rotational velocity vector. We also investigate the effects of rotation on colours in the Walraven photometric system. We show that positions of B7-B9 single dwarfs above the main sequence are a consequence of rotation. This establishes the influence of rotation on the Walraven colours, due primarily to surface gravity effects.

Simulation of the Acoustic Pulse Expected from the Interaction of Ultra-High Energy Neutrinos and Seawater

DTIC Science & Technology

2006-03-01

the diameter. This equation is given by Sulak et. al. [1979] as: Eq 3 2 2 sin 8 o p EK cP C r d x ≅ x ’ Where sinLx π θ λ ⎛ ⎞= ⎜ ⎟ ⎝ ⎠ , L is...and others, "Sensitivity of an Underwater Acoustic Array to Ultra-High Energy Neutrinos", Astroparticle Physics, n.17, 2002. Sulak , L., Armstrong

Development and validation of the Single Item Narcissism Scale (SINS).

PubMed

Konrath, Sara; Meier, Brian P; Bushman, Brad J

2014-01-01

The narcissistic personality is characterized by grandiosity, entitlement, and low empathy. This paper describes the development and validation of the Single Item Narcissism Scale (SINS). Although the use of longer instruments is superior in most circumstances, we recommend the SINS in some circumstances (e.g. under serious time constraints, online studies). In 11 independent studies (total N = 2,250), we demonstrate the SINS' psychometric properties. The SINS is significantly correlated with longer narcissism scales, but uncorrelated with self-esteem. It also has high test-retest reliability. We validate the SINS in a variety of samples (e.g., undergraduates, nationally representative adults), intrapersonal correlates (e.g., positive affect, depression), and interpersonal correlates (e.g., aggression, relationship quality, prosocial behavior). The SINS taps into the more fragile and less desirable components of narcissism. The SINS can be a useful tool for researchers, especially when it is important to measure narcissism with constraints preventing the use of longer measures.

A Strapdown Interial Navigation System/Beidou/Doppler Velocity Log Integrated Navigation Algorithm Based on a Cubature Kalman Filter

PubMed Central

Gao, Wei; Zhang, Ya; Wang, Jianguo

2014-01-01

The integrated navigation system with strapdown inertial navigation system (SINS), Beidou (BD) receiver and Doppler velocity log (DVL) can be used in marine applications owing to the fact that the redundant and complementary information from different sensors can markedly improve the system accuracy. However, the existence of multisensor asynchrony will introduce errors into the system. In order to deal with the problem, conventionally the sampling interval is subdivided, which increases the computational complexity. In this paper, an innovative integrated navigation algorithm based on a Cubature Kalman filter (CKF) is proposed correspondingly. A nonlinear system model and observation model for the SINS/BD/DVL integrated system are established to more accurately describe the system. By taking multi-sensor asynchronization into account, a new sampling principle is proposed to make the best use of each sensor's information. Further, CKF is introduced in this new algorithm to enable the improvement of the filtering accuracy. The performance of this new algorithm has been examined through numerical simulations. The results have shown that the positional error can be effectively reduced with the new integrated navigation algorithm. Compared with the traditional algorithm based on EKF, the accuracy of the SINS/BD/DVL integrated navigation system is improved, making the proposed nonlinear integrated navigation algorithm feasible and efficient. PMID:24434842

Measurement of neutrino and antineutrino oscillations by the T2K experiment including a new additional sample of νe interactions at the far detector

NASA Astrophysics Data System (ADS)

Abe, K.; Amey, J.; Andreopoulos, C.; Antonova, M.; Aoki, S.; Ariga, A.; Ashida, Y.; Ban, S.; Barbi, M.; Barker, G. J.; Barr, G.; Barry, C.; Batkiewicz, M.; Berardi, V.; Berkman, S.; Bhadra, S.; Bienstock, S.; Blondel, A.; Bolognesi, S.; Bordoni, S.; Boyd, S. B.; Brailsford, D.; Bravar, A.; Bronner, C.; Buizza Avanzini, M.; Calland, R. G.; Campbell, T.; Cao, S.; Cartwright, S. L.; Catanesi, M. G.; Cervera, A.; Chappell, A.; Checchia, C.; Cherdack, D.; Chikuma, N.; Christodoulou, G.; Coleman, J.; Collazuol, G.; Coplowe, D.; Cudd, A.; Dabrowska, A.; De Rosa, G.; Dealtry, T.; Denner, P. F.; Dennis, S. R.; Densham, C.; Di Lodovico, F.; Dolan, S.; Drapier, O.; Duffy, K. E.; Dumarchez, J.; Dunne, P.; Emery-Schrenk, S.; Ereditato, A.; Feusels, T.; Finch, A. J.; Fiorentini, G. A.; Fiorillo, G.; Friend, M.; Fujii, Y.; Fukuda, D.; Fukuda, Y.; Garcia, A.; Giganti, C.; Gizzarelli, F.; Golan, T.; Gonin, M.; Hadley, D. R.; Haegel, L.; Haigh, J. T.; Hansen, D.; Harada, J.; Hartz, M.; Hasegawa, T.; Hastings, N. C.; Hayashino, T.; Hayato, Y.; Hillairet, A.; Hiraki, T.; Hiramoto, A.; Hirota, S.; Hogan, M.; Holeczek, J.; Hosomi, F.; Huang, K.; Ichikawa, A. K.; Ikeda, M.; Imber, J.; Insler, J.; Intonti, R. A.; Ishida, T.; Ishii, T.; Iwai, E.; Iwamoto, K.; Izmaylov, A.; Jamieson, B.; Jiang, M.; Johnson, S.; Jonsson, P.; Jung, C. K.; Kabirnezhad, M.; Kaboth, A. C.; Kajita, T.; Kakuno, H.; Kameda, J.; Karlen, D.; Katori, T.; Kearns, E.; Khabibullin, M.; Khotjantsev, A.; Kim, H.; Kim, J.; King, S.; Kisiel, J.; Knight, A.; Knox, A.; Kobayashi, T.; Koch, L.; Koga, T.; Koller, P. P.; Konaka, A.; Kormos, L. L.; Koshio, Y.; Kowalik, K.; Kudenko, Y.; Kurjata, R.; Kutter, T.; Lagoda, J.; Lamont, I.; Lamoureux, M.; Lasorak, P.; Laveder, M.; Lawe, M.; Licciardi, M.; Lindner, T.; Liptak, Z. J.; Litchfield, R. P.; Li, X.; Longhin, A.; Lopez, J. P.; Lou, T.; Ludovici, L.; Lu, X.; Magaletti, L.; Mahn, K.; Malek, M.; Manly, S.; Maret, L.; Marino, A. D.; Martin, J. F.; Martins, P.; Martynenko, S.; Maruyama, T.; Matveev, V.; Mavrokoridis, K.; Ma, W. Y.; Mazzucato, E.; McCarthy, M.; McCauley, N.; McFarland, K. S.; McGrew, C.; Mefodiev, A.; Metelko, C.; Mezzetto, M.; Minamino, A.; Mineev, O.; Mine, S.; Missert, A.; Miura, M.; Moriyama, S.; Morrison, J.; Mueller, Th. A.; Nakadaira, T.; Nakahata, M.; Nakamura, K. G.; Nakamura, K.; Nakamura, K. D.; Nakanishi, Y.; Nakayama, S.; Nakaya, T.; Nakayoshi, K.; Nantais, C.; Nielsen, C.; Nishikawa, K.; Nishimura, Y.; Novella, P.; Nowak, J.; O'Keeffe, H. M.; Okumura, K.; Okusawa, T.; Oryszczak, W.; Oser, S. M.; Ovsyannikova, T.; Owen, R. A.; Oyama, Y.; Palladino, V.; Palomino, J. L.; Paolone, V.; Patel, N. D.; Paudyal, P.; Pavin, M.; Payne, D.; Petrov, Y.; Pickering, L.; Pinzon Guerra, E. S.; Pistillo, C.; Popov, B.; Posiadala-Zezula, M.; Poutissou, J.-M.; Pritchard, A.; Przewlocki, P.; Quilain, B.; Radermacher, T.; Radicioni, E.; Ratoff, P. N.; Rayner, M. A.; Reinherz-Aronis, E.; Riccio, C.; Rodrigues, P. A.; Rondio, E.; Rossi, B.; Roth, S.; Ruggeri, A. C.; Rychter, A.; Sakashita, K.; Sánchez, F.; Scantamburlo, E.; Scholberg, K.; Schwehr, J.; Scott, M.; Seiya, Y.; Sekiguchi, T.; Sekiya, H.; Sgalaberna, D.; Shah, R.; Shaikhiev, A.; Shaker, F.; Shaw, D.; Shiozawa, M.; Shirahige, T.; Smy, M.; Sobczyk, J. T.; Sobel, H.; Steinmann, J.; Stewart, T.; Stowell, P.; Suda, Y.; Suvorov, S.; Suzuki, A.; Suzuki, S. Y.; Suzuki, Y.; Tacik, R.; Tada, M.; Takeda, A.; Takeuchi, Y.; Tamura, R.; Tanaka, H. K.; Tanaka, H. A.; Thakore, T.; Thompson, L. F.; Tobayama, S.; Toki, W.; Tomura, T.; Tsukamoto, T.; Tzanov, M.; Vagins, M.; Vallari, Z.; Vasseur, G.; Vilela, C.; Vladisavljevic, T.; Wachala, T.; Walter, C. W.; Wark, D.; Wascko, M. O.; Weber, A.; Wendell, R.; Wilking, M. J.; Wilkinson, C.; Wilson, J. R.; Wilson, R. J.; Wret, C.; Yamada, Y.; Yamamoto, K.; Yanagisawa, C.; Yano, T.; Yen, S.; Yershov, N.; Yokoyama, M.; Yu, M.; Zalewska, A.; Zalipska, J.; Zambelli, L.; Zaremba, K.; Ziembicki, M.; Zimmerman, E. D.; Zito, M.; T2K Collaboration

2017-11-01

The T2K experiment reports an updated analysis of neutrino and antineutrino oscillations in appearance and disappearance channels. A sample of electron neutrino candidates at Super-Kamiokande in which a pion decay has been tagged is added to the four single-ring samples used in previous T2K oscillation analyses. Through combined analyses of these five samples, simultaneous measurements of four oscillation parameters, |Δ m322 |, sin2θ23, sin2θ13, and δCP and of the mass ordering are made. A set of studies of simulated data indicates that the sensitivity to the oscillation parameters is not limited by neutrino interaction model uncertainty. Multiple oscillation analyses are performed, and frequentist and Bayesian intervals are presented for combinations of the oscillation parameters with and without the inclusion of reactor constraints on sin2θ13. When combined with reactor measurements, the hypothesis of C P conservation (δCP=0 or π ) is excluded at 90% confidence level. The 90% confidence region for δCP is [-2.95 ,-0.44 ] ([-1.47 ,-1.27 ] ) for normal (inverted) ordering. The central values and 68% confidence intervals for the other oscillation parameters for normal (inverted) ordering are Δ m322=2.54 ±0.08 (2.51 ±0.08 )×10-3 eV2/c4 and sin2θ23 =0.5 5-0.09+0.05 (0.5 5-0.08+0.05), compatible with maximal mixing. In the Bayesian analysis, the data weakly prefer normal ordering (Bayes factor 3.7) and the upper octant for sin2θ23 (Bayes factor 2.4).

Neutrino oscillation physics potential of the T2K experiment

NASA Astrophysics Data System (ADS)

T2K Collaboration; Abe, K.; Adam, J.; Aihara, H.; Akiri, T.; Andreopoulos, C.; Aoki, S.; Ariga, A.; Assylbekov, S.; Autiero, D.; Barbi, M.; Barker, G. J.; Barr, G.; Bartet-Friburg, P.; Bass, M.; Batkiewicz, M.; Bay, F.; Berardi, V.; Berger, B. E.; Berkman, S.; Bhadra, S.; Blaszczyk, F. d. M.; Blondel, A.; Bojechko, C.; Bordoni, S.; Boyd, S. B.; Brailsford, D.; Bravar, A.; Bronner, C.; Buchanan, N.; Calland, R. G.; Caravaca Rodríguez, J.; Cartwright, S. L.; Castillo, R.; Catanesi, M. G.; Cervera, A.; Cherdack, D.; Christodoulou, G.; Clifton, A.; Coleman, J.; Coleman, S. J.; Collazuol, G.; Connolly, K.; Cremonesi, L.; Dabrowska, A.; Danko, I.; Das, R.; Davis, S.; de Perio, P.; de Rosa, G.; Dealtry, T.; Dennis, S. R.; Densham, C.; Dewhurst, D.; Di Lodovico, F.; Di Luise, S.; Drapier, O.; Duboyski, T.; Duffy, K.; Dumarchez, J.; Dytman, S.; Dziewiecki, M.; Emery-Schrenk, S.; Ereditato, A.; Escudero, L.; Feusels, T.; Finch, A. J.; Fiorentini, G. A.; Friend, M.; Fujii, Y.; Fukuda, Y.; Furmanski, A. P.; Galymov, V.; Garcia, A.; Giffin, S.; Giganti, C.; Gilje, K.; Goeldi, D.; Golan, T.; Gonin, M.; Grant, N.; Gudin, D.; Hadley, D. R.; Haegel, L.; Haesler, A.; Haigh, M. D.; Hamilton, P.; Hansen, D.; Hara, T.; Hartz, M.; Hasegawa, T.; Hastings, N. C.; Hayashino, T.; Hayato, Y.; Hearty, C.; Helmer, R. L.; Hierholzer, M.; Hignight, J.; Hillairet, A.; Himmel, A.; Hiraki, T.; Hirota, S.; Holeczek, J.; Horikawa, S.; Huang, K.; Ichikawa, A. K.; Ieki, K.; Ieva, M.; Ikeda, M.; Imber, J.; Insler, J.; Irvine, T. J.; Ishida, T.; Ishii, T.; Iwai, E.; Iwamoto, K.; Iyogi, K.; Izmaylov, A.; Jacob, A.; Jamieson, B.; Johnson, R. A.; Johnson, S.; Jo, J. H.; Jonsson, P.; Jung, C. K.; Kabirnezhad, M.; Kaboth, A. C.; Kajita, T.; Kakuno, H.; Kameda, J.; Kanazawa, Y.; Karlen, D.; Karpikov, I.; Katori, T.; Kearns, E.; Khabibullin, M.; Khotjantsev, A.; Kielczewska, D.; Kikawa, T.; Kilinski, A.; Kim, J.; King, S.; Kisiel, J.; Kitching, P.; Kobayashi, T.; Koch, L.; Koga, T.; Kolaceke, A.; Konaka, A.; Kormos, L. L.; Korzenev, A.; Koshio, Y.; Kropp, W.; Kubo, H.; Kudenko, Y.; Kurjata, R.; Kutter, T.; Lagoda, J.; Laihem, K.; Lamont, I.; Larkin, E.; Laveder, M.; Lawe, M.; Lazos, M.; Lindner, T.; Lister, C.; Litchfield, R. P.; Longhin, A.; Lopez, J. P.; Ludovici, L.; Magaletti, L.; Mahn, K.; Malek, M.; Manly, S.; Marino, A. D.; Marteau, J.; Martin, J. F.; Martins, P.; Martynenko, S.; Maruyama, T.; Matveev, V.; Mavrokoridis, K.; Mazzucato, E.; McCarthy, M.; McCauley, N.; McFarland, K. S.; McGrew, C.; Mefodiev, A.; Metelko, C.; Mezzetto, M.; Mijakowski, P.; Miller, C. A.; Minamino, A.; Mineev, O.; Missert, A.; Miura, M.; Moriyama, S.; Mueller, Th. A.; Murakami, A.; Murdoch, M.; Murphy, S.; Myslik, J.; Nakadaira, T.; Nakahata, M.; Nakamura, K. G.; Nakamura, K.; Nakayama, S.; Nakaya, T.; Nakayoshi, K.; Nantais, C.; Nielsen, C.; Nirkko, M.; Nishikawa, K.; Nishimura, Y.; Nowak, J.; O'Keeffe, H. M.; Ohta, R.; Okumura, K.; Okusawa, T.; Oryszczak, W.; Oser, S. M.; Ovsyannikova, T.; Owen, R. A.; Oyama, Y.; Palladino, V.; Palomino, J. L.; Paolone, V.; Payne, D.; Perevozchikov, O.; Perkin, J. D.; Petrov, Y.; Pickard, L.; Pinzon Guerra, E. S.; Pistillo, C.; Plonski, P.; Poplawska, E.; Popov, B.; Posiadala-Zezula, M.; Poutissou, J.-M.; Poutissou, R.; Przewlocki, P.; Quilain, B.; Radicioni, E.; Ratoff, P. N.; Ravonel, M.; Rayner, M. A. M.; Redij, A.; Reeves, M.; Reinherz-Aronis, E.; Riccio, C.; Rodrigues, P. A.; Rojas, P.; Rondio, E.; Roth, S.; Rubbia, A.; Ruterbories, D.; Sacco, R.; Sakashita, K.; Sánchez, F.; Sato, F.; Scantamburlo, E.; Scholberg, K.; Schoppmann, S.; Schwehr, J.; Scott, M.; Seiya, Y.; Sekiguchi, T.; Sekiya, H.; Sgalaberna, D.; Shah, R.; Shaker, F.; Shiozawa, M.; Short, S.; Shustrov, Y.; Sinclair, P.; Smith, B.; Smy, M.; Sobczyk, J. T.; Sobel, H.; Sorel, M.; Southwell, L.; Stamoulis, P.; Steinmann, J.; Still, B.; Suda, Y.; Suzuki, A.; Suzuki, K.; Suzuki, S. Y.; Suzuki, Y.; Tacik, R.; Tada, M.; Takahashi, S.; Takeda, A.; Takeuchi, Y.; Tanaka, H. K.; Tanaka, H. A.; Tanaka, M. M.; Terhorst, D.; Terri, R.; Thompson, L. F.; Thorley, A.; Tobayama, S.; Toki, W.; Tomura, T.; Totsuka, Y.; Touramanis, C.; Tsukamoto, T.; Tzanov, M.; Uchida, Y.; Vacheret, A.; Vagins, M.; Vasseur, G.; Wachala, T.; Waldron, A. V.; Wakamatsu, K.; Walter, C. W.; Wark, D.; Warzycha, W.; Wascko, M. O.; Weber, A.; Wendell, R.; Wilkes, R. J.; Wilking, M. J.; Wilkinson, C.; Williamson, Z.; Wilson, J. R.; Wilson, R. J.; Wongjirad, T.; Yamada, Y.; Yamamoto, K.; Yanagisawa, C.; Yano, T.; Yen, S.; Yershov, N.; Yokoyama, M.; Yoshida, K.; Yuan, T.; Yu, M.; Zalewska, A.; Zalipska, J.; Zambelli, L.; Zaremba, K.; Ziembicki, M.; Zimmerman, E. D.; Zito, M.; Żmuda, J.

2015-04-01

The observation of the recent electron neutrino appearance in a muon neutrino beam and the high-precision measurement of the mixing angle θ _{13} have led to a re-evaluation of the physics potential of the T2K long-baseline neutrino oscillation experiment. Sensitivities are explored for CP violation in neutrinos, non-maximal sin ^22θ _{23}, the octant of θ _{23}, and the mass hierarchy, in addition to the measurements of δ _{CP}, sin ^2θ _{23}, and Δ m^2_{32}, for various combinations of ν-mode and bar {ν }-mode data-taking. With an exposure of 7.8× 10^{21} protons-on-target, T2K can achieve 1σ resolution of 0.050 (0.054) on sin ^2θ _{23} and 0.040 (0.045)× 10^{-3} {eV}^2 on Δ m^2_{32} for 100% (50%) neutrino beam mode running assuming sin ^2θ _{23}=0.5 and Δ m^2_{32} = 2.4× 10^{-3} eV^2. T2K will have sensitivity to the CP-violating phase δ _{CP} at 90% C.L. or better over a significant range. For example, if sin ^22θ _{23} is maximal (i.e. θ _{23}=45°) the range is -115° < δ _{CP}< -60° for normal hierarchy and +50° < δ _{CP}< +130° for inverted hierarchy. When T2K data is combined with data from the NOνA experiment, the region of oscillation parameter space where there is sensitivity to observe a non-zero δ _{CP} is substantially increased compared to if each experiment is analyzed alone.

TCF and Groucho-related genes influence pituitary growth and development.

PubMed

Brinkmeier, Michelle L; Potok, Mary Anne; Cha, Kelly B; Gridley, Thomas; Stifani, Stefano; Meeldijk, Jan; Clevers, Hans; Camper, Sally A

2003-11-01

Mutations in the prophet of PIT1 gene (PROP1) are the most common cause of multiple pituitary hormone deficiency in humans; however, the mechanism of PROP1 action is not well understood. We report that Prop1 is essential for dorsally restricted expression of a Groucho-related gene, transducin-like enhancer of split 3 (Tle3), which encodes a transcriptional corepressor. Deficiency of a related gene, amino terminal enhancer of split (Aes), causes pituitary anomalies and growth insufficiency. TLE3 and AES have been shown to interact with TCF/LEF (transcripiton factors of the T cell-specific and lymphoid enhancer specific group) family members in cell culture systems. In the absence of TCF4 (Tcf7L2), Prop1 levels are elevated, pituitary hyperplasia ensues and palate closure is abnormal. Thus, we demonstrate that Tcf4 and Aes influence pituitary growth and development, and place Tcf4 and Tle3 in the genetic hierarchy with Prop1.

Rotation-Activity Correlations in K and M Dwarfs. I. Stellar Parameters and Compilations of v sin I and P/sin I for a Large Sample of Late-K and M Dwarfs

NASA Astrophysics Data System (ADS)

Houdebine, E. R.; Mullan, D. J.; Paletou, F.; Gebran, M.

2016-05-01

The reliable determination of rotation-activity correlations (RACs) depends on precise measurements of the following stellar parameters: T eff, parallax, radius, metallicity, and rotational speed v sin I. In this paper, our goal is to focus on the determination of these parameters for a sample of K and M dwarfs. In a future paper (Paper II), we will combine our rotational data with activity data in order to construct RACs. Here, we report on a determination of effective temperatures based on the (R-I) C color from the calibrations of Mann et al. and Kenyon & Hartmann for four samples of late-K, dM2, dM3, and dM4 stars. We also determine stellar parameters (T eff, log(g), and [M/H]) using the principal component analysis-based inversion technique for a sample of 105 late-K dwarfs. We compile all effective temperatures from the literature for this sample. We determine empirical radius-[M/H] correlations in our stellar samples. This allows us to propose new effective temperatures, stellar radii, and metallicities for a large sample of 612 late-K and M dwarfs. Our mean radii agree well with those of Boyajian et al. We analyze HARPS and SOPHIE spectra of 105 late-K dwarfs, and we have detected v sin I in 92 stars. In combination with our previous v sin I measurements in M and K dwarfs, we now derive P/sin I measures for a sample of 418 K and M dwarfs. We investigate the distributions of P/sin I, and we show that they are different from one spectral subtype to another at a 99.9% confidence level. Based on observations available at Observatoire de Haute Provence and the European Southern Observatory databases and on Hipparcos parallax measurements.

ROTATION–ACTIVITY CORRELATIONS IN K AND M DWARFS. I. STELLAR PARAMETERS AND COMPILATIONS OF v sin i AND P /sin i FOR A LARGE SAMPLE OF LATE-K AND M DWARFS

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

Houdebine, E. R.; Mullan, D. J.; Paletou, F.

The reliable determination of rotation–activity correlations (RACs) depends on precise measurements of the following stellar parameters: T {sub eff}, parallax, radius, metallicity, and rotational speed v sin i . In this paper, our goal is to focus on the determination of these parameters for a sample of K and M dwarfs. In a future paper (Paper II), we will combine our rotational data with activity data in order to construct RACs. Here, we report on a determination of effective temperatures based on the ( R – I ){sub C} color from the calibrations of Mann et al. and Kenyon andmore » Hartmann for four samples of late-K, dM2, dM3, and dM4 stars. We also determine stellar parameters ( T {sub eff}, log( g ), and [M/H]) using the principal component analysis–based inversion technique for a sample of 105 late-K dwarfs. We compile all effective temperatures from the literature for this sample. We determine empirical radius–[M/H] correlations in our stellar samples. This allows us to propose new effective temperatures, stellar radii, and metallicities for a large sample of 612 late-K and M dwarfs. Our mean radii agree well with those of Boyajian et al. We analyze HARPS and SOPHIE spectra of 105 late-K dwarfs, and we have detected v sin i in 92 stars. In combination with our previous v sin i measurements in M and K dwarfs, we now derive P /sin i measures for a sample of 418 K and M dwarfs. We investigate the distributions of P /sin i , and we show that they are different from one spectral subtype to another at a 99.9% confidence level.« less

Two-bit multi-level phase change random access memory with a triple phase change material stack structure

NASA Astrophysics Data System (ADS)

Gyanathan, Ashvini; Yeo, Yee-Chia

2012-11-01

This work demonstrates a novel two-bit multi-level device structure comprising three phase change material (PCM) layers, separated by SiN thermal barrier layers. This triple PCM stack consisted of (from bottom to top), Ge2Sb2Te5 (GST), an ultrathin SiN barrier, nitrogen-doped GST, another ultrathin SiN barrier, and Ag0.5In0.5Sb3Te6. The PCM layers can selectively amorphize to form 4 different resistance levels ("00," "01," "10," and "11") using respective voltage pulses. Electrical characterization was extensively performed on these devices. Thermal analysis was also done to understand the physics behind the phase changing characteristics of the two-bit memory devices. The melting and crystallization temperatures of the PCMs play important roles in the power consumption of the multi-level devices. The electrical resistivities and thermal conductivities of the PCMs and the SiN thermal barrier are also crucial factors contributing to the phase changing behaviour of the PCMs in the two-bit multi-level PCRAM device.

CALQ8: A FORTRAN-IV Calculator Emulation Program.

DTIC Science & Technology

1980-11-18

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Common and distinct DNA-binding and regulatory activities of the BEN-solo transcription factor family.

PubMed

Dai, Qi; Ren, Aiming; Westholm, Jakub O; Duan, Hong; Patel, Dinshaw J; Lai, Eric C

2015-01-01

Recently, the BEN (BANP, E5R, and NAC1) domain was recognized as a new class of conserved DNA-binding domain. The fly genome encodes three proteins that bear only a single BEN domain ("BEN-solo" factors); namely, Insensitive (Insv), Bsg25A (Elba1), and CG9883 (Elba2). Insv homodimers preferentially bind CCAATTGG palindromes throughout the genome to mediate transcriptional repression, whereas Bsg25A and Elba2 heterotrimerize with their obligate adaptor, Elba3 (i.e., the ELBA complex), to recognize a CCAATAAG motif in the Fab-7 insulator. While these data suggest distinct DNA-binding properties of BEN-solo proteins, we performed reporter assays that indicate that both Bsg25A and Elba2 can individually recognize Insv consensus sites efficiently. We confirmed this by solving the structure of Bsg25A complexed to the Insv site, which showed that key aspects of the BEN:DNA recognition strategy are similar between these proteins. We next show that both Insv and ELBA proteins are competent to mediate transcriptional repression via Insv consensus sequences but that the ELBA complex appears to be selective for the ELBA site. Reciprocally, genome-wide analysis reveals that Insv exhibits significant cobinding to class I insulator elements, indicating that it may also contribute to insulator function. Indeed, we observed abundant Insv binding within the Hox complexes with substantial overlaps with class I insulators, many of which bear Insv consensus sites. Moreover, Insv coimmunoprecipitates with the class I insulator factor CP190. Finally, we observed that Insv harbors exclusive activity among fly BEN-solo factors with respect to regulation of Notch-mediated cell fate choices in the peripheral nervous system. This in vivo activity is recapitulated by BEND6, a mammalian BEN-solo factor that conserves the Notch corepressor function of Insv but not its capacity to bind Insv consensus sites. Altogether, our data define an array of common and distinct biochemical and functional properties of this new family of transcription factors. © 2015 Dai et al.; Published by Cold Spring Harbor Laboratory Press.

Common and distinct DNA-binding and regulatory activities of the BEN-solo transcription factor family

PubMed Central

Dai, Qi; Ren, Aiming; Westholm, Jakub O.; Duan, Hong; Patel, Dinshaw J.

2015-01-01

Recently, the BEN (BANP, E5R, and NAC1) domain was recognized as a new class of conserved DNA-binding domain. The fly genome encodes three proteins that bear only a single BEN domain (“BEN-solo” factors); namely, Insensitive (Insv), Bsg25A (Elba1), and CG9883 (Elba2). Insv homodimers preferentially bind CCAATTGG palindromes throughout the genome to mediate transcriptional repression, whereas Bsg25A and Elba2 heterotrimerize with their obligate adaptor, Elba3 (i.e., the ELBA complex), to recognize a CCAATAAG motif in the Fab-7 insulator. While these data suggest distinct DNA-binding properties of BEN-solo proteins, we performed reporter assays that indicate that both Bsg25A and Elba2 can individually recognize Insv consensus sites efficiently. We confirmed this by solving the structure of Bsg25A complexed to the Insv site, which showed that key aspects of the BEN:DNA recognition strategy are similar between these proteins. We next show that both Insv and ELBA proteins are competent to mediate transcriptional repression via Insv consensus sequences but that the ELBA complex appears to be selective for the ELBA site. Reciprocally, genome-wide analysis reveals that Insv exhibits significant cobinding to class I insulator elements, indicating that it may also contribute to insulator function. Indeed, we observed abundant Insv binding within the Hox complexes with substantial overlaps with class I insulators, many of which bear Insv consensus sites. Moreover, Insv coimmunoprecipitates with the class I insulator factor CP190. Finally, we observed that Insv harbors exclusive activity among fly BEN-solo factors with respect to regulation of Notch-mediated cell fate choices in the peripheral nervous system. This in vivo activity is recapitulated by BEND6, a mammalian BEN-solo factor that conserves the Notch corepressor function of Insv but not its capacity to bind Insv consensus sites. Altogether, our data define an array of common and distinct biochemical and functional properties of this new family of transcription factors. PMID:25561495

Retinoid X receptor suppresses a metastasis-promoting transcriptional program in myeloid cells via a ligand-insensitive mechanism

PubMed Central

Kiss, Mate; Czimmerer, Zsolt; Nagy, Gergely; Bieniasz-Krzywiec, Pawel; Ehling, Manuel; Pap, Attila; Poliska, Szilard; Boto, Pal; Tzerpos, Petros; Horvath, Attila; Kolostyak, Zsuzsanna; Daniel, Bence; Szatmari, Istvan; Mazzone, Massimiliano; Nagy, Laszlo

2017-01-01

Retinoid X receptor (RXR) regulates several key functions in myeloid cells, including inflammatory responses, phagocytosis, chemokine secretion, and proangiogenic activity. Its importance, however, in tumor-associated myeloid cells is unknown. In this study, we demonstrate that deletion of RXR in myeloid cells enhances lung metastasis formation while not affecting primary tumor growth. We show that RXR deficiency leads to transcriptomic changes in the lung myeloid compartment characterized by increased expression of prometastatic genes, including important determinants of premetastatic niche formation. Accordingly, RXR-deficient myeloid cells are more efficient in promoting cancer cell migration and invasion. Our results suggest that the repressive activity of RXR on prometastatic genes is mediated primarily through direct DNA binding of the receptor along with nuclear receptor corepressor (NCoR) and silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) corepressors and is largely unresponsive to ligand activation. In addition, we found that expression and transcriptional activity of RXRα is down-modulated in peripheral blood mononuclear cells of patients with lung cancer, particularly in advanced and metastatic disease. Overall, our results identify RXR as a regulator in the myeloid cell-assisted metastatic process and establish lipid-sensing nuclear receptors in the microenvironmental regulation of tumor progression. PMID:28923935

Molecular characterization of SMILE as a novel corepressor of nuclear receptors.

PubMed

Xie, Yuan-Bin; Nedumaran, Balachandar; Choi, Hueng-Sik

2009-07-01

SMILE (small heterodimer partner interacting leucine zipper protein) has been identified as a coregulator in ER signaling. In this study, we have examined the effects of SMILE on other NRs (nuclear receptors). SMILE inhibits GR, CAR and HNF4 alpha-mediated transactivation. Knockdown of SMILE gene expression increases the transactivation of the NRs. SMILE interacts with GR, CAR and HNF4 alpha in vitro and in vivo. SMILE and these NRs colocalize in the nucleus. SMILE binds to the ligand-binding domain or AF2 domain of the NRs. Competitions between SMILE and the coactivators GRIP1 or PGC-1 alpha have been demonstrated in vitro and in vivo. Furthermore, an intrinsic repressive activity of SMILE is observed in Gal4-fusion system, and the intrinsic repressive domain is mapped to the C-terminus of SMILE, spanning residues 203-354. Moreover, SMILE interacts with specific HDACs (histone deacetylases) and SMILE-mediated repression is released by HDAC inhibitor trichostatin A, in a NR-specific manner. Finally, ChIP (chromatin immunoprecipitation) assays reveal that SMILE associates with the NRs on the target gene promoters. Adenoviral overexpression of SMILE represses GR-, CAR- and HNF4 alpha-mediated target gene expression. Overall, these results suggest that SMILE functions as a novel corepressor of NRs via competition with coactivators and the recruitment of HDACs.

Repression of endogenous Smad7 by Ski.

PubMed

Denissova, Natalia G; Liu, Fang

2004-07-02

The Ski protein has been proposed to serve as a corepressor for Smad4 to maintain a transforming growth factor-beta (TGF-beta)-responsive promoter at a repressed, basal level. However, there have been no reports so far that it indeed acts on a natural promoter. We have previously cloned the human Smad7 promoter and shown that it contains the 8-base pair palindromic Smad-binding element (SBE) necessary for TGF-beta induction. In this report, we have characterized the negative regulation of Smad7 promoter basal activity by Ski. We show that Ski inhibits the Smad7 promoter basal activity in a SBE-dependent manner. Mutation of the SBE abrogates the inhibitory effect of Ski on the Smad7 promoter. Moreover, mutation of the SBE increases the Smad7 promoter basal activity. Using the chromatin immunoprecipitation assay, we further show that Ski together with Smad4 binds to the endogenous Smad7 promoter. Finally, we show that RNAi knockdown of Ski increases Smad7 reporter gene activity in transient transfection assays as well as elevating the endogenous level of Smad7 mRNA. Taken together, our results provide the first evidence that Ski is indeed a corepressor for Smad4, which can inhibit a natural TGF-beta responsive gene at the basal state.

Ku proteins function as corepressors to regulate farnesoid X receptor-mediated gene expression

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

Ohno, Masae; Kunimoto, Masaaki; Nishizuka, Makoto

2009-12-18

The farnesoid X receptor (FXR; NR1H4) is a member of the nuclear receptor superfamily and regulates the expression of genes involved in enterohepatic circulation and the metabolism of bile acids. Based on functional analyses, nuclear receptors are divided into regions A-F. To explore the cofactors interacting with FXR, we performed a pull-down assay using GST-fused to the N-terminal A/B region and the C region, which are required for the ligand-independent transactivation and DNA-binding, respectively, of FXR, and nuclear extracts from HeLa cells. We identified DNA-dependent protein kinase catalytic subunit (DNA-PKcs), Ku80, and Ku70 as FXR associated factors. These proteins aremore » known to have an important role in DNA repair, recombination, and transcription. DNA-PKcs mainly interacted with the A/B region of FXR, whereas the Ku proteins interacted with the C region and with the D region (hinge region). Chromatin immunoprecipitation assays revealed that the Ku proteins associated with FXR on the bile salt export pump (BSEP) promoter. Furthermore, we demonstrated that ectopic expression of the Ku proteins decreased the promoter activity and expression of BSEP gene mediated by FXR. These results suggest that the Ku proteins function as corepressors for FXR.« less

Tristetraprolin Represses Estrogen Receptor α Transactivation in Breast Cancer Cells*

PubMed Central

Barrios-García, Tonatiuh; Tecalco-Cruz, Angeles; Gómez-Romero, Vania; Reyes-Carmona, Sandra; Meneses-Morales, Iván; León-Del-Río, Alfonso

2014-01-01

Estrogen receptor α (ERα) mediates the effects of 17β-estradiol (E2) in normal mammary gland, and it is a key participant in breast cancer tumor development. ERα transactivation activity is mediated by the synergistic interaction of two domains designated AF1 and AF2. The function of AF2 is to recruit coactivator and corepressor proteins that allow ERα to oscillate between the roles of transcriptional activator and repressor. In contrast, the mechanism responsible for AF-1 transcriptional activity is not completely understood. In this study, we identified tristetraproline (TTP) as a novel ERα-associated protein. TTP expression in MCF7 cells repressed ERα transactivation and reduced MCF7 cell proliferation and the ability of the cells to form tumors in a mouse model. We show that TTP transcriptional activity is mediated through its recruitment to the promoter region of ERα target genes and its interaction with histone deacetylases, in particular with HDAC1. TTP expression attenuates the coactivating activity of SRC-1, suggesting that exchange between TTP and other coactivators may play an important role in fine-tuning ERα transactivation. These results indicate that TTP acts as a bona fide ERα corepressor and suggest that this protein may be a contributing factor in the development of E2-dependent tumors in breast cancer. PMID:24737323

Regulation of Small Ubiquitin-Like Modifier-1, Nuclear Receptor Coreceptor, Histone Deacetylase 3, and Peroxisome Proliferator-Activated Receptor-γ in Human Adipose Tissue

PubMed Central

Bodles-Brakhop, Angela M.; Yao-Borengasser, Aiwei; Zhu, Beibei; Starnes, Catherine P.; McGehee, Robert E.; Peterson, Charlotte A.; Kern, Philip A.

2012-01-01

Abstract Background This study investigated the regulation of peroxisome proliferator-activated receptor-γ (PPARγ), the histone deacetylase 3 (HDAC3)–nuclear receptor coreceptor (NCoR) complex (a corepressor of transcription used by PPARγ), and small ubiquitin-like modifier-1 (SUMO-1) (a posttranslational modifier of PPARγ) in human adipose tissue and both adipocyte and macrophage cell lines. The objective was to determine whether there were alterations in the human adipose tissue gene expression levels of PPARγ, HDAC3, NCoR, and SUMO-1 associated either with obesity or with treatment of impaired glucose tolerance (IGT) subjects with insulin-sensitizing medications. Methods We obtained subcutaneous adipose tissue biopsies from 86 subjects with a wide range of body mass index (BMI) and insulin sensitivity (SI). Additionally, adipose tissue biopsies were obtained from a randomized subgroup of IGT subjects before and after 10 weeks of treatment with either pioglitazone or metformin. Results The adipose mRNA levels of PPARγ, NCoR, HDAC3, and SUMO-1 correlated strongly with each other (P<0.0001); however, SUMO-1, NCoR, and HDAC3 gene expression were not significantly associated with BMI or SI. Pioglitazone increased SUMO-1 expression by 23% (P<0.002) in adipose tissue and an adipocyte cell line (P<0.05), but not in macrophages. Small interfering RNA (siRNA)-mediated knockdown of SUMO-1 decreased PPARγ, HDAC3, and NCoR in THP-1 cells and increased tumor necrosis factor-α (TNF-α) induction in response to lipopolysaccharide (LPS). Conclusions These results suggest that the coordinate regulation of SUMO-1, PPARγ1/2, HDAC3, and NCoR may be more tightly controlled in macrophages than in adipocytes in human adipose and that these modulators of PPARγ activity may be particularly important in the negative regulation of macrophage-mediated adipose inflammation by pioglitazone. PMID:22651256

Computer Simulation of Artillery Safing and Arming Mechanism in Aeroballistic Environment (Involute Gear Train and Straight-Sided Verge Runaway Escapement)

DTIC Science & Technology

1984-07-01

r N 2 sin y (D-345) A7 0 -r- 1 rc1 N3 1 cos y (D-346) A71 cosr - 86) + a s, sin (B -01 (D- 347 ) 118 ’ .+ + ’ • ., , , ’ , ,• i...Note that this is also now independent of entrance or exit condition. Nowo F23 (eq Dl-520) is substituted into the above expression. This leads to: 02

Untangling the Energetics and Dynamics of Boron Monoxide Radical Reactions (11BO; X2Sigma+)

DTIC Science & Technology

2015-04-15

Reaction products of isoelectronic boron monoxide (BO), cyano (CN), ethynyl (CCH), and silicon nitride (SiN) radicals with acetylene and ethylene. 3.10...Isoelectronicity in the Reactions of the Cyano (CN), Boron Monoxide (BO), Silicon Nitride (SiN), and Ethynyl (C2H) Radicals with Unsaturated Hydrocarbons...AFRL-OSR-VA-TR-2015-0111 Untangling the Energetics and Dynamics of Boron Monoxide Radical Reactions Ralf Kaiser UNIVERSITY OF HAWAII SYSTEMS HONOLULU

Seafloor Soil Sampling and Geotechnical Parameter Determination - Handbook

DTIC Science & Technology

1979-08-01

Ko + Au(I- Ko )] (7-1) 97 I where ;v = effective overburden pressure (Section 6.1.3) K 0 = coefficient of lateral earLh pressure AU = reference pore...sin i+(6/a Vcos i su [ Ko i 0 V(7-2) a 1 + (2 A -1) sin 4 Vf 99 to oiU - ~1 where ; = overburden pressure ot depth where strength, Su, is to be...Rickivdo ANtON TfIW)I* SKO 11"will NY tIAltA. JOh I~ 11 Acwtx. CO IIRAI Ir/ IA M6I~. CA IIKOWN. RODEIRT Unoily. At. IIUILOCK 1.3 Ju4 I.AYri3X lt,! WA WM TA IIIf O~mc CA 128

Comparative Analyses of Multi-Pulse Phase Controlled Rectifiers in Continuous Conduction Mode with a Two-Pole LC Output Filter for Surface Ship DC Applications

DTIC Science & Technology

2013-03-01

for this sub-mode, the minimum inductor current occurs at an angle 3 3t  (where 3 60    referenced to  ), as shown in Figure 13. 24...can be rewritten as    sin cos cosb b b ApA B      . (73) Grouping similar terms, yields  sin cosb b ApA B         , (74...where the fundamental frequency and each harmonic component are displayed graphically in a bar chart format as shown in Figure 25. The total current

Prediction of the electron redundant SinNn fullerenes

NASA Astrophysics Data System (ADS)

Yang, Huihui; Song, Yan; Zhang, Yan; Chen, Hongshan

2018-05-01

The stabilities and electronic structures of SimAln-mNn and SinNn (n = 16, 20, m = 12 and n = 24, m = 16) fullerene-like cages have been investigated using density functional method B3LYP and the second-order perturbation theory MP2. The results show that the SimAln-mNn and SinNn fullerenes are more stable than the AlN counterparts. Comparing with the corresponding AlnNn cages, one silicon atom in each Si2N2 square protrudes and the excess electrons reside as lone pair electrons at the outside of the protrudent Si atoms. Analyses on the electronic structures suggest that the Sisbnd N bonds are covalent bonding with strong polarity. The ELF (electron localization function) shows large electron pair probability between Si and N atoms. The orbital interactions between Si and N are stronger than that between Al and N atoms; the overlap integral is 0.40 per Sisbnd N bond in SinNn and 0.34 per Alsbnd N bond in AlnNn. The AIM (atoms in molecule) charges on the Al atoms in AlnNn and SimAln-mNn are 2.37 and 2.40. The charges on the in-plane and protrudent Si atoms are about 2.88 and 1.50 respectively. Considering the large local dipole moments around the protrudent Si atoms, the electrostatic interactions are also favorable to the SiN cages.

New Precision Orbits of Bright Double-Lined Spectroscopic Binaries. III. HD 82191, ω Draconis, and 108 Herculis

NASA Astrophysics Data System (ADS)

Fekel, Francis C.; Tomkin, Jocelyn; Williamson, Michael H.

2009-04-01

We have determined improved spectroscopic orbits for three double-lined binaries, HD 82191 (Am), ω Dra (F5 V), and 108 Her (Am), using radial velocities from the 2.1 m telescope at McDonald Observatory, the coudé feed telescope at Kitt Peak National Observatory, and 2 m telescope at Fairborn Observatory. The orbital periods range from 5.28 to 9.01 days, and all three systems have circular orbits. The new orbital dimensions (a 1 sin i and a 2 sin i) and minimum masses (m 1 sin3 i and m 2 sin3 i) have accuracies of 0.2% or better. Our improved results confirm the large minimum masses of HD 82191 and also agree with the values previously found for ω Dra. However, for the components of 108 Her our minimum masses are about 20% larger than the previous best values. We conclude that both components of HD 82191 as well as the primary of 108 Her are Am stars. However, the A9 secondary of 108 Her has normal abundances. We estimate spectral types of F4 dwarf and G0 dwarf for the components of ω Dra. The primaries of the three binaries are synchronously rotating as is the secondary of 108 Her. The secondaries of HD 82191 and ω Dra are possibly synchronously rotating.

Development and evaluation of the British English coordinate response measure speech-in-noise test as an occupational hearing assessment tool.

PubMed

Semeraro, Hannah D; Rowan, Daniel; van Besouw, Rachel M; Allsopp, Adrian A

2017-10-01

The studies described in this article outline the design and development of a British English version of the coordinate response measure (CRM) speech-in-noise (SiN) test. Our interest in the CRM is as a SiN test with high face validity for occupational auditory fitness for duty (AFFD) assessment. Study 1 used the method of constant stimuli to measure and adjust the psychometric functions of each target word, producing a speech corpus with equal intelligibility. After ensuring all the target words had similar intelligibility, for Studies 2 and 3, the CRM was presented in an adaptive procedure in stationary speech-spectrum noise to measure speech reception thresholds and evaluate the test-retest reliability of the CRM SiN test. Studies 1 (n = 20) and 2 (n = 30) were completed by normal-hearing civilians. Study 3 (n = 22) was completed by hearing impaired military personnel. The results display good test-retest reliability (95% confidence interval (CI) < 2.1 dB) and concurrent validity when compared to the triple-digit test (r ≤ 0.65), and the CRM is sensitive to hearing impairment. The British English CRM using stationary speech-spectrum noise is a "ready to use" SiN test, suitable for investigation as an AFFD assessment tool for military personnel.

Observation and modelling of main-sequence star chromospheres - XIV. Rotation of dM1 stars

NASA Astrophysics Data System (ADS)

Houdebine, E. R.

2010-09-01

We have measured v sin i for a selected sample of dM1-type stars. We give 114 measurements of v sin i for 88 different stars, and six upper detection limits. These are the first measurements of v sin i for most of the stars studied here. This represents the largest sample of v sin i measurements for M dwarfs at a given spectral type. For these measurements, we used four different spectrographs: HARPS (ESO), SOPHIE (OHP), ÉLODIE (OHP) and UVES (ESO). Two of these spectrographs (HARPS and SOPHIE) are particularly stable in wavelength since they were designed for exoplanet searches. We measured v sin i down to an accuracy of 0.3kms-1 for the highest resolution spectrographs and a detection limit of about 1kms-1. We show that this unprecedented accuracy for M dwarfs in our data set is possible because all the targets have the same spectral type. This is an advantage and it facilitates the determination of the narrowest line profiles for v sin i ~ 0. Although it is possible to derive the zero-point profiles using several spectral types at a time. These values were combined with other measurements taken from the literature. The total sample represents detected rotation for 100 stars (10 dM1e and 90 dM1 stars). We confirm our finding of Paper VII that the distribution of the projected rotation period is bimodal for dM1 stars with a much larger sample, i.e. there are two groups of stars: the fast rotators with P/sin i ~ 4.5d and the slow rotators with P/sin i ~ 14.4d. There is a gap between these two groups. We find that the distribution of stars as a function of P/sin i has two very abrupt cuts, below 10d and above 18d. There are very few stars observed out of this range 10-18d. We also observe that the distribution increases slightly from 18 to 10d. We find that the M1 subdwarfs (very low metallicity dwarfs) rotate with an average period of P/sin i ~ 7.2d, which is about twice faster as the main group of normal M1 dwarfs. We also find a correlation for P/sin i to decrease with stellar radius among dM1e stars. Such a trend is also observed in dM1 stars. We also derive metallicity and radius for all our target stars using the same method as in Paper VII. We notably found that 11 of our target stars are subdwarfs with metallicities below -0.5dex. Based on observations available at Observatoire de Haute Provence and the European Southern Observatory data bases and on Hipparcos parallax measurements. E-mail: eric_houdebine@yahoo.fr

Sinomenine inhibits lipopolysaccharide-induced inflammatory injury by regulation of miR-101/MKP-1/JNK pathway in keratinocyte cells.

PubMed

Liu, Shumei; Man, Yigang; Zhao, Li

2018-05-01

Recent studies have demonstrated that Sinomenine (SIN) exerted anti-inflammatory effect in various immune-related diseases. However, the effect of SIN on glucocorticoids dermatitis has not been investigated. In our study, we aimed to explore the effect of SIN on lipopolysaccharide (LPS)-induced inflammatory injury in HaCaT cells. We constructed an inflammatory injury model of LPS-induced HaCaT cells, then SIN was added to LPS-treated cells, cell viability, apoptosis, apoptosis-associated factors and inflammatory cytokines were detected by CCK-8, flow cytometry, western blot, qRT-PCR and ELISA. Subsequently, miR-101 mimic and mimic control were transfected into HaCaT cells to investigate the effect of SIN and miR-101 on LPS-induced cells injury. Furthermore, MKP-1 and JNK signal pathways were measured by qRT-PCR and western blot. Finally, the animal experiment was performed to further clarify the effect of SIN on inflammatoty injury. LPS suppressed cell viability, promoted apoptosis and increased IL-6, IL-8 and TNF-α expressions and secretions in HaCaT cells. SIN significantly alleviated LPS-induced HaCaT cells injury. Additionally, SIN down-regulated miR-101 expression, and the protective effect of SIN on LPS-induced inflammatory injury was abolished by miR-101 overexpression. Besides, SIN promoted MKP-1 expression by down-regulation of miR-101, and SIN inhibited JNK signal pathway by up-regulation of MKP-1 expression in LPS-treated HaCaT cells. Animal experiments revealed that SIN exhibited anti-inflammatory effects in vivo. The data indicated that SIN attenuated LPS-induced inflammatory injury by regulation of miR-101, MKP-1 and JNK pathway. These findings might provide a novel method for treatment of glucocorticoids dermatitis. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Hedgehog restricts its expression domain in the Drosophila wing

PubMed Central

Bejarano, Fernando; Pérez, Lidia; Apidianakis, Yiorgos; Delidakis, Christos; Milán, Marco

2007-01-01

The stable subdivision of Drosophila limbs into anterior and posterior compartments is a consequence of asymmetrical signalling by Hedgehog (Hh), from the posterior to anterior cells. The activity of the homeodomain protein Engrailed in posterior cells helps to generate this asymmetry by inducing the expression of Hh in the posterior compartment and, at the same time, repressing the expression of the essential downstream component Cubitus interruptus (Ci). Therefore, only anterior cells that receive the Hh signal across the compartment boundary will respond by stabilizing Ci. Here, we describe a new molecular mechanism that helps to maintain the Hh-expressing and Hh-responding cells in different non-overlapping cell populations. Master of thickveins (mtv)—a target of Hh activity encoding a nuclear zinc-finger protein—is required to repress hh expression in anterior cells. Mtv exerts this action in a protein complex with Groucho (Gro)—the founding member of a superfamily of transcriptional corepressors that are conserved throughout eukaryotes. Therefore, Hh restricts its own expression domain in the Drosophila wing through the activity of Mtv and Gro. PMID:17571073

Histone deacetylase inhibition reduces hypothyroidism-induced neurodevelopmental defects in rats.

PubMed

Kumar, Praveen; Mohan, Vishwa; Sinha, Rohit Anthony; Chagtoo, Megha; Godbole, Madan M

2015-11-01

Thyroid hormone (TH) through its receptor (TRα/β) influences spatio-temporal regulation of its target gene repertoire during brain development. Though hypothyroidism in WT rodent models of perinatal hypothyroidism severely impairs neurodevelopment, its effect on TRα/β knockout mice is less severe. An explanation to this paradox is attributed to a possible repressive action of unliganded TRs during development. Since unliganded TRs suppress gene expression through the recruitment of histone deacetylase (HDACs) via co-repressor complexes, we tested whether pharmacological inhibition of HDACs may prevent the effects of hypothyroidism on brain development. Using valproate, an HDAC inhibitor, we show that HDAC inhibition significantly blocks the deleterious effects of hypothyroidism on rat cerebellum, evident by recovery of TH target genes like Bdnf, Pcp2 and Mbp as well as improved dendritic structure of cerebellar Purkinje neurons. Together with this, HDAC inhibition also rescues hypothyroidism-induced motor and cognitive defects. This study therefore provides an insight into the role of HDACs in TH insufficiency during neurodevelopment and their inhibition as a possible therapeutics for treatment. © 2015 Society for Endocrinology.

NFκB1 is a suppressor of neutrophil-driven hepatocellular carcinoma

NASA Astrophysics Data System (ADS)

Wilson, C. L.; Jurk, D.; Fullard, N.; Banks, P.; Page, A.; Luli, S.; Elsharkawy, A. M.; Gieling, R. G.; Chakraborty, J. Bagchi; Fox, C.; Richardson, C.; Callaghan, K.; Blair, G. E.; Fox, N.; Lagnado, A.; Passos, J. F.; Moore, A. J.; Smith, G. R.; Tiniakos, D. G.; Mann, J.; Oakley, F.; Mann, D. A.

2015-04-01

Hepatocellular carcinoma (HCC) develops on the background of chronic hepatitis. Leukocytes found within the HCC microenvironment are implicated as regulators of tumour growth. We show that diethylnitrosamine (DEN)-induced murine HCC is attenuated by antibody-mediated depletion of hepatic neutrophils, the latter stimulating hepatocellular ROS and telomere DNA damage. We additionally report a previously unappreciated tumour suppressor function for hepatocellular nfkb1 operating via p50:p50 dimers and the co-repressor HDAC1. These anti-inflammatory proteins combine to transcriptionally repress hepatic expression of a S100A8/9, CXCL1 and CXCL2 neutrophil chemokine network. Loss of nfkb1 promotes ageing-associated chronic liver disease (CLD), characterized by steatosis, neutrophillia, fibrosis, hepatocyte telomere damage and HCC. Nfkb1S340A/S340Amice carrying a mutation designed to selectively disrupt p50:p50:HDAC1 complexes are more susceptible to HCC; by contrast, mice lacking S100A9 express reduced neutrophil chemokines and are protected from HCC. Inhibiting neutrophil accumulation in CLD or targeting their tumour-promoting activities may offer therapeutic opportunities in HCC.

Sox2 acts in a dose-dependent fashion to regulate proliferation of cortical progenitors.

PubMed

Hagey, Daniel W; Muhr, Jonas

2014-12-11

Organ formation and maintenance depends on slowly self-renewing stem cells that supply an intermediate population of rapidly dividing progenitors, but how this proliferative hierarchy is regulated is unknown. By performing genome-wide single-cell and functional analyses in the cortex, we demonstrate that reduced Sox2 expression is a key regulatory signature of the transition between stem cells and rapidly dividing progenitors. In stem cells, Sox2 is expressed at high levels, which enables its repression of proproliferative genes, of which Cyclin D1 is the most potent target. Sox2 confers this function through binding to low-affinity motifs, which facilitate the recruitment of Gro/Tle corepressors in synergy with Tcf/Lef proteins. Upon differentiation, proneural factors reduce Sox2 expression, which derepresses Cyclin D1 and promotes proliferation. Our results show how concentration-dependent Sox2 occupancy of DNA motifs of varying affinities translates into recruitment of repressive complexes, which regulate the proliferative dynamics of neural stem and progenitor cells. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Development and Validation of the Single Item Narcissism Scale (SINS)

PubMed Central

Konrath, Sara; Meier, Brian P.; Bushman, Brad J.

2014-01-01

Main Objectives The narcissistic personality is characterized by grandiosity, entitlement, and low empathy. This paper describes the development and validation of the Single Item Narcissism Scale (SINS). Although the use of longer instruments is superior in most circumstances, we recommend the SINS in some circumstances (e.g. under serious time constraints, online studies). Methods In 11 independent studies (total N = 2,250), we demonstrate the SINS' psychometric properties. Results The SINS is significantly correlated with longer narcissism scales, but uncorrelated with self-esteem. It also has high test-retest reliability. We validate the SINS in a variety of samples (e.g., undergraduates, nationally representative adults), intrapersonal correlates (e.g., positive affect, depression), and interpersonal correlates (e.g., aggression, relationship quality, prosocial behavior). The SINS taps into the more fragile and less desirable components of narcissism. Significance The SINS can be a useful tool for researchers, especially when it is important to measure narcissism with constraints preventing the use of longer measures. PMID:25093508

Fermion Universality Manifesting Itself in the Dirac Component of Neutrino Mass Matrix

NASA Astrophysics Data System (ADS)

Krolikowski, Wojciech

2002-02-01

An effective texture is presented for six Majorana conventional neutrinos (three active and three sterile), based on a 6× 6 neutrino mixing matrix whose 3× 3 active--active component arises from the popular bimaximal mixing matrix of active neutrinos ν e, ν μ , ν τ by three small rotations in the 14, 25, 36 planes of ν 1 , ν 2 , ν 3 and ν 4 , ν5, ν 6 neutrino mass states. The Dirac component (i.e. , 3 × 3 active-sterile component) of the resulting 6 × 6 neutrino mass matrix is conjectured to get a structure similar to the charged-lepton and quark 3 × 3 mass matrices, after the bimaximal mixing, specific for neutrinos, is transformed out unitarily from the neutrino mass matrix. The charged-lepton and quark mass matrices are taken in a universal form constructed previously by the author with a conside- rable phenomenological success. Then, for the option of m21 ≃ m22 ≃ m23 ≫ m24 ≃ m25 ≃ m26 ≃ 0, the proposed texture predicts oscillations of solar ν e's with Δ m2sol ≡ Δ m221 ˜ (1.1 to 1.2) × 10-5 eV2, not inconsistent with the LMA solar solution, if the SuperKamiokande value Δ m2atm ≡ Δ m232 ˜ (3 to 3.5) × 10-3eV2 for oscillations of atmospheric ν μ 's is taken as an input. Here, sin2 2θ sol ˜ 1 and sin2 2 θ atm ˜ 1. The texture predicts also an LSND effect with sin2 2θ LSND (1.4 to 1.9)× 10-11 (eV/m1)4 and Δ m2LSND ≡ Δ m225 ˜ m21 + (1.1 to 1.2) 10-5 eV}2. Unfortunately, the Chooz experiment imposes on the LSND effect (in our texture) a very small upper bound sin2 2θ LSND ≲ 1.3 × 10-3, which corresponds to the lower limit m1 ≳ (1.0 to 1.1)× 10-2 eV.

The Association Between Cognitive Performance and Speech-in-Noise Perception for Adult Listeners: A Systematic Literature Review and Meta-Analysis

PubMed Central

Allen, Harriet A.; Henshaw, Helen; Heinrich, Antje

2017-01-01

Published studies assessing the association between cognitive performance and speech-in-noise (SiN) perception examine different aspects of each, test different listeners, and often report quite variable associations. By examining the published evidence base using a systematic approach, we aim to identify robust patterns across studies and highlight any remaining gaps in knowledge. We limit our assessment to adult unaided listeners with audiometric profiles ranging from normal hearing to moderate hearing loss. A total of 253 articles were independently assessed by two researchers, with 25 meeting the criteria for inclusion. Included articles assessed cognitive measures of attention, memory, executive function, IQ, and processing speed. SiN measures varied by target (phonemes or syllables, words, and sentences) and masker type (unmodulated noise, modulated noise, >2-talker babble, and ≤2-talker babble. The overall association between cognitive performance and SiN perception was r = .31. For component cognitive domains, the association with (pooled) SiN perception was as follows: processing speed (r = .39), inhibitory control (r = .34), working memory (r = .28), episodic memory (r = .26), and crystallized IQ (r = .18). Similar associations were shown for the different speech target and masker types. This review suggests a general association of r≈.3 between cognitive performance and speech perception, although some variability in association appeared to exist depending on cognitive domain and SiN target or masker assessed. Where assessed, degree of unaided hearing loss did not play a major moderating role. We identify a number of cognitive performance and SiN perception combinations that have not been tested and whose future investigation would enable further fine-grained analyses of these relationships. PMID:29237334

The Association Between Cognitive Performance and Speech-in-Noise Perception for Adult Listeners: A Systematic Literature Review and Meta-Analysis.

PubMed

Dryden, Adam; Allen, Harriet A; Henshaw, Helen; Heinrich, Antje

2017-01-01

Published studies assessing the association between cognitive performance and speech-in-noise (SiN) perception examine different aspects of each, test different listeners, and often report quite variable associations. By examining the published evidence base using a systematic approach, we aim to identify robust patterns across studies and highlight any remaining gaps in knowledge. We limit our assessment to adult unaided listeners with audiometric profiles ranging from normal hearing to moderate hearing loss. A total of 253 articles were independently assessed by two researchers, with 25 meeting the criteria for inclusion. Included articles assessed cognitive measures of attention, memory, executive function, IQ, and processing speed. SiN measures varied by target (phonemes or syllables, words, and sentences) and masker type (unmodulated noise, modulated noise, >2-talker babble, and ≤2-talker babble. The overall association between cognitive performance and SiN perception was r = .31. For component cognitive domains, the association with (pooled) SiN perception was as follows: processing speed ( r = .39), inhibitory control ( r = .34), working memory ( r = .28), episodic memory ( r = .26), and crystallized IQ ( r = .18). Similar associations were shown for the different speech target and masker types. This review suggests a general association of r≈.3 between cognitive performance and speech perception, although some variability in association appeared to exist depending on cognitive domain and SiN target or masker assessed. Where assessed, degree of unaided hearing loss did not play a major moderating role. We identify a number of cognitive performance and SiN perception combinations that have not been tested and whose future investigation would enable further fine-grained analyses of these relationships.

IN GRAMMAR'S FALL, WE SINNED ALL.

ERIC Educational Resources Information Center

TIBBETTS, A.M.

THROUGH THEIR LOSS OF FAITH IN TRADITIONAL GRAMMAR, MEN HAVE "SINNED" AND CONTRIBUTED SLIGHTLY BUT IMPORTANTLY TO THE CREATION OF AN AMORAL AND RELATIVISTIC SOCIETY. PROMPTED BY THE SIN OF INTELLECTUAL PRIDE, SOME LINGUISTS SEEM TO ASSUME THAT GRAMMATICAL PROBLEMS CAN BE SOLVED BY RATIOCINATION ALONE. IGNORANCE OF THE PAST--ANOTHER SIN--AND…

Differential in Vitro Biological Action, Coregulator Interactions, and Molecular Dynamic Analysis of Bisphenol A (BPA), BPAF, and BPS Ligand-ERα Complexes.

PubMed

Li, Yin; Perera, Lalith; Coons, Laurel A; Burns, Katherine A; Tyler Ramsey, J; Pelch, Katherine E; Houtman, René; van Beuningen, Rinie; Teng, Christina T; Korach, Kenneth S

2018-01-31

Bisphenol A (BPA) is an endocrine-disrupting chemical (EDC) that might be harmful to human health. Recently, there has been widespread usage of bisphenol chemicals (BPs), such as bisphenol AF (BPAF) and bisphenol S (BPS), as replacements for BPA. However, the potential biological actions, toxicity, and the molecular mechanism of these compounds are still poorly understood. Our objective was to examine the estrogenic effects of BPA, BPAF, and BPS and the molecular mechanisms of action in the estrogen receptor alpha (ERα) complex. In vitro cell models were used to compare the estrogenic effects of BPA, BPAF, and BPS to estrogen. Microarray Assay for Real-Time Coregulator-Nuclear receptor Interaction (MARCoNI) analysis was used to identify coregulators of BPA, BPAF, and BPS, and molecular dynamic (MD) simulations were used to determine the compounds binding in the ERα complex. We demonstrated that BPA and BPAF have agonistic activity for both ERα and ERβ, but BPS has ERα-selective specificity. We concluded that coregulators were differentially recruited in the presence of BPA, BPAF, or BPS. Interestingly, BPS recruited more corepressors when compared to BPA and BPAF. From a series of MD analysis, we concluded that BPA, BPAF, and BPS can bind to the ER-ligand-binding domain with differing energetics and conformations. In addition, the binding surface of coregulator interactions on ERα was characterized for the BPA, BPAF, and BPS complexes. These findings further our understanding of the molecular mechanisms of EDCs, such as BPs, in ER-mediated transcriptional activation, biological activity, and their effects on physiological functions in human health. https://doi.org/10.1289/EHP2505.

Ionospheric Irregularities: Source, Structure, Plasma Processes and Effects on Sensor Systems

DTIC Science & Technology

1989-10-31

modified by using y - ye + w sin 0 sin 0 (20h) some of M orf et al.’s ideas. Fougere [1981] added a set of subroutines which find for each channel, the...correlation analysis has employed the modified Fedor algo- rithm (Fedor. 1967. CFB, this issue]. 3. ALGORITHM FOR THE SPECTRAL ANALYSIS The elements of the...knowledge, this paper presents with the every 240 m along the orbital track [Ifeelis et al., 1981]. Thus above data set the most detailed analysis of

Two bodies with high eccentricity around the cataclysmic variable QS Vir

NASA Astrophysics Data System (ADS)

Almeida, Leonardo A.; Jablonski, Francisco

2011-11-01

QS Vir is an eclipsing cataclysmic variable with 3.618 hrs orbital period. This system has the interesting characteristics that it does not show mass transfer between the components through the L1 Lagrangian point and shows a complex orbital period variation history. Qian et al. (2010) associated the orbital period variations to the presence of a giant planet in the system plus angular momentum loss via magnetic braking. Parsons et al. (2010) obtained new eclipse timings and observed that the orbital period variations associated to a hypothetical giant planet disagree with their measurements and concluded that the decrease in orbital period is part of a cyclic variation with period ~16 yrs. In this work, we present 28 new eclipse timings of QS Vir and suggest that the orbital period variations can be explained by a model with two circumbinary bodies. The best fitting gives the lower limit to the masses M1 sin(i) ~ 0.0086 M⊙ and M2 sin(i) ~ 0.054 M⊙ orbital periods P1 ~ 14.4 yrs and P2 ~ 16.99 yrs, and eccentricities e1 ~ 0.62 and e2~0.92 for the two external bodies. Under the assumption of coplanarity among the two external bodies and the inner binary, we obtain a giant planet with ~0.009 M⊙ and a brown dwarf with ~ 0.056 M⊙ around the eclipsing binary QS Vir.

The framed Standard Model (II) — A first test against experiment

NASA Astrophysics Data System (ADS)

Chan, Hong-Mo; Tsou, Sheung Tsun

2015-10-01

Apart from the qualitative features described in Paper I (Ref. 1), the renormalization group equation derived for the rotation of the fermion mass matrices are amenable to quantitative study. The equation depends on a coupling and a fudge factor and, on integration, on 3 integration constants. Its application to data analysis, however, requires the input from experiment of the heaviest generation masses mt, mb, mτ, mν3 all of which are known, except for mν3. Together then with the theta-angle in the QCD action, there are in all 7 real unknown parameters. Determining these 7 parameters by fitting to the experimental values of the masses mc, mμ, me, the CKM elements |Vus|, |Vub|, and the neutrino oscillation angle sin2θ 13, one can then calculate and compare with experiment the following 12 other quantities ms, mu/md, |Vud|, |Vcs|, |Vtb|, |Vcd|, |Vcb|, |Vts|, |Vtd|, J, sin22θ 12, sin22θ 23, and the results all agree reasonably well with data, often to within the stringent experimental error now achieved. Counting the predictions not yet measured by experiment, this means that 17 independent parameters of the standard model are now replaced by 7 in the FSM.

Investigation on navigation patterns of inertial/celestial integrated systems

NASA Astrophysics Data System (ADS)

Luo, Dacheng; Liu, Yan; Liu, Zhiguo; Jiao, Wei; Wang, Qiuyan

2014-11-01

It is known that Strapdown Inertial Navigation System (SINS), Global Navigation Satellite System (GNSS) and Celestial Navigation System (CNS) can complement each other's advantages. The SINS/CNS integrated system, which has the characteristics of strong autonomy, high accuracy and good anti-jamming, is widely used in military and civilian applications. Similar to SINS/GNSS integrated system, the SINS/CNS integrated system can also be divided into three kinds according to the difference of integrating depth, i.e., loosely coupled pattern, tightly coupled pattern and deeply coupled pattern. In this paper, the principle and characteristics of each pattern of SINS/CNS system are analyzed. Based on the comparison of these patterns, a novel deeply coupled SINS/CNS integrated navigation scheme is proposed. The innovation of this scheme is that a new star pattern matching method aided by SINS information is put forward. Thus the complementary features of these two subsystems are reflected.

The role of androgen receptor activity mediated by the CAG repeat polymorphism in the pathogenesis of PCOS.

PubMed

Baculescu, N

2013-03-15

Polycystic ovary syndrome (PCOS), one of the most common and complex endocrine disorders affecting up to 15 % of reproductive age women, is considered a predominantly hyperandrogenic syndrome according to the Androgen Excess Society. It is generally accepted that androgens determine the characteristic features of PCOS; in this context, a hyperactive androgen receptor (AR) at the levels of the GnRH pulse generator in the hypothalamus and at the granulosa cells in the ovary, skeletal muscle or adipocytes senses initially normal testosterone and dihydrotestosterone as biochemical hyperandrogenism and might be a crucial connection between the vicious circles of the PCOS pathogenesis. Polymorphism of the AR gene has been associated with different androgen pattern diseases. Several studies have demonstrated an association between AR with increased activity encoded by shorter CAG repeat polymorphism in the exon 1 of the AR gene and PCOS, although there are conflicting results in this field. The phenomenon is more complex because the AR activity is determined by the epigenetic effect of X chromosome inactivation (XCI). Moreover, we must evaluate the AR as a dynamic heterocomplex, with a large number of coactivators and corepressors that are essential to its function, thus mediating tissue-specific effects. In theory, any of these factors could modify the activity of AR, which likely explains the inconsistent results obtained when this activity was quantified by only the CAG polymorphism in PCOS.

BASIC PENTACYSTEINE Proteins Mediate MADS Domain Complex Binding to the DNA for Tissue-Specific Expression of Target Genes in Arabidopsis[W

PubMed Central

Simonini, Sara; Roig-Villanova, Irma; Gregis, Veronica; Colombo, Bilitis; Colombo, Lucia; Kater, Martin M.

2012-01-01

BASIC PENTACYSTEINE (BPC) transcription factors have been identified in a large variety of plant species. In Arabidopsis thaliana there are seven BPC genes, which, except for BPC5, are expressed ubiquitously. BPC genes are functionally redundant in a wide range of developmental processes. Recently, we reported that BPC1 binds to guanine and adenine (GA)–rich consensus sequences in the SEEDSTICK (STK) promoter in vitro and induces conformational changes. Here we show by chromatin immunoprecipitation experiments that in vivo BPCs also bind to the consensus boxes, and when these were mutated, expression from the STK promoter was derepressed, resulting in ectopic expression in the inflorescence. We also reveal that SHORT VEGETATIVE PHASE (SVP) is a direct regulator of STK. SVP is a floral meristem identity gene belonging to the MADS box gene family. The SVP-APETALA1 (AP1) dimer recruits the SEUSS (SEU)-LEUNIG (LUG) transcriptional cosuppressor to repress floral homeotic gene expression in the floral meristem. Interestingly, we found that GA consensus sequences in the STK promoter to which BPCs bind are essential for recruitment of the corepressor complex to this promoter. Our data suggest that we have identified a new regulatory mechanism controlling plant gene expression that is probably generally used, when considering BPCs’ wide expression profile and the frequent presence of consensus binding sites in plant promoters. PMID:23054472

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

Yin, Qingqiao; Xia, Yuanyu, E-mail: xiayuanyu.wh@gmail.com; Wang, Guan

As an early sign of diabetic cardiovascular disease, endothelial dysfunction may contribute to progressive diabetic nephropathy (DN). Endothelial hyperpermeability induced by hyperglycemia (HG) is a central pathogenesis for DN. Sinomenine (SIN) has strong anti-inflammatory and renal protective effects, following an unknown protective mechanism against HG-induced hyperpermeability. We herein explored the role of SIN in vitro in an HG-induced barrier dysfunction model in human renal glomerular endothelial cells (HRGECs). The cells were exposed to SIN and/or HG for 24 h, the permeability of which was significantly increased by HG. Moreover, junction protein occludin in the cell-cell junction area and its total expression inmore » HRGECs were significantly decreased by HG. However, the dysfunction of tight junction and hyperpermeability of HRGECs were significantly reversed by SIN. Furthermore, SIN prevented HG-increased reactive oxygen species (ROS) by activating nuclear factor-E2-related factor 2 (Nrf2). Interestingly, activation of RhoA/ROCK induced by HG was reversed by SIN or ROCK inhibitor. HG-induced hyperpermeability was prevented by SIN. High ROS level, tight junction dysfunction and RhoA/ROCK activation were significantly attenuated with knockdown of Nrf2. Mediated by activation of Nrf2, SIN managed to significantly prevent HG-disrupted renal endothelial barrier function by suppressing the RhoA/ROCK signaling pathway through reducing ROS. We successfully identified a novel pathway via which SIN exerted antioxidative and renal protective functions, and provided a molecular basis for potential SIN applications in treating DN vascular disorders.« less

Transcription factors, coregulators, and epigenetic marks are linearly correlated and highly redundant

PubMed Central

Ahsendorf, Tobias; Müller, Franz-Josef; Topkar, Ved; Gunawardena, Jeremy; Eils, Roland

2017-01-01

The DNA microstates that regulate transcription include sequence-specific transcription factors (TFs), coregulatory complexes, nucleosomes, histone modifications, DNA methylation, and parts of the three-dimensional architecture of genomes, which could create an enormous combinatorial complexity across the genome. However, many proteins and epigenetic marks are known to colocalize, suggesting that the information content encoded in these marks can be compressed. It has so far proved difficult to understand this compression in a systematic and quantitative manner. Here, we show that simple linear models can reliably predict the data generated by the ENCODE and Roadmap Epigenomics consortia. Further, we demonstrate that a small number of marks can predict all other marks with high average correlation across the genome, systematically revealing the substantial information compression that is present in different cell lines. We find that the linear models for activating marks are typically cell line-independent, while those for silencing marks are predominantly cell line-specific. Of particular note, a nuclear receptor corepressor, transducin beta-like 1 X-linked receptor 1 (TBLR1), was highly predictive of other marks in two hematopoietic cell lines. The methodology presented here shows how the potentially vast complexity of TFs, coregulators, and epigenetic marks at eukaryotic genes is highly redundant and that the information present can be compressed onto a much smaller subset of marks. These findings could be used to efficiently characterize cell lines and tissues based on a small number of diagnostic marks and suggest how the DNA microstates, which regulate the expression of individual genes, can be specified. PMID:29216191

Loss of RUNX1/AML1 arginine-methylation impairs in peripheral T cell homeostasis

PubMed Central

Mizutani, Shinsuke; Yoshida, Tatsushi; Zhao, Xinyang; Nimer, Stephen D.; Taniwaki, Masafumi; Okuda, Tsukasa

2016-01-01

Summary RUNX1 (previously termed AML1) is a frequent target of human leukaemia-associated gene aberrations, and it encodes the DNA-binding subunit of the Core-Binding Factor transcription factor complex. RUNX1 expression is essential for the initiation of definitive haematopoiesis, for steady-state thrombopoiesis, and for normal lymphocytes development. Recent studies revealed that protein arginine methyltransferase 1 (PRMT1), which accounts for the majority of the type I PRMT activity in cells, methylates two arginine residues in RUNX1 (R206 and R210), and these modifications inhibit corepressor-binding to RUNX1 thereby enhancing its transcriptional activity. In order to elucidate the biological significance of these methylations, we established novel knock-in mouse lines with non-methylable, double arginine-to-lysine (RTAMR-to-KTAMK) mutations in RUNX1. Homozygous Runx1KTAMK/KTAMK mice are born alive and appear normal during adulthood. However, Runx1KTAMK/KTAMK mice showed a reduction in CD3+ T lymphoid cells and a decrease in CD4+ T cells in peripheral lymphoid organs, in comparison to their wild-type littermates, leading to a reduction in the CD4+ to CD8+ T-cell ratio. These findings suggest that arginine-methylation of RUNX1 in the RTAMR-motif is dispensable for the development of definitive haematopoiesis and for steady-state platelet production, however this modification affects the role of RUNX1 in the maintenance of the peripheral CD4+ T-cell population. PMID:26010396

Nitric oxide-related species-induced protein oxidation: reversible, irreversible, and protective effects on enzyme function of papain.

PubMed

Väänänen, Antti J; Kankuri, Esko; Rauhala, Pekka

2005-04-15

Protein oxidation, irreversible modification, and inactivation may play key roles in various neurodegenerative disorders. Therefore, we studied the effects of the potentially in vivo occurring nitric oxide-related species on two different markers of protein oxidation: protein carbonyl generation on bovine serum albumine (BSA) and loss of activity of a cysteine-dependent protease, papain, in vitro by using Angeli's salt, papanonoate, SIN-1, and S-nitrosoglutathione (GSNO) as donors of nitroxyl, nitric oxide, peroxynitrite, and nitrosonium ions, respectively. Angeli's salt, SIN-1, and papanonoate (0-1000 microM) all generated a concentration-dependent increase in carbonyl formation on BSA (107, 60, and 45%, respectively). GSNO did not affect carbonyl formation. Papain was inhibited by Angeli's salt, SIN-1, papanonoate, and GSNO with IC50 values of 0.62, 2.3, 54, and 80 microM, respectively. Angeli's salt (3.16 microM)-induced papain inactivation was only partially reversible, while the effects of GSNO (316 microM) and papanonoate (316 microM) were reversible upon addition of excess DTT. The Angeli's salt-mediated DTT-irreversible inhibition of papain was prevented by GSNO or papanonoate pretreatment, hypothetically through mixed disulfide formation or S-nitrosylation of the catalytically critical thiol group of papain. These results, for the first time, compare the generation of carbonyls in proteins by Angeli's salt, papanonoate, and SIN-1. Furthermore, these results suggest that S-nitrosothiols may have a novel function in protecting critical thiols from irreversible oxidative damage.

Sinomenine alleviates high glucose-induced renal glomerular endothelial hyperpermeability by inhibiting the activation of RhoA/ROCK signaling pathway.

PubMed

Yin, Qingqiao; Xia, Yuanyu; Wang, Guan

2016-09-02

As an early sign of diabetic cardiovascular disease, endothelial dysfunction may contribute to progressive diabetic nephropathy (DN). Endothelial hyperpermeability induced by hyperglycemia (HG) is a central pathogenesis for DN. Sinomenine (SIN) has strong anti-inflammatory and renal protective effects, following an unknown protective mechanism against HG-induced hyperpermeability. We herein explored the role of SIN in vitro in an HG-induced barrier dysfunction model in human renal glomerular endothelial cells (HRGECs). The cells were exposed to SIN and/or HG for 24 h, the permeability of which was significantly increased by HG. Moreover, junction protein occludin in the cell-cell junction area and its total expression in HRGECs were significantly decreased by HG. However, the dysfunction of tight junction and hyperpermeability of HRGECs were significantly reversed by SIN. Furthermore, SIN prevented HG-increased reactive oxygen species (ROS) by activating nuclear factor-E2-related factor 2 (Nrf2). Interestingly, activation of RhoA/ROCK induced by HG was reversed by SIN or ROCK inhibitor. HG-induced hyperpermeability was prevented by SIN. High ROS level, tight junction dysfunction and RhoA/ROCK activation were significantly attenuated with knockdown of Nrf2. Mediated by activation of Nrf2, SIN managed to significantly prevent HG-disrupted renal endothelial barrier function by suppressing the RhoA/ROCK signaling pathway through reducing ROS. We successfully identified a novel pathway via which SIN exerted antioxidative and renal protective functions, and provided a molecular basis for potential SIN applications in treating DN vascular disorders. Copyright © 2016 Elsevier Inc. All rights reserved.

Pseudo-constitutivity of nitrate-responsive genes in nitrate reductase mutants

PubMed Central

Schinko, Thorsten; Gallmetzer, Andreas; Amillis, Sotiris; Strauss, Joseph

2013-01-01

In fungi, transcriptional activation of genes involved in NO3- assimilation requires the presence of an inducer (nitrate or nitrite) and low intracellular concentrations of the pathway products ammonium or glutamine. In Aspergillus nidulans, the two transcription factors NirA and AreA act synergistically to mediate nitrate/nitrite induction and nitrogen metabolite derepression, respectively. In all studied fungi and in plants, mutants lacking nitrate reductase (NR) activity express nitrate-metabolizing enzymes constitutively without the addition of inducer molecules. Based on their work in A. nidulans, Cove and Pateman proposed an “autoregulation control” model for the synthesis of nitrate metabolizing enzymes in which the functional nitrate reductase molecule would act as co-repressor in the absence and as co-inducer in the presence of nitrate. However, NR mutants could simply show “pseudo-constitutivity” due to induction by nitrate which accumulates over time in NR-deficient strains. Here we examined this possibility using strains which lack flavohemoglobins (fhbs), and are thus unable to generate nitrate internally, in combination with nitrate transporter mutations (nrtA, nrtB) and a GFP-labeled NirA protein. Using different combinations of genotypes we demonstrate that nitrate transporters are functional also in NR null mutants and show that the constitutive phenotype of NR mutants is not due to nitrate accumulation from intracellular sources but depends on the activity of nitrate transporters. However, these transporters are not required for nitrate signaling because addition of external nitrate (10 mM) leads to standard induction of nitrate assimilatory genes in the nitrate transporter double mutants. We finally show that NR does not regulate NirA localization and activity, and thus the autoregulation model, in which NR would act as a co-repressor of NirA in the absence of nitrate, is unlikely to be correct. Results from this study instead suggest that transporter-mediated NO3- accumulation in NR deficient mutants, originating from traces of nitrate in the media, is responsible for the constitutive expression of NirA-regulated genes, and the associated phenotype is thus termed “pseudo-constitutive”. PMID:23454548

Bistability and Biofilm Formation in Bacillus subtilis

PubMed Central

Chai, Yunrong; Chu, Frances; Kolter, Roberto; Losick, Richard

2008-01-01

Summary Biofilms of Bacillus subtilis consist of long chains of cells that are held together in bundles by an extracellular matrix of exopolysaccharide and the protein TasA. The exopolysaccharide is produced by enzymes encoded by the epsA-O operon and the gene encoding TasA is located in the yqxM-sipW-tasA operon. Both operons are under the control of the repressor SinR. Derepression is mediated by the antirepressor SinI, which binds to SinR with a 1:1 stoichiometry. Paradoxically, in medium promoting derepression of the matrix operons, the overall concentration of SinR in the culture greatly exceeded that of SinI. We show that under biofilm-promoting conditions sinI, which is under the control of the response regulator Spo0A, was expressed only in a small subpopulation of cells, whereas sinR was expressed in almost all cells. Activation of Spo0A is known to be subject to a bistable switch, and we infer that SinI reaches levels sufficient to trigger matrix production only in the subpopulation of cells in which Spo0A is active. Additionally, evidence suggests that sinI is expressed at intermediate, but not low or high, levels of Spo0A activity, which may explain why certain nutritional conditions are more effective in promoting biofilm formation than others. PMID:18047568

Observation of interacting polaronic gas behavior in Ta-doped TiO2 thin films via terahertz time-domain spectroscopy

NASA Astrophysics Data System (ADS)

Chia, Elbert; Cheng, Liang; Lourembam, James; Wu, S. G.; Motapothula, Mallikarjuna R.; Sarkar, Tarapada; Venkatesan, Venky

Using terahertz time-domain spectroscopy (THz-TDS), we obtained the complex optical conductivity [ σ (ω) ] of Ta-doped TiO2 thin films - a transparent conducting oxide (TCO), in the frequency range 0.3-2.7 THz, temperature range 10-300 K and various Ta dopings. Our results reveal the existence of an interacting polaronic gas in these TCOs, and suggest that their large conductivity is caused by the combined effects of large carrier density and small electron-phonon coupling constant due to Ta doping. NUSNNI-NanoCore, NRF-CRP (NRF2008NRF-CRP002-024), NUS cross-faculty Grant and FRC (ARF Grant No. R-144-000-278-112), MOE Tier 1 (RG123/14), SinBeRISE CREATE.

AUV Positioning Method Based on Tightly Coupled SINS/LBL for Underwater Acoustic Multipath Propagation.

PubMed

Zhang, Tao; Shi, Hongfei; Chen, Liping; Li, Yao; Tong, Jinwu

2016-03-11

This paper researches an AUV (Autonomous Underwater Vehicle) positioning method based on SINS (Strapdown Inertial Navigation System)/LBL (Long Base Line) tightly coupled algorithm. This algorithm mainly includes SINS-assisted searching method of optimum slant-range of underwater acoustic propagation multipath, SINS/LBL tightly coupled model and multi-sensor information fusion algorithm. Fuzzy correlation peak problem of underwater LBL acoustic propagation multipath could be solved based on SINS positional information, thus improving LBL positional accuracy. Moreover, introduction of SINS-centered LBL locating information could compensate accumulative AUV position error effectively and regularly. Compared to loosely coupled algorithm, this tightly coupled algorithm can still provide accurate location information when there are fewer than four available hydrophones (or within the signal receiving range). Therefore, effective positional calibration area of tightly coupled system based on LBL array is wider and has higher reliability and fault tolerance than loosely coupled. It is more applicable to AUV positioning based on SINS/LBL.

AUV Positioning Method Based on Tightly Coupled SINS/LBL for Underwater Acoustic Multipath Propagation

PubMed Central

Zhang, Tao; Shi, Hongfei; Chen, Liping; Li, Yao; Tong, Jinwu

2016-01-01

This paper researches an AUV (Autonomous Underwater Vehicle) positioning method based on SINS (Strapdown Inertial Navigation System)/LBL (Long Base Line) tightly coupled algorithm. This algorithm mainly includes SINS-assisted searching method of optimum slant-range of underwater acoustic propagation multipath, SINS/LBL tightly coupled model and multi-sensor information fusion algorithm. Fuzzy correlation peak problem of underwater LBL acoustic propagation multipath could be solved based on SINS positional information, thus improving LBL positional accuracy. Moreover, introduction of SINS-centered LBL locating information could compensate accumulative AUV position error effectively and regularly. Compared to loosely coupled algorithm, this tightly coupled algorithm can still provide accurate location information when there are fewer than four available hydrophones (or within the signal receiving range). Therefore, effective positional calibration area of tightly coupled system based on LBL array is wider and has higher reliability and fault tolerance than loosely coupled. It is more applicable to AUV positioning based on SINS/LBL. PMID:26978361

[In Process Citation].

PubMed

Guzmán-Mercado, Elizabeth; Vásquez-Garibay, Edgar M; Troyo-Sanroman, Rogelio; Romero-Velarde, Enrique

2016-03-25

Objetivo: identificar los hábitos alimentarios de adolescentes embarazadas en cuatro estados civiles diferentes: casada, cohabita con una pareja, soltera sin pareja y soltera con una pareja. Métodos: en estudio transversal, se incluyeron 321 adolescentes embarazadas de 13-19 años que acudieron al Hospital Civil de Guadalajara Dr. Juan I Menchaca, Guadalajara (Jalisco, México). Se encontraban sanas, en cualquier trimestre del embarazo y pertenecían a un nivel socioe-conómico bajo o medio-bajo. El estado civil se estratificó en: casadas; en unión libre; soltera con una pareja y soltera sin pareja. Se incluyeron datos socio-demográficos, económicos y de hábitos de alimentación. Se utilizaron pruebas de ANOVA, pruebas post-hoc para Chi 2 , razón de momios y modelos de regresión logística. Resultados: la frecuencia de las adolescentes casadas fue de 9,3%, 59,8% en unión libre, 15,3% eran solteras sin pareja y 15,6% solteras con pareja. La baja escolaridad (RM 2,6 [1,5-4,4]) y la ocupación en el hogar (RM 4,47 [1,99-10,0]) predominaron entre las adolescentes en unión libre; la ocupación en el hogar (RM 0,28 [0,127-0,61]) y cenar sin compañía (RM 4,12 [1,62-10,8]) fueron significativamente más frecuentes en adolescentes sin pareja. El consumo de verduras fue menor en las adolescentes casadas y en quienes cohabitaban con pareja; el consumo de frijoles y pan dulce fue menor en adolescentes embarazadas casadas. Conclusión: debido a que ciertas variables y hábitos de alimentación mostraron diferencias entre los grupos es pertinente analizar las adolescentes embarazadas de acuerdo a su estado civil.

Spectroscopic Study of the Early-Type Binary HX Vel A

NASA Astrophysics Data System (ADS)

Özkardeş, Burcu; Sürgit, Derya; Erdem, Ahmet; Budding, Edwin; Soydugan, Faruk; Demircan, Osman

2012-04-01

This paper presents high resolution spectroscopy of the HX Vel (IDS 08390-4744 AB) multiple system. New spectroscopic observations of the system were made at Mt. John University Observatory in 2007 and 2008. Radial velocities of both components of HX Vel A were measured using gaussian fitting. The spectroscopic mass ratio of the close binary was determined as 0.599+/-0.052, according to a Keplerian orbital solution. The resulting orbital elements are a1sini=0.0098+/-0.0003 AU, a2sini=0.0164+/-0.0003 AU, M1sin3i=1.19+/-0.07 M⊙ and M2sin3i=0.71+/-0.04 M⊙.

Publisher Correction: NCoR/SMRT co-repressors cooperate with c-MYC to create an epigenetic barrier to somatic cell reprogramming.

PubMed

Zhuang, Qiang; Li, Wenjuan; Benda, Christina; Huang, Zhijian; Ahmed, Tanveer; Liu, Ping; Guo, Xiangpeng; Ibañez, David P; Luo, Zhiwei; Zhang, Meng; Abdul, Mazid Md; Yang, Zhongzhou; Yang, Jiayin; Huang, Yinghua; Zhang, Hui; Huang, Dehao; Zhou, Jianguo; Zhong, Xiaofen; Zhu, Xihua; Fu, Xiuling; Fan, Wenxia; Liu, Yulin; Xu, Yan; Ward, Carl; Khan, Muhammad Jadoon; Kanwal, Shahzina; Mirza, Bushra; Tortorella, Micky D; Tse, Hung-Fat; Chen, Jiayu; Qin, Baoming; Bao, Xichen; Gao, Shaorong; Hutchins, Andrew P; Esteban, Miguel A

2018-06-15

In the version of this Article originally published, in Fig. 2c, the '+' sign and 'OSKM' were superimposed in the label '+OSKM'. In Fig. 4e, in the labels, all instances of 'Ant' should have been 'Anti-'. And, in Fig. 7a, the label '0.0' was misplaced; it should have been on the colour scale bar. These figures have now been corrected in the online versions.

A KAP1 phosphorylation switch controls MyoD function during skeletal muscle differentiation.

PubMed

Singh, Kulwant; Cassano, Marco; Planet, Evarist; Sebastian, Soji; Jang, Suk Min; Sohi, Gurjeev; Faralli, Hervé; Choi, Jinmi; Youn, Hong-Duk; Dilworth, F Jeffrey; Trono, Didier

2015-03-01

The transcriptional activator MyoD serves as a master controller of myogenesis. Often in partnership with Mef2 (myocyte enhancer factor 2), MyoD binds to the promoters of hundreds of muscle genes in proliferating myoblasts yet activates these targets only upon receiving cues that launch differentiation. What regulates this off/on switch of MyoD function has been incompletely understood, although it is known to reflect the action of chromatin modifiers. Here, we identify KAP1 (KRAB [Krüppel-like associated box]-associated protein 1)/TRIM28 (tripartite motif protein 28) as a key regulator of MyoD function. In myoblasts, KAP1 is present with MyoD and Mef2 at many muscle genes, where it acts as a scaffold to recruit not only coactivators such as p300 and LSD1 but also corepressors such as G9a and HDAC1 (histone deacetylase 1), with promoter silencing as the net outcome. Upon differentiation, MSK1-mediated phosphorylation of KAP1 releases the corepressors from the scaffold, unleashing transcriptional activation by MyoD/Mef2 and their positive cofactors. Thus, our results reveal KAP1 as a previously unappreciated interpreter of cell signaling, which modulates the ability of MyoD to drive myogenesis. © 2015 Singh et al.; Published by Cold Spring Harbor Laboratory Press.

Insulin-Inducible SMILE Inhibits Hepatic Gluconeogenesis.

PubMed

Lee, Ji-Min; Seo, Woo-Young; Han, Hye-Sook; Oh, Kyoung-Jin; Lee, Yong-Soo; Kim, Don-Kyu; Choi, Seri; Choi, Byeong Hun; Harris, Robert A; Lee, Chul-Ho; Koo, Seung-Hoi; Choi, Hueng-Sik

2016-01-01

The role of a glucagon/cAMP-dependent protein kinase-inducible coactivator PGC-1α signaling pathway is well characterized in hepatic gluconeogenesis. However, an opposing protein kinase B (PKB)/Akt-inducible corepressor signaling pathway is unknown. A previous report has demonstrated that small heterodimer partner-interacting leucine zipper protein (SMILE) regulates the nuclear receptors and transcriptional factors that control hepatic gluconeogenesis. Here, we show that hepatic SMILE expression was induced by feeding in normal mice but not in db/db and high-fat diet (HFD)-fed mice. Interestingly, SMILE expression was induced by insulin in mouse primary hepatocyte and liver. Hepatic SMILE expression was not altered by refeeding in liver-specific insulin receptor knockout (LIRKO) or PKB β-deficient (PKBβ(-/-)) mice. At the molecular level, SMILE inhibited hepatocyte nuclear factor 4-mediated transcriptional activity via direct competition with PGC-1α. Moreover, ablation of SMILE augmented gluconeogenesis and increased blood glucose levels in mice. Conversely, overexpression of SMILE reduced hepatic gluconeogenic gene expression and ameliorated hyperglycemia and glucose intolerance in db/db and HFD-fed mice. Therefore, SMILE is an insulin-inducible corepressor that suppresses hepatic gluconeogenesis. Small molecules that enhance SMILE expression would have potential for treating hyperglycemia in diabetes. © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Measurement of the Weak Mixing Angle in Moller Scattering

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

Klejda, B.

2005-01-28

The weak mixing parameter, sin{sup 2} {theta}{sub w}, is one of the fundamental parameters of the Standard Model. Its tree-level value has been measured with high precision at energies near the Z{sup 0} pole; however, due to radiative corrections at the one-loop level, the value of sin{sup 2} {theta}{sub w} is expected to change with the interaction energy. As a result, a measurement of sin{sup 2} {theta}{sub w} at low energy (Q{sup 2} << m{sub Z}, where Q{sup 2} is the momentum transfer and m{sub Z} is the Z boson mass), provides a test of the Standard Model at themore » one-loop level, and a probe for new physics beyond the Standard Model. One way of obtaining sin{sup 2} {theta}{sub w} at low energy is from measuring the left-right, parity-violating asymmetry in electron-electron (Moeller) scattering: A{sub PV} = {sigma}{sub R}-{sigma}{sub L}/{sigma}{sub R}+{sigma}{sub L}, where {sigma}{sub R} and {sigma}{sub L} are the cross sections for right- and left-handed incident electrons, respectively. The parity violating asymmetry is proportional to the pseudo-scalar weak neutral current coupling in Moeller scattering, g{sub ee}. At tree level g{sub ee} = (1/4 -sin{sup 2} {theta}{sub w}). A precision measurement of the parity-violating asymmetry in Moeller scattering was performed by Experiment E158 at the Stanford Linear Accelerator Center (SLAC). During the experiment, {approx}50 GeV longitudinally polarized electrons scattered off unpolarized atomic electrons in a liquid hydrogen target, corresponding to an average momentum transfer Q{sup 2} {approx} 0.03 (GeV/c){sup 2}. The tree-level prediction for A{sub PV} at such energy is {approx}300 ppb. However one-loop radiative corrections reduce its value by {approx}40%. This document reports the E158 results from the 2002 data collection period. The parity-violating asymmetry was found to be A{sub PV} = -160 {+-} 21 (stat.) {+-} 17 (syst.) ppb, which represents the first observation of a parity-violating asymmetry in Moeller scattering. This value corresponds to a weak mixing angle at Q{sup 2} = 0.026 (GeV/c){sup 2} of sin{sup 2} {theta}{sub w{ovr MS}} = 0.2379 {+-} 0.0016 (stat.) {+-} 0.0013 (syst.), which is -0.3 standard deviations away from the Standard Model prediction: sin{sup 2} {theta}{sub w{ovr MS}}{sup predicted} = 0.2385 {+-} 0.0006 (theory). The E158 measurement of sin{sup 2} {theta}{sub w} at a precision of {delta}(sin{sup 2} {theta}{sub w}) = 0.0020 provides new physics sensitivity at the TeV scale.« less

Analysis of Hairless Corepressor Mutants to Characterize Molecular Cooperation with the Vitamin D Receptor in Promoting the Mammalian Hair Cycle

PubMed Central

Hsieh, Jui-Cheng; Slater, Stephanie A.; Whitfield, G. Kerr; Dawson, Jamie L.; Hsieh, Grace; Sheedy, Craig; Haussler, Carol A.; Haussler, Mark R.

2010-01-01

The mammalian hair cycle requires both the vitamin D receptor (VDR) and the hairless (Hr) corepressor, each of which is expressed in the hair follicle. Hr interacts directly with VDR to repress VDR-targeted transcription. Herein, we further map the VDR-interaction domain to regions in the C-terminal half of Hr that contain two LXXLL-like pairs of motifs known to mediate contact of Hr with the RAR-related orphan receptor alpha and with the thyroid hormone receptor, respectively. Site-directed mutagenesis indicates that all four hydrophobic motifs are required for VDR transrepression by Hr. Point mutation of rat Hr at conserved residues corresponding to natural mutants causing alopecia in mice (G985W and a C-terminal deletion ΔAK) and in humans (P95S, C422Y, E611G, R640Q, C642G, N988S, D1030N, A1040T, V1074M and V1154D), as well as alteration of residues in the C-terminal Jumonji C domain implicated in histone demethylation activity (C1025G/E1027G and H1143G) revealed that all Hr mutants retained VDR association, and that transrepressor activity was selectively abrogated in C642G, G985W, N988S, D1030N, V1074M, H1143G and V1154D. Four of these latter Hr mutants (C642G, N988S, D1030N and V1154D) were found to associate normally with histone deacetylase-3. Finally, we identified three regions of human VDR necessary for association with Hr, namely residues 109–111, 134–201, and 202–303. It is concluded that Hr and VDR interact via multiple protein-protein interfaces, with Hr recruiting histone deacetylases and possibly itself catalyzing histone demethylation to effect chromatin remodeling and repress the transcription of VDR target genes that control the hair cycle. PMID:20512927

Measurement of sin2θw and ϱ in deep inelastic neutrino-nucleon scattering

NASA Astrophysics Data System (ADS)

Reutens, P. G.; Merritt, F. S.; Macfarlane, D. B.; Messner, R. L.; Novikoff, D. B.; Purohit, M. V.; Blair, R. E.; Sciulli, F. J.; Shaevitz, M. H.; Fisk, H. E.; Fukushima, Y.; Jin, B. N.; Kondo, T.; Rapidis, P. A.; Yovanovitch, D. D.; Bodek, A.; Coleman, R. N.; Marsh, W. L.; Fackler, O. D.; Jenkins, K. A.

1985-03-01

We describe a high statistics measurement from deep inelastic neutrino-nucleon scattering of the electroweak parameters ϱ and sin2θw, performed in the Fermilab narrow-band neutrino beam. Our measurement uses a radius-dependent cut in y = EH/Ev which reduces the systematic error in sin2θw, and incorporates electromagnetic and electroweak radiative corrections. In a renormalization scheme where sin2θw ≡ 1-m2W/m2Z, a value of sin2θw = 0.242+/-0.011+/-0.005 is obtained fixing ϱ = 1. If both sin2θw and ϱ are allowed to vary in a fit to our data, we measure ϱ = 0.991 +/- 0.025 +/- 0.009. Present address: IBM Thomas J. Watson Research Center, PO Box 218, Yorktown Heights, NY 10598, USA.

Structural Basis for Catalytic Activation of a Serine Recombinase

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

Keenholtz, Ross A.; Rowland, Sally-J.; Boocock, Martin R.

2014-10-02

Sin resolvase is a site-specific serine recombinase that is normally controlled by a complex regulatory mechanism. A single mutation, Q115R, allows the enzyme to bypass the entire regulatory apparatus, such that no accessory proteins or DNA sites are required. Here, we present a 1.86 {angstrom} crystal structure of the Sin Q115R catalytic domain, in a tetrameric arrangement stabilized by an interaction between Arg115 residues on neighboring subunits. The subunits have undergone significant conformational changes from the inactive dimeric state previously reported. The structure provides a new high-resolution view of a serine recombinase active site that is apparently fully assembled, suggestingmore » roles for the conserved active site residues. The structure also suggests how the dimer-tetramer transition is coupled to assembly of the active site. The tetramer is captured in a different rotational substate than that seen in previous hyperactive serine recombinase structures, and unbroken crossover site DNA can be readily modeled into its active sites.« less

The Saccharomyces cerevisiae Mre11-Rad50-Xrs2 complex promotes trinucleotide repeat expansions independently of homologous recombination.

PubMed

Ye, Yanfang; Kirkham-McCarthy, Lucy; Lahue, Robert S

2016-07-01

Trinucleotide repeats (TNRs) are tandem arrays of three nucleotides that can expand in length to cause at least 17 inherited human diseases. Somatic expansions in patients can occur in differentiated tissues where DNA replication is limited and cannot be a primary source of somatic mutation. Instead, mouse models of TNR diseases have shown that both inherited and somatic expansions can be suppressed by the loss of certain DNA repair factors. It is generally believed that these repair factors cause misprocessing of TNRs, leading to expansions. Here we extend this idea to show that the Mre11-Rad50-Xrs2 (MRX) complex of Saccharomyces cerevisiae is a causative factor in expansions of short TNRs. Mutations that eliminate MRX subunits led to significant suppression of expansions whereas mutations that inactivate Rad51 had only a minor effect. Coupled with previous evidence, this suggests that MRX drives expansions of short TNRs through a process distinct from homologous recombination. The nuclease function of Mre11 was dispensable for expansions, suggesting that expansions do not occur by Mre11-dependent nucleolytic processing of the TNR. Epistasis between MRX and post-replication repair (PRR) was tested. PRR protects against expansions, so a rad5 mutant gave a high expansion rate. In contrast, the mre11 rad5 double mutant gave a suppressed expansion rate, indistinguishable from the mre11 single mutant. This suggests that MRX creates a TNR substrate for PRR. Protein acetylation was also tested as a mechanism regulating MRX activity in expansions. Six acetylation sites were identified in Rad50. Mutation of all six lysine residues to arginine gave partial bypass of a sin3 HDAC mutant, suggesting that Rad50 acetylation is functionally important for Sin3-mediated expansions. Overall we conclude that yeast MRX helps drive expansions of short TNRs by a mechanism distinct from its role in homologous recombination and independent of the nuclease function of Mre11. Copyright © 2016 Elsevier B.V. All rights reserved.

An inherently bi-functional subset of Foxp3+ T helper cells is controlled by the transcription factor Eos

PubMed Central

Sharma, Madhav D.; Huang, Lei; Choi, Jeong-Hyeon; Lee, Eun-Joon; Wilson, James M.; Lemos, Henrique; Pan, Fan; Blazar, Bruce R.; Pardoll, Drew M.; Mellor, Andrew L; Shi, Huidong; Munn, David H.

2013-01-01

SUMMARY At sites of inflammation, certain regulatory T cells (Treg cells) can undergo rapid reprogramming into helper-like cells, without loss of the transcription factor Foxp3. We show that reprogramming is controlled by down-regulation of the transcription factor Eos (Ikzf4), an obligate co-repressor for Foxp3. Reprogramming was restricted to a specific subset of “Eoslabile” Treg cells which were present in the thymus and identifiable by characteristic surface markers and DNA methylation. Mice made deficient in this subset became impaired in their ability to provide help for presentation of new antigens to naive T cells. Down-regulation of Eos required the pro-inflammatory cytokine IL-6, and mice lacking IL-6 had impaired development and function of the Eos-labile subset. Conversely, the immunoregulatory enzyme IDO blocked loss of Eos, and prevented the Eos-labile Treg cells from reprogramming. Thus, the Foxp3+ lineage contains a committed subset of Treg cells capable of rapid conversion into biologically important helper cells. PMID:23684987

Development of Ultra-Low-Noise TES Bolometer Arrays

NASA Astrophysics Data System (ADS)

Suzuki, T.; Khosropanah, P.; Ridder, M. L.; Hijmering, R. A.; Gao, J. R.; Akamatsu, H.; Gottardi, L.; van der Kuur, J.; Jackson, B. D.

2016-07-01

SRON is developing ultra-low-noise transition edge sensors (TESs) based on a superconducting Ti/Au bilayer on a suspended SiN island with SiN legs for SAFARI aboard SPICA. We have two major concerns about realizing TESs with an ultra-low NEP of 2× 10^{-19} hbox {W}/√{{ {Hz}}}: achieving lower thermal conductance and no excess noise with respect to the phonon noise. To realize TESs with phonon-noise-limited NEPs, we need to make thinner ({<}0.25 \\upmu hbox {m}) and narrower ({<}1 \\upmu hbox {m}) SiN legs. With deep reactive-ion etching, three types of TESs were fabricated in combination with different SiN island sizes and the presence or absence of an optical absorber. Those TESs have a thin (0.20 \\upmu hbox {m}), narrow (0.5-0.7 \\upmu hbox {m}), and long (340-460 \\upmu hbox {m}) SiN legs and show Tc of {˜ }93 hbox {mK} and Rn of {˜ }158 hbox {m}{Ω }. These TESs were characterized under AC bias using our frequency-division multiplexing readout (1-3 MHz) system. TESs without the absorber show NEPs as low as 1.1 × 10^{-19} hbox {W}/√{{ {Hz}}} with a reasonable response speed ({<}1 hbox {ms}), which achieved the phonon noise limit. For TESs with the absorber, we confirmed a higher hbox {NEP}_{el} ({˜ }5 × 10^{-19} hbox {W}/√{{ {Hz}}}) than that of TESs without the absorber likely due to stray light. The lowest NEP can make the new version of SAFARI with a grating spectrometer feasible.

"... As we forgive those who trespass against us...": theological reflections on sin and guilt in the hospital environment.

PubMed

Schmidt, Kurt W

2005-08-01

In general parlance the term sin has lost its existential meaning. Originally a Jewish-Christian term within a purely religious context, referring to a wrongdoing with regard to God, sin has slowly become reduced to guilt in the course of the secularization process. Guilt refers to a wrongdoing, especially with regard to fellow human beings. It also refers to errors of judgement with what can be tragic consequences. These errors can occur whenever human beings are called upon to act, including the hospital environment. A Christian hospital has to address the issue of how to deal not only with guilt-ridden misdemeanors, but also with wrongdoing unto God, which overshadows every instance of guilt-ridden human behavior. Here, as in every parish, the Church Service is the place to acknowledge sin, confess sin, and forgive sin, beyond the boundaries of the parish itself.

Sin1, a Mutation Affecting Female Fertility in Arabidopsis, Interacts with Mod1, Its Recessive Modifier

PubMed Central

Lang, J. D.; Ray, S.; Ray, A.

1994-01-01

In Arabidopsis thaliana, a mutation in the SIN1 gene causes aberrant ovule development and female-specific sterility. The effect of the sin1 mutation is polymorphic and pleiotropic in different genetic backgrounds. The polymorphism concerns morphology of the mutant ovules. The pleiotropism involves internodal distance and inflorescence initiation time. The particular ovule phenotype and the length of internodes are dependent on an interaction of sin1 with a second recessive gene, which we term mod1. The recessive mod1 allele in a homozygous sin1 mutant plant reduces internode length and ovule integument size. The mutation sin1, but not mod1, has a demonstrable effect on ovule morphology when acting idependently. In our crosses mod1 was inseparably linked to the well known mutation erecta that is known to cause a reduction in internode and pedicel lengths. PMID:7982564

Advanced Passivation Technology and Loss Factor Minimization for High Efficiency Solar Cells.

PubMed

Park, Cheolmin; Balaji, Nagarajan; Jung, Sungwook; Choi, Jaewoo; Ju, Minkyu; Lee, Seunghwan; Kim, Jungmo; Bong, Sungjae; Chung, Sungyoun; Lee, Youn-Jung; Yi, Junsin

2015-10-01

High-efficiency Si solar cells have attracted great attention from researchers, scientists, photovoltaic (PV) industry engineers for the past few decades. With thin wafers, surface passivation becomes necessary to increase the solar cells efficiency by overcoming several induced effects due to associated crystal defects and impurities of c-Si. This paper discusses suitable passivation schemes and optimization techniques to achieve high efficiency at low cost. SiNx film was optimized with higher transmittance and reduced recombination for using as an effective antireflection and passivation layer to attain higher solar cell efficiencies. The higher band gap increased the transmittance with reduced defect states that persisted at 1.68 and 1.80 eV in SiNx films. The thermal stability of SiN (Si-rich)/SiN (N-rich) stacks was also studied. Si-rich SiN with a refractive index of 2.7 was used as a passivation layer and N-rich SiN with a refractive index of 2.1 was used for thermal stability. An implied Voc of 720 mV with a stable lifetime of 1.5 ms was obtained for the stack layer after firing. Si-N and Si-H bonding concentration was analyzed by FTIR for the correlation of thermally stable passivation mechanism. The passivation property of spin coated Al2O3 films was also investigated. An effective surface recombination velocity of 55 cm/s with a high density of negative fixed charges (Qf) on the order of 9 x 10(11) cm(-2) was detected in Al2O3 films.

Evaluation of the residual stresses in 95wt%Al2O3-5wt% SiC wear protection coating using X-Ray diffraction technique

NASA Astrophysics Data System (ADS)

Mahmoud, Adel K.; Hammoudi, Zaid S.; Student Samah Rasheed, M. Sc.

2018-02-01

This paper aims to measuring the residual stresses practically in wear protection coatings using the sin2ψ method according to X-ray diffraction technique. The wear protection coatings used in this study was composite coating 95wt% Al2O3-5wt% SiC, while bond coat was AlNi alloy produced by using flame spraying technique on the mild steel substrate. The diffraction angle, 2θ, is measured experimentally and then the lattice spacing is calculated from the diffraction angle, and the known X-ray wavelength using Bragg’s Law. Once the dspacing values are known, they can be plotted versus sin2ψ, (ψ is the tilt angle). In this paper, stress measurement of the samples that exhibit a linear behavior as in the case of a homogenous isotropic sample in a biaxial stress state is included. The plot of dspacing versus sin2ψ is a straight line which slope is proportional to stress. On the other hand, the second set of samples showed oscillatory dspacing versus sin2ψ behaviour. The oscillatory behaviour indicates the presence of inhomogeneous stress distribution. In this case the X-ray elastic constants must be used instead of Young’s modulus (E) and Poisson ratio (ν)values. These constants can be obtained from the literature for a given material and reflection combination. The value of the residual stresses for the present coating calculated was compressive stresses (-325.6758MPa).

Triosephosphate isomerase tyrosine nitration induced by heme-NaNO2 -H2 O2 or peroxynitrite: Effects of different natural phenolic compounds.

PubMed

Gao, Wanxia; Zhao, Jie; Li, Hailing; Gao, Zhonghong

2017-06-01

Peroxynitrite and heme peroxidases (or heme)-H 2 O 2 -NaNO 2 system are the two common ways to cause protein tyrosine nitration in vitro, but the effects of antioxidants on reducing these two pathways-induced protein nitration and oxidation are controversial. Both nitrating systems can dose-dependently induce triosephosphate isomerase (TIM) nitration, however, heme-H 2 O 2 -NaNO 2 was less destructive to protein secondary structures and led to more nitrated tyrosine residue than 3-morpholinosydnonimine hydrochloride (SIN-1, a peroxynitrite donor). Both of desferrioxamine and catechin could inhibit TIM nitration induced by heme-H 2 O 2 -NaNO 2 and SIN-1 and protein oxidation induced by SIN-1, but promoted heme-H 2 O 2 -NaNO 2 -induced protein oxidation. Moreover, the antagonism of natural phenolic compounds on SIN-1-induced tyrosine nitration was consistent with their radical scavenging ability, but no similar consensus was found in heme-H 2 O 2 -NaNO 2 -induced nitration. Our results indicated that peroxynitrite and heme-H 2 O 2 -NaNO 2 -induced protein nitration was different, and the later one could be a better model for anti-nitration compounds screening. © 2017 Wiley Periodicals, Inc.

Studies of early-type variable stars. XIV. Spectroscopic orbit and absolute parameters of HU Tauri.

NASA Astrophysics Data System (ADS)

Maxted, P. F. L.; Hill, G.; Hilditch, R. W.

1995-09-01

We present a new spectroscopic orbit for the Algol-type eclipsing binary system HU Tau (HD 29365, P=2.0563 days α(2000.0) = 04 38 15.80, δ= +20 41 05.3, V=5.87-6.8, B8V + G2). We find : m_1_ sin^3^i=4.17+/-0.09Msun_, m_2_ sin^3^i=1.07+/-0.025Msun_, (a_p_+a_s_)sin i=11.8 +/-0.1Rsun_, m_1_/m_2_=3.90+/-0.07. The spectroscopic orbit includes corrections for non-Keplerian effects derived from the solutions of the BV light curves of Ito (1988). We have been able to derive much improved absolute parameters for this system as follows: M_1_=4.43+/-0.09Msun_, M_2_=1.14+/-0.03Msun_, R _1_=2.57+/-0.03Rsun_, R _2_=4.21+/-0.03Rsun_, log(L_1_/Lsun_)= 2.09+/-0.15, log(L_2_/Lsun_)= 0.92+/-0.05. Comparison of HU Tau with non-conservative case B evolution models of De Greve (1993) suggests that the system evolved from an initial mass ratio <~0.5. However, the orbital period of HU Tau is more than 3 days shorter than any of the model systems, and the observed secondary luminosity of order 10 times less than a model star of the same mass during the slow mass transfer phase.

48 CFR 538.7001 - Definitions.

Code of Federal Regulations, 2010 CFR

2010-10-01

... used in this subpart, means Schedule 70 information technology contracts, and Consolidated Products and Services Schedule contracts containing information technology SINs. The Consolidated Products and Services... Purchasing. No other Schedules, or SINs, containing information technology outside of Schedule 70 SINs, and...

48 CFR 538.7001 - Definitions.

Code of Federal Regulations, 2011 CFR

2011-10-01

... used in this subpart, means Schedule 70 information technology contracts, and Consolidated Products and Services Schedule contracts containing information technology SINs. The Consolidated Products and Services... Purchasing. No other Schedules, or SINs, containing information technology outside of Schedule 70 SINs, and...

48 CFR 538.7001 - Definitions.

Code of Federal Regulations, 2012 CFR

2012-10-01

... used in this subpart, means Schedule 70 information technology contracts, and Consolidated Products and Services Schedule contracts containing information technology SINs. The Consolidated Products and Services... Purchasing. No other Schedules, or SINs, containing information technology outside of Schedule 70 SINs, and...

48 CFR 538.7001 - Definitions.

Code of Federal Regulations, 2013 CFR

2013-10-01

... used in this subpart, means Schedule 70 information technology contracts, and Consolidated Products and Services Schedule contracts containing information technology SINs. The Consolidated Products and Services... Purchasing. No other Schedules, or SINs, containing information technology outside of Schedule 70 SINs, and...

48 CFR 538.7001 - Definitions.

Code of Federal Regulations, 2014 CFR

2014-10-01

... used in this subpart, means Schedule 70 information technology contracts, and Consolidated Products and Services Schedule contracts containing information technology SINs. The Consolidated Products and Services... Purchasing. No other Schedules, or SINs, containing information technology outside of Schedule 70 SINs, and...

Changes in nuclear receptor corepressor RIP140 do not influence mitochondrial content in the cortex.

PubMed

Herbst, Eric A F; Bonen, Arend; Holloway, Graham P

2015-10-01

Changes in nuclear receptor interacting protein 140 (RIP140) influences mitochondrial content in skeletal muscle; however, the translation of these findings to the brain has not been investigated. The present study examined the impact of overexpressing and ablating RIP140 on mitochondrial content in muscle and the cortex through examining mRNA, mtDNA, and mitochondrial protein content. Our results show that changes in RIP140 expression significantly alters markers of mitochondrial content in skeletal muscle but not the brain.

Targeting Prostate Cancer with Bifunctional Modulators of the Androgen Receptor

DTIC Science & Technology

2014-10-01

androgen receptor/coactivator disruptors. ACS Chem. Biol. 2009, 4, 435–440. (7) Guenther, M.; Barak , O.; Lazar, M. The SMRT and N-CoR corepressors are...17) Welsbie, D. S.; Xu, J.; Chen, Y.; Borsu, L.; Scher, H. I.; Rosen , N.; Sawyers, C. L. Histone deacetylases are required for androgen receptor...J.; Di Vizio, D.; Zhang, X.; Albanese, C.; Balk, S.; Chang, C.; Fan, S.; Rosen , E.; Palvimo, J. J.; Jänne, O. A.; Muratoglu, S.; Avantaggiati, M. L

Glutaminolysis and carcinogenesis of oral squamous cell carcinoma.

PubMed

Cetindis, Marcel; Biegner, Thorsten; Munz, Adelheid; Teriete, Peter; Reinert, Siegmar; Grimm, Martin

2016-02-01

Glutaminolysis is a crucial factor for tumor metabolism in the carcinogenesis of several tumors but has not been clarified for oral squamous cell carcinoma (OSCC) yet. Expression of glutaminolysis-related solute carrier family 1, member 5 (SLC1A5)/neutral amino acid transporter (ASCT2), glutaminase (GLS), and glutamate dehydrogenase (GLDH) was analyzed in normal oral mucosa (n = 5), oral precursor lesions (simple hyperplasia, n = 11; squamous intraepithelial neoplasia, SIN I-III, n = 35), and OSCC specimen (n = 42) by immunohistochemistry. SLC1A5/ASCT2 and GLS were significantly overexpressed in the carcinogenesis of OSCC compared with normal tissue, while GLDH was weakly detected. Compared with SIN I-III SLC1A5/ASCT2 and GLS expression were significantly increased in OSCC. GLDH expression did not significantly differ from SIN I-III compared with OSCC. This study shows the first evidence of glutaminolysis-related SLC1A5/ASCT2, GLS, and GLDH expression in OSCC. The very weak GLDH expression indicates that glutamine metabolism is rather related to nucleotide or protein/hexosamine biosynthesis or to the function as an antioxidant (glutathione) than to energy production or generation of lactate through entering the tricarboxylic acid cycle. Overcoming glutaminolysis by targeting c-Myc oncogene (e.g. by natural compounds) and thereby cross-activation of mammalian target of rapamycin complex 1 or SLC1A5/ASCT2, GLS inhibitors may be a useful strategy to sensitize cancer cells to common OSCC cancer therapies.

Approximation properties of Fejér- and de la Valleé-Poussin-type means for partial sums of a special series in the system \\{\\sin x\\sin kx\\}_{k=1}^\\infty

NASA Astrophysics Data System (ADS)

Sharapudinov, I. I.

2015-04-01

This paper is concerned with series of the form \\displaystyle Φ(θ)=A_Φ(θ)+\\sinθ\\sumk=1^∞\\varphi_k\\sin kθ, where Φ(θ) is an even 2π-periodic function with finite values Φ(0) and Φ(π), \\displaystyle A_Φ(θ)=\\frac{Φ(0)+Φ(π)}{2}+\\frac{Φ(0)-Φ(π)}{2}\\cosθ,\\qquad\\varphi(θ)=Φ(θ)-A_Φ(θ), \\displaystyle \\varphi_k=\\frac{2}π\\int_0^π\\varphi(t)\\frac{\\sin kt}{\\sin t} dt. Series of this type appear as a particular case of more general special series in ultraspherical Jacobi polynomials, which were first introduced and studied by the author. Partial sums of the form \\Pi_n(Φ)=\\Pi_n(Φ,θ)=A_Φ(θ)+\\sinθ\\sumk=1n-1\\varphi_k\\sin kθ are shown to have a number of important properties, which give them an advantage over trigonometric Fourier sums of the form S_n(Φ,θ)=\\frac{a_0}{2}+\\sumk=1^na_k\\cos kθ. Approximation properties of Fejér- and de la Valleé-Poussin-type means for the partial sums \\Pi_n(Φ,θ) are studied. Bibliography: 7 titles.

Dma1-dependent degradation of SIN proteins during meiosis in Schizosaccharomyces pombe.

PubMed

Krapp, Andrea; Simanis, Viesturs

2014-07-15

The Schizosaccharomyces pombe septation initiation network (SIN) is required for cytokinesis during vegetative growth and for spore formation during meiosis. Regulation of the SIN during mitosis has been studied extensively, but less is known about its meiotic regulation. Here, we show that several aspects of SIN regulation differ between mitosis and meiosis. First, the presence of GTP-bound Spg1p is not the main determinant of the timing of Cdc7p and Sid1p association with the spindle pole body (SPB) during meiosis. Second, the localisation dependencies of SIN proteins differ from those in mitotic cells, suggesting a modified functional organisation of the SIN during meiosis. Third, there is stage-specific degradation of SIN components in meiosis; Byr4p is degraded after meiosis I, whereas the degradation of Cdc7p, Cdc11p and Sid4p occurs after the second meiotic division and depends upon the ubiquitin ligase Dma1p. Finally, Dma1p-dependent degradation is not restricted to the SIN, as we show that Dma1p is needed for the degradation of Mcp6p (also known as Hrs1p) during meiosis I. Taken together, these data suggest that stage-specific targeted proteolysis plays an important role in regulating meiotic progression. © 2014. Published by The Company of Biologists Ltd.

Influence of the direct NO-donor SIN-1 on the interaction between platelets and stainless steel stents under dynamic conditions.

PubMed

Jung, F; Mrowietz, C; Seyfert, U T; Grewe, R; Franke, R P

2003-01-01

It was investigated whether the NO-donor SIN-1, the active metabolite of molsidomine, influenced the activation of platelets, the formation of circulating platelet aggregates, the spontaneous aggregation of platelets and the activation of the clotting system triggered by a body foreign surface in an in vitro closed-loop perfusion model. With human platelet-rich plasma at micromolar concentrations SIN-1 exerted pronounced effects on the interaction between platelets and an exogenous surface. In the absence of SIN-1, the number of circulating single platelets decreased significantly, which could be due either to the formation of circulating platelet aggregates or to the adhesion of platelets to the stent. Both these processes were blocked by the addition of SIN-1. Moreover, the platelets exhibited hyperaggregability in the absence of SIN-1 whereas the NO-donor was able to completely inhibit spontaneous platelet aggregation. Similar results were obtained in flow cytometry experiments. Without SIN-1, high platelet surface densities of both the GPIb/IX and GPIIb/IIIa receptors were observed. In addition, the density of the fibrinogen receptor increased significantly with the number of perfusion cycles. SIN-1 was able to suppress the augmented GPIIb/IIIa receptor expression significantly. Molsidomine seemed to have the potential to reduce the incidence of thrombotic processes triggered by the exogenous surface of the stent.

Protective Effects of Sinomenine on CFA-Induced Inflammatory Pain in Rats.

PubMed

Yuan, Yan; Zhang, Yongjun; He, Xiaofeng; Fan, Shengdeng

2018-04-05

BACKGROUND The purpose of this study was to investigate the effects of sinomenine (SIN) on CFA-induced inflammatory pain in rats, and to explore the underlying molecular mechanisms. MATERIAL AND METHODS To determine the potential influences of SIN in the pathogenesis of inflammatory pain, an inflammatory pain (IP) mouse model was established and rats were treated with SIN (30 mg/kg). Behavioral tests were used to assess the MWT and TWL of the rats. ELISA assay was used to detect the level of inflammation cytokines. Western blotting and qRT-PCR were carried out to measure the related protein and mRNA expression level, respectively. RESULTS We found that the MWT and TWL of the CFA-treated rats were markedly lower than that of the control rats, and they were significantly increased by SIN administration. The results suggest that IP rats had higher levels of TNF-α, IL-1β and IL-6 compared with the control rats. SIN administration decreased the levels of TNF-α, IL-1β, and IL-6. In addition, we found that p-p65 and p-p38 expression notably decreased after SIN treatment in IP rats. Moreover, the results showed that SIN inhibited Cox-2 and PGE2 expression in IP rats. CONCLUSIONS The data indicate that SIN had a protective role in inflammatory pain through repressing inflammatory mediators via preventing the p38MAPK-NF-κB pathway.

Quantitative Analysis of Etching Rate Profiles for 11B+-Implanted Si3N4 Film

NASA Astrophysics Data System (ADS)

Nakata, Jyoji; Kajiyama, Kenji

1983-01-01

Etching rate enhancement for 11B+-implanted Si3N4 film was investigated both experimentally and theoretically. The etching solution was concentrated H3PO4 at ˜165°C Film thicknesses were precisely measured by ellipsometry. Enhancement resulted from Si-N bond breaking. This was confirmed by a decrease of infrared absorption at a 12.0 μm wavelength for Si-N bond vibration. Main and additional peaks were observed in the etching rate profile. The former was due to nuclear damage and was well represented by the calculated etching rate profile deduced from the nuclear deposited energy density distribution. The latter existed in the surface region only when the ion projected range was shorter than the film thickness. This peak was possibly caused by charge accumulation in the insulating Si3N4 film during 11B+ implantation.

A high-resolution structure of the DNA-binding domain of AhrC, the arginine repressor/activator protein from Bacillus subtilis

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

Garnett, James A.; Baumberg, Simon; Stockley, Peter G.

2007-11-01

The structure of the winged helix–turn–helix DNA-binding domain of AhrC has been determined at 1.0 Å resolution. The largely hydrophobic β-wing shows high B factors and may mediate the dimer interface in operator complexes. In Bacillus subtilis the concentration of l-arginine is controlled by the transcriptional regulator AhrC, which interacts with 18 bp DNA operator sites called ARG boxes in the promoters of arginine biosynthetic and catabolic operons. AhrC is a 100 kDa homohexamer, with each subunit having two domains. The C-terminal domains form the core, mediating intersubunit interactions and binding of the co-repressor l-arginine, whilst the N-terminal domains containmore » a winged helix–turn–helix DNA-binding motif and are arranged around the periphery. The N-terminal domain of AhrC has been expressed, purified and characterized and it has been shown that the fragment still binds DNA operators as a recombinant monomer. The DNA-binding domain has also been crystallized and the crystal structure refined to 1.0 Å resolution is presented.« less

Regulation of amino acid transport in Escherichia coli by transcription termination factor rho.

PubMed

Quay, S C; Oxender, D L

1977-06-01

Amino acid transport rates and amino acid binding proteins were examined in a strain containing the rho-120 mutation (formerly SuA), which has been shown to lower the rho-dependent, ribonucleic acid-activated adenosine triphosphatase activity to 9% of the rho activity in the isogenic wild-type strain. Tryptophan and proline transport, which occur by membrane-bound systems, were not altered. On the other hand, arginine, histidine, leucine, isoleucine, and valine transport were variably increased by a factor of 1.4 to 5.0. Kinetics of leucine transport showed that the LIV (leucine, isoleucine, and valine)-I (binding protein-associated) transport system is increased 8.5-fold, whereas the LIV-II (membrane-bound) system is increased 1.5-fold in the rho mutant under leucine-limited growth conditions. The leucine binding protein is increased fourfold under the same growth conditions. The difference in leucine transport in these strains was greatest during leucine-limited growth; growth on complex media repressed both strains to the same transport activity. We propose that rho-dependent transcriptional termination is important for leucine-specific repression of branched-chain amino acid transport, although rho-independent regulation, presumably by a corepressor-aporepressor-type mechanism, must also occur.

A chimeric alphavirus replicon particle vaccine expressing the hemagglutinin and fusion proteins protects juvenile and infant rhesus macaques from measles.

PubMed

Pan, Chien-Hsiung; Greer, Catherine E; Hauer, Debra; Legg, Harold S; Lee, Eun-Young; Bergen, M Jeff; Lau, Brandyn; Adams, Robert J; Polo, John M; Griffin, Diane E

2010-04-01

Measles remains a major cause of child mortality, in part due to an inability to vaccinate young infants with the current live attenuated virus vaccine (LAV). To explore new approaches to infant vaccination, chimeric Venezuelan equine encephalitis/Sindbis virus (VEE/SIN) replicon particles were used to express the hemagglutinin (H) and fusion (F) proteins of measles virus (MV). Juvenile rhesus macaques vaccinated intradermally with a single dose of VEE/SIN expressing H or H and F proteins (VEE/SIN-H or VEE/SIN-H+F, respectively) developed high titers of MV-specific neutralizing antibody and gamma-interferon (IFN-gamma)-producing T cells. Infant macaques vaccinated with two doses of VEE/SIN-H+F also developed neutralizing antibody and IFN-gamma-producing T cells. Control animals were vaccinated with LAV or with a formalin-inactivated measles vaccine (FIMV). Neutralizing antibody remained above the protective level for more than 1 year after vaccination with VEE/SIN-H, VEE/SIN-H+F, or LAV. When challenged with wild-type MV 12 to 17 months after vaccination, all vaccinated juvenile and infant monkeys vaccinated with VEE/SIN-H, VEE/SIN-H+F, and LAV were protected from rash and viremia, while FIMV-vaccinated monkeys were not. Antibody was boosted by challenge in all groups. T-cell responses to challenge were biphasic, with peaks at 7 to 25 days and at 90 to 110 days in all groups, except for the LAV group. Recrudescent T-cell activity coincided with the presence of MV RNA in peripheral blood mononuclear cells. We conclude that VEE/SIN expressing H or H and F induces durable immune responses that protect from measles and offers a promising new approach for measles vaccination. The viral and immunological factors associated with long-term control of MV replication require further investigation.

SKI promotes Smad3 linker phosphorylations associated with the tumor-promoting trait of TGFbeta.

PubMed

Lin, Qiushi; Chen, Dahu; Timchenko, Nikolai A; Medrano, Estela E

2010-05-01

The transcriptional co-regulator SKI is a potent inhibitor of TGFbeta-growth inhibitory signals. SKI binds to receptor-activated Smads in the nucleus, forming repressor complexes containing HDACs, mSin3, NCoR, and other protein partners. Alternatively, SKI binds to activated Smads in the cytoplasm, preventing their nuclear translocation. SKI is necessary for anchorage-independent growth of melanoma cells in vitro, and most important, for human melanoma xenograft growth in vivo. We recently identified a novel role of SKI in TGFbeta signaling. SKI promotes the switch of Smad3 from repressor of proliferation to activator of oncogenesis by facilitating phosphorylations in the linker domain. High levels of endogenous SKI are required by the tumor promoting trait of TGFbeta to induce expression of the plasminogen-activator inhibitor-1 (PAI-1), sustained expression of C-Myc and for aborting upregulation of p21(Waf-1). Here we discuss how SKI diversifies and amplifies its functions by associating with multiple protein partners and by promoting Smad3 linker phosphorylation(s) in response to TGFbeta signaling in melanoma cells.

Bearing-only Cooperative Localization: Simulation and Experimental Results

DTIC Science & Technology

2013-01-01

matrix Fi and Bi are the system jacobian with respect to state Xi and control ui, which are given below Fi = I3 + Ts ∂fi ∂Xi |Xi=Xi(k) =  1 0 − ViTs ...sinψ(k)0 1 ViTs cosψ(k) 0 0 1  , (8) Bi = Ts ∂fi ∂ui |ui=ui(k) Ts cosψk 0Ts sinψk 0 0 Ts  , (9) and Qi(k) = ( σ2vi 0 0 σ2ωi ) , where σvi and σωi

Integrated Positioning for Coal Mining Machinery in Enclosed Underground Mine Based on SINS/WSN

PubMed Central

Hui, Jing; Wu, Lei; Yan, Wenxu; Zhou, Lijuan

2014-01-01

To realize dynamic positioning of the shearer, a new method based on SINS/WSN is studied in this paper. Firstly, the shearer movement model is built and running regularity of the shearer in coal mining face has been mastered. Secondly, as external calibration of SINS using GPS is infeasible in enclosed underground mine, WSN positioning strategy is proposed to eliminate accumulative error produced by SINS; then the corresponding coupling model is established. Finally, positioning performance is analyzed by simulation and experiment. Results show that attitude angle and position of the shearer can be real-timely tracked by integrated positioning strategy based on SINS/WSN, and positioning precision meet the demand of actual working condition. PMID:24574891

The sin in the aetiological concept of Johann Christian August Heinroth (1773-1843). Part 1: Between theology and psychiatry. Heinroth's concepts of 'whose being', 'freedom', 'reason' and 'disturbance of the soul'.

PubMed

Steinberg, Holger

2004-09-01

Throughout his work Johann Christian August Heinroth regarded sin to be the cause of mental illness. The present two-part paper investigates what exactly Heinroth understood by sin. Based on a thorough analysis of his own texts, this study shows that on the one hand Heinroth referred to sin in a Christian-Protestant sense. On the other, however, a moral-ethical code of conduct was also involved. Thus, Heinroth did not regard sin as a singular event, but rather as a life conducted in a wrong way for years or even decades, by which he meant a steady striving towards earthly, bodily satisfaction.

A new material platform of Si photonics for implementing architecture of dense wavelength division multiplexing on Si bulk wafer.

PubMed

Zhang, Ziyi; Yako, Motoki; Ju, Kan; Kawai, Naoyuki; Chaisakul, Papichaya; Tsuchizawa, Tai; Hikita, Makoto; Yamada, Koji; Ishikawa, Yasuhiko; Wada, Kazumi

2017-01-01

A new materials group to implement dense wavelength division multiplexing (DWDM) in Si photonics is proposed. A large thermo-optic (TO) coefficient of Si malfunctions multiplexer/demultiplexer (MUX/DEMUX) on a chip under thermal fluctuation, and thus DWDM implementation, has been one of the most challenging targets in Si photonics. The present study specifies an optical materials group for DWDM by a systematic survey of their TO coefficients and refractive indices. The group is classified as mid-index contrast optics (MiDex) materials, and non-stoichiometric silicon nitride (SiN x ) is chosen to demonstrate its significant thermal stability. The TO coefficient of non-stoichiometric SiN x is precisely measured in the temperature range 24-76 °C using the SiN x rings prepared by two methods: chemical vapor deposition (CVD) and physical vapor deposition (PVD). The CVD-SiN x ring reveals nearly the same TO coefficient reported for stoichiometric CVD-Si 3 N 4 , while the value for the PVD-SiN x ring is slightly higher. Both SiN x rings lock their resonance frequencies within 100 GHz in this temperature range. Since CVD-SiN x needs a high temperature annealing to reduce N-H bond absorption, it is concluded that PVD-SiN x is suited as a MiDex material introduced in the CMOS back-end-of-line. Further stabilization is required, considering the crosstalk between two channels; a 'silicone' polymer is employed to compensate for the temperature fluctuation using its negative TO coefficient, called athermalization. This demonstrates that the resonance of these SiN x rings is locked within 50 GHz at the same temperature range in the wavelength range 1460-1620 nm (the so-called S, C, and L bands in optical fiber communication networks). A further survey on the MiDex materials strongly suggests that Al 2 O 3 , Ga 2 O 3 Ta 2 O 5 , HfO 2 and their alloys should provide even more stable platforms for DWDM implementation in MiDex photonics. It is discussed that the MiDex photonics will find various applications such as medical and environmental sensing and in-vehicle data-communication.

Internal quantum efficiency mapping analysis for a >20%-efficiency n-type bifacial solar cell with front-side emitter formed by BBr3 thermal diffusion

NASA Astrophysics Data System (ADS)

Simayi, Shalamujiang; Mochizuki, Toshimitsu; Kida, Yasuhiro; Shirasawa, Katsuhiko; Takato, Hidetaka

2017-10-01

This paper presents a large-area (239-cm2) high-efficiency n-type bifacial solar cell that is processed using tube-furnace thermal diffusion employing liquid sources BBr3 for the front-side boron emitter and POCl3 for the rear-side phosphorus back surface field (BSF). The SiN x /Al2O3 stack was applied to the front-side boron emitter as a passivation layer. Both the front and rear-side electrodes are obtained using screen-printed contacts with H-patterns. The resulting highest-efficiency solar cell has front- and rear-side efficiencies of 20.3 and 18.7%, respectively, while the corresponding bifaciality is up to 92%. Finally, the passivation quality of the SiN x /Al2O3 stack on the front-side boron emitter and rear-side phosphorus BSF is investigated and visualized by measuring the internal quantum efficiency mapping of the bifacial solar cell.

Structural and optical characterization of pure Si-rich nitride thin films

NASA Astrophysics Data System (ADS)

Debieu, Olivier; Nalini, Ramesh Pratibha; Cardin, Julien; Portier, Xavier; Perrière, Jacques; Gourbilleau, Fabrice

2013-01-01

The specific dependence of the Si content on the structural and optical properties of O- and H-free Si-rich nitride (SiN x>1.33) thin films deposited by magnetron sputtering is investigated. A semiempirical relation between the composition and the refractive index was found. In the absence of Si-H, N-H, and Si-O vibration modes in the FTIR spectra, the transverse and longitudinal optical (TO-LO) Si-N stretching pair modes could be unambiguously identified using the Berreman effect. With increasing Si content, the LO and the TO bands shifted to lower wavenumbers, and the LO band intensity dropped suggesting that the films became more disordered. Besides, the LO and the TO bands shifted to higher wavenumbers with increasing annealing temperature which may result from the phase separation between Si nanoparticles (Si-np) and the host medium. Indeed, XRD and Raman measurements showed that crystalline Si-np formed upon 1100°C annealing but only for SiN x<0.8. Besides, quantum confinement effects on the Raman peaks of crystalline Si-np, which were observed by HRTEM, were evidenced for Si-np average sizes between 3 and 6 nm. A contrario, visible photoluminescence (PL) was only observed for SiN x>0.9, demonstrating that this PL is not originating from confined states in crystalline Si-np. As an additional proof, the PL was quenched while crystalline Si-np could be formed by laser annealing. Besides, the PL cannot be explained neither by defect states in the bandgap nor by tail to tail recombination. The PL properties of SiN x>0.9 could be then due to a size effect of Si-np but having an amorphous phase.

Drosophila C-terminal binding protein, dCtBP is required for sensory organ prepattern and sharpens proneural transcriptional activity of the GATA factor Pnr.

PubMed

Biryukova, Inna; Heitzler, Pascal

2008-11-01

The peripheral nervous system is required for animals to detect and to relay environmental stimuli to central nervous system for the information processing. In Drosophila, the precise spatial and temporal expression of two proneural genes achaete (ac) and scute (sc), is necessary for development of the sensory organs. Here we present an evidence that the transcription co-repressor, dCtBP acts as a negative regulator of sensory organ prepattern. Loss of dCtBP function mutant exhibits ectopic sensory organs, while overexpression of dCtBP results in a dramatic loss of sensory organs. These phenotypes are correlated with mis-emerging of sensory organ precursors and perturbated expression of proneural transcription activator Ac. Mammalian CtBP-1 was identified via interaction with the consensus motif PXDLSX(K/R) of adenovirus E1A oncoprotein. We demonstrated that dCtBP binds directly to PLDLS motif of Drosophila Friend of GATA-1 protein, U-shaped and sharpens the adult sensory organ development. Moreover, we found that dCtBP mediates multivalent interaction with the GATA transcriptional activator Pannier and acts as a direct co-repressor of the Pannier-mediated activation of proneural genes. We demonstrated that Pannier genetically interacts with dCtBP-interacting protein HDAC1, suggesting that the dCtBP-dependent regulation of Pannier activity could utilize a repressive mechanism involving alteration of local chromatine structure.

De-repression of RaRF-mediated RAR repression by adenovirus E1A in the nucleolus.

PubMed

Um, Soo-Jong; Youn, Hye Sook; Kim, Eun-Joo

2014-02-21

Transcriptional activity of the retinoic acid receptor (RAR) is regulated by diverse binding partners, including classical corepressors and coactivators, in response to its ligand retinoic acid (RA). Recently, we identified a novel corepressor of RAR called the retinoic acid resistance factor (RaRF) (manuscript submitted). Here, we report how adenovirus E1A stimulates RAR activity by associating with RaRF. Based on immunoprecipitation (IP) assays, E1A interacts with RaRF through the conserved region 2 (CR2), which is also responsible for pRb binding. The first coiled-coil domain of RaRF was sufficient for this interaction. An in vitro glutathione-S-transferase (GST) pull-down assay was used to confirm the direct interaction between E1A and RaRF. Further fluorescence microscopy indicated that E1A and RaRF were located in the nucleoplasm and nucleolus, respectively. However, RaRF overexpression promoted nucleolar translocation of E1A from the nucleoplasm. Both the RA-dependent interaction of RAR with RaRF and RAR translocation to the nucleolus were disrupted by E1A. RaRF-mediated RAR repression was impaired by wild-type E1A, but not by the RaRF binding-defective E1A mutant. Taken together, our data suggest that E1A is sequestered to the nucleolus by RaRF through a specific interaction, thereby leaving RAR in the nucleoplasm for transcriptional activation. Copyright © 2014 Elsevier Inc. All rights reserved.

Aspirin-triggered lipoxin A4 and lipoxin A4 up-regulate transcriptional corepressor NAB1 in human neutrophils.

PubMed

Qiu, F H; Devchand, P R; Wada, K; Serhan, C N

2001-12-01

Aspirin-triggered 15-epi-lipoxin A4 (ATL) is an endogenous lipid mediator that mimics the actions of native lipoxin A4, a putative "stop signal" involved in regulating resolution of inflammation. A metabolically more stable analog of ATL, 15-epi-16-(para-fluoro)-phenoxy-lipoxin A4 analog (ATLa), inhibits neutrophil recruitment in vitro and in vivo and displays potent anti-inflammatory actions. ATLa binds with high affinity to the lipoxin A4 receptor, a G protein-coupled receptor on the surface of leukocytes. In this study, we used freshly isolated human neutrophils to examine ATLa's potential for initiating rapid nuclear responses. Using differential display reverse transcription polymerase chain reaction, we identified a subset of genes that was selectively up-regulated upon short exposure of polymorphonuclear leukocytes to ATLa but not to the chemoattractant leukotriene B4 or vehicle alone. We further investigated ATLa regulation of one of the genes, NAB1, a transcriptional corepressor identified previously as a glucocorticoid-responsive gene in hamster smooth muscle cells. Treatment of human neutrophils with pertussis toxin blocked ATLa up-regulation of NAB1. In addition, ATLa stimulated NAB1 gene expression in murine lung vascular smooth muscle in vivo. These findings provide evidence for rapid transcriptional induction of a cassette of genes via an ATLa-stimulated G protein-coupled receptor pathway that is potentially protective and overlaps with the anti-inflammatory glucocorticoid regulatory circuit.

Sterile Neutrino Search at the NEOS Experiment

NASA Astrophysics Data System (ADS)

Ko, Y. J.; Kim, B. R.; Kim, J. Y.; Han, B. Y.; Jang, C. H.; Jeon, E. J.; Joo, K. K.; Kim, H. J.; Kim, H. S.; Kim, Y. D.; Lee, Jaison; Lee, J. Y.; Lee, M. H.; Oh, Y. M.; Park, H. K.; Park, H. S.; Park, K. S.; Seo, K. M.; Siyeon, Kim; Sun, G. M.; NEOS Collaboration

2017-03-01

An experiment to search for light sterile neutrinos is conducted at a reactor with a thermal power of 2.8 GW located at the Hanbit nuclear power complex. The search is done with a detector consisting of a ton of Gd-loaded liquid scintillator in a tendon gallery approximately 24 m from the reactor core. The measured antineutrino event rate is 1976 per day with a signal to background ratio of about 22. The shape of the antineutrino energy spectrum obtained from the eight-month data-taking period is compared with a hypothesis of oscillations due to active-sterile antineutrino mixing. No strong evidence of 3 +1 neutrino oscillation is found. An excess around the 5 MeV prompt energy range is observed as seen in existing longer-baseline experiments. The mixing parameter sin22 θ14 is limited up to less than 0.1 for Δ m412 ranging from 0.2 to 2.3 eV2 with a 90% confidence level.

The seven deadly sins of yellow-page advertising...and why most health-care providers commit them!

PubMed

Cody, Michael

2004-01-01

Yellow-page advertising is thought to be necessary for many practices. Purchasing such advertising is a relatively complex and expensive undertaking. This article outlines some of the pitfalls managers should consider when making such purchases. They should not be left to a neophyte. They should be considered within the general context of the practice's ability to market to patients directly, and careful attention must be given to the type, pricing, and placement of the advertising.

Valence and charge-transfer optical properties for some SinCm (m, n ≤ 12) clusters: Comparing TD-DFT, complete-basis-limit EOMCC, and benchmarks from spectroscopy

NASA Astrophysics Data System (ADS)

Lutz, Jesse J.; Duan, Xiaofeng F.; Ranasinghe, Duminda S.; Jin, Yifan; Margraf, Johannes T.; Perera, Ajith; Burggraf, Larry W.; Bartlett, Rodney J.

2018-05-01

Accurate optical characterization of the closo-Si12C12 molecule is important to guide experimental efforts toward the synthesis of nano-wires, cyclic nano-arrays, and related array structures, which are anticipated to be robust and efficient exciton materials for opto-electronic devices. Working toward calibrated methods for the description of closo-Si12C12 oligomers, various electronic structure approaches are evaluated for their ability to reproduce measured optical transitions of the SiC2, Si2Cn (n = 1-3), and Si3Cn (n = 1, 2) clusters reported earlier by Steglich and Maier [Astrophys. J. 801, 119 (2015)]. Complete-basis-limit equation-of-motion coupled-cluster (EOMCC) results are presented and a comparison is made between perturbative and renormalized non-iterative triples corrections. The effect of adding a renormalized correction for quadruples is also tested. Benchmark test sets derived from both measurement and high-level EOMCC calculations are then used to evaluate the performance of a variety of density functionals within the time-dependent density functional theory (TD-DFT) framework. The best-performing functionals are subsequently applied to predict valence TD-DFT excitation energies for the lowest-energy isomers of SinC and Sin-1C7-n (n = 4-6). TD-DFT approaches are then applied to the SinCn (n = 4-12) clusters and unique spectroscopic signatures of closo-Si12C12 are discussed. Finally, various long-range corrected density functionals, including those from the CAM-QTP family, are applied to a charge-transfer excitation in a cyclic (Si4C4)4 oligomer. Approaches for gauging the extent of charge-transfer character are also tested and EOMCC results are used to benchmark functionals and make recommendations.

Experimental evidence of trap level modulation in silicon nitride thin films by hydrogen annealing

NASA Astrophysics Data System (ADS)

Seki, Harumi; Kamimuta, Yuuichi; Mitani, Yuichiro

2018-06-01

The energy level of electron traps in silicon nitride (SiN x ) thin films was investigated by discharging current transient spectroscopy (DCTS). Results indicate that the trap level of the SiN x thin films becomes deeper with decreasing composition (N/Si) and shallower after hydrogen annealing. The dependence of the trap level on the SiN x composition and the modulation of the trap level by hydrogen annealing are possibly related to the change in the number of Si–H bonds in the SiN x thin films.

The sin in the aetiological concept of Johann Christian August Heinroth (1773-1843): Part 2: Self-guilt as turning away from reason in the framework of Heinroth's concept of the interrelationships between body and soul.

PubMed

Steinberg, Holger

2004-12-01

Throughout his work Johann Christian August Heinroth regarded sin to be the cause of mental illness. The present two-part paper investigates what exactly Heinroth understood by sin. Based on a thorough analysis of his own texts, this study shows that on the one hand Heinroth referred to sin in a Christian-Protestant sense. On the other, however, a moral-ethical code of conduct was also involved. Thus, Heinroth did not regard sin as a singular event, but rather as a life conducted in a wrong way for years or even decades, by which he meant a steady striving towards earthly, bodily satisfaction.

Selective layer disordering in intersubband Al 0.028Ga 0.972 N/AlN superlattices with silicon nitride capping layer

DOE PAGES

Wierer, Jonathan J.; Allerman, Andrew A.; Skogen, Erik J.; ...

2015-06-01

We demonstrate the selective layer disordering in intersubband Al 0.028Ga 0.972 N/AlN superlattices using a silicon nitride (SiN x) capping layer. The (SiN x) capped superlattice exhibits suppressed layer disordering under high-temperature annealing. In addition, the rate of layer disordering is reduced with increased SiN x thickness. The layer disordering is caused by Si diffusion, and the SiN x layer inhibits vacancy formation at the crystal surface and ultimately, the movement of Al and Ga atoms across the heterointerfaces. In conclusion, patterning of the SiN x layer results in selective layer disordering, an attractive method to integrate active and passivemore » III–nitride-based intersubband devices.« less

What Is Happening at Spectral Type F5 in Hyades F Stars?

NASA Technical Reports Server (NTRS)

Boehm-Vitense, Erika; Robinson, Richard; Carpenter, Kenneth; Mena-Werth, Jose

2002-01-01

Aiming at a better understanding of the mechanisms heating the chromospheres, transition regions, and coronae of cool stars, we study ultraviolet, low-resolution Hubble Space Telescope/Space Telescope Imaging Spectrograph spectra of Hyades main-sequence F stars. We study the B-V dependence(s) of the chromospheric and transition layer emission line fluxes and their dependences on rotational velocities. We find that the transition layer emission line fluxes and also those of strong chromospheric lines decrease steeply between B-V = 0.42 and 0.45, i.e., at spectral type F5, for which the rotational velocities also decrease steeply. The magnitude of the line-flux decrease increases for lines of ions with increasing degree of ionization. This shows that the line-flux decrease is not due to a change in the surface filling factor but rather due to a change of the relative importance of different heating mechanisms. For early F stars with B-V < 0.42 we find for the transition layer emission lines increasing fluxes for increasing v sin i, indicating magnetohydrodynamic heating. The v sin i dependence is strongest for the high-ionization lines. On the other hand, the low chromospheric lines show no dependence on v sin i, indicating acoustic shock heating for these layers. This also contributes to the heating of the transition layers. The Mg II and Ca II lines show decreasing fluxes for increasing v sin i, as long as v sin i is less than approx. 40 km/s. The coronal X-ray emission also decreases for increasing v sin i, except for v sin i larger than approx. 100 km/s. We have at present no explanation for this behavior. For late F stars the chromospheric lines show v sin i dependences similar to those observed for early F stars, again indicating acoustic heating for these layers. We were unable to determine the v sin i dependence of the transition layer lines because of too few single star targets. The decrease of emission line fluxes at the spectral type F5, with steeply decreasing v sin i, indicates, however, a decreasing contribution of magnetohydrodynamic heating for the late F stars. The X-ray emission for the late F stars increases for increasing v sin i, indicating magnetohydrodynamic heating for the coronae of the late F stars, different from the early F stars.

Adverse Outcomes After Palliative Radiation Therapy for Uncomplicated Spine Metastases: Role of Spinal Instability and Single-Fraction Radiation Therapy

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

Lam, Tai-Chung, E-mail: lamtaichung@gmail.com; Uno, Hajime; Krishnan, Monica

2015-10-01

Purpose: Level I evidence demonstrates equivalent pain response after single-fraction (SF) or multifraction (MF) radiation therapy (RT) for bone metastases. The purpose of this study is to provide additional data to inform the incidence and predictors of adverse outcomes after RT for spine metastases. Methods and Materials: At a single institution, 299 uncomplicated spine metastases (without cord compression, prior RT, or surgery) treated with RT from 2008 to 2013 were retrospectively reviewed. The spinal instability neoplastic score (SINS) was used to assess spinal instability. The primary outcome was time to first spinal adverse event (SAE) at the site, including symptomaticmore » vertebral fracture, hospitalization for site-related pain, salvage surgery, interventional procedure, new neurologic symptoms, or cord compression. Fine and Gray's multivariable model assessed associations of the primary outcome with SINS, SF RT, and other significant baseline factors. Propensity score matched analysis further assessed the relationship of SF RT to first SAEs. Results: The cumulative incidence of first SAE after SF RT (n=66) was 6.8% at 30 days, 16.9% at 90 days, and 23.6% at 180 days. For MF RT (n=233), the incidence was 3.5%, 6.4%, and 9.2%, respectively. In multivariable analysis, SF RT (hazard ratio [HR] = 2.8, 95% confidence interval [CI] 1.5-5.2, P=.001) and SINS ≥11 (HR=2.5 , 95% CI 1.3-4.9, P=.007) were predictors of the incidence of first SAE. In propensity score matched analysis, first SAEs had developed in 22% of patients with SF RT versus 6% of those with MF RT cases (HR=3.9, 95% CI 1.6-9.6, P=.003) at 90 days after RT. Conclusion: In uncomplicated spinal metastases treated with RT alone, spinal instability with SINS ≥11 and SF RT were associated with a higher rate of SAEs.« less

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

Pavlovski, K.; Kolbas, V.; Southworth, J.

We present a spectroscopic study of the eclipsing binary system AS Camelopardalis, the first such study based on phase-resolved CCD echelle spectra. Via a spectral disentangling analysis we measure the minimum masses of the stars to be M{sub A}sin {sup 3} i = 3.213 {+-} 0.032 M{sub sun} and M{sub B}sin {sup 3} i = 2.323 {+-} 0.032 M{sub sun}, their effective temperatures to be T{sub eff}(A) = 12, 840 {+-} 120 K and T{sub eff}(B) = 10, 580 {+-} 240 K, and their projected rotational velocities to be v{sub A}sin i{sub A} = 14.5 {+-} 0.1 km s{sup -1}more » and v{sub B}sin i{sub B} {<=} 4.6 {+-} 0.1 km s{sup -1}. These projected rotational velocities appear to be much lower than the synchronous values. We show that measurements of the apsidal motion of the system suffer from a degeneracy between orbital eccentricity and apsidal motion rate. We use our spectroscopically measured e = 0.164 {+-} 0.004 to break this degeneracy and measure {omega}-dot{sub obs} = 0{sup 0}.133{+-}0{sup 0}.010 yr{sup -1}. Subtracting the relativistic contribution of {omega}-dot{sub GR} = 0{sup 0}.0963{+-}0{sup 0}0002 yr{sup -1} yields the contribution due to tidal torques: {omega}-dot{sub cl} = 0{sup 0}.037{+-}0{sup 0}.010 yr{sup -1}. This value is much smaller than the rate predicted by stellar theory, 0.{sup 0}40-0.{sup 0}87 yr{sup -1}. We interpret this as a misalignment between the orbital axis of the close binary and the rotational axes of its component stars, which also explains their apparently low rotational velocities. The observed and predicted apsidal motion rates could be brought into agreement if the stars were rotating three times faster than synchronous about axes perpendicular to the orbital axis. Measurement of the Rossiter-McLaughlin effect can be used to confirm this interpretation.« less

Detection of planet candidates around K giants. HD 40956, HD 111591, and HD 113996

NASA Astrophysics Data System (ADS)

Jeong, G.; Lee, B.-C.; Han, I.; Omiya, M.; Izumiura, H.; Sato, B.; Harakawa, H.; Kambe, E.; Mkrtichian, D.

2018-02-01

Aims: The purpose of this paper is to detect and investigate the nature of long-term radial velocity (RV) variations of K-type giants and to confirm planetary companions around the stars. Methods: We have conducted two planet search programs by precise RV measurement using the 1.8 m telescope at Bohyunsan Optical Astronomy Observatory (BOAO) and the 1.88 m telescope at Okayama Astrophysical Observatory (OAO). The BOAO program searches for planets around 55 early K giants. The OAO program is looking for 190 G-K type giants. Results: In this paper, we report the detection of long-period RV variations of three K giant stars, HD 40956, HD 111591, and HD 113996. We investigated the cause of the observed RV variations and conclude the substellar companions are most likely the cause of the RV variations. The orbital analyses yield P = 578.6 ± 3.3 d, m sin i = 2.7 ± 0.6 MJ, a = 1.4 ± 0.1 AU for HD 40956; P = 1056.4 ± 14.3 d, m sin i = 4.4 ± 0.4 MJ, a = 2.5 ± 0.1 AU for HD 111591; P = 610.2 ± 3.8 d, m sin i = 6.3 ± 1.0 MJ, a = 1.6 ± 0.1 AU for HD 113996. Based on observations made with the BOES at BOAO in Korea and HIDES at OAO in Japan.Tables 3-5 are only available at the CDS via anonymous ftp to http://cdsarc.u-strasbg.fr (http://130.79.128.5) or via http://cdsarc.u-strasbg.fr/viz-bin/qcat?J/A+A/610/A3

Oxygen impact on the electronic and vibrational properties of black phosphorus probed by synchrotron infrared nanospectroscopy

NASA Astrophysics Data System (ADS)

Grasseschi, D.; Bahamon, D. A.; Maia, F. C. B.; Castro Neto, A. H.; Freitas, R. O.; de Matos, C. J. S.

2017-09-01

Black phosphorus (BP) is a layered crystalline structure presenting a thickness-tunable direct bandgap and a high charge carrier mobility, with, therefore, enormous interest to photonics, optoelectronics and electronics. However, BP’s high susceptibility to oxidation when exposed to ambient conditions is a critical challenge for its implementation into functional systems. Here, we investigate the degradation of BP flakes exposed to various environmental conditions by synchrotron infrared nanospectroscopy (SINS). As a near-field based technique, SINS provides sub-diffractional mid-infrared images and spectra from nano-sized domains. Supported by density functional theory (DFT) calculations, our SINS spectra reveal the formation of nanoscale PO x domains, with x between 0.5 and 1, and a 100 meV red shift in the bandgap of flakes exposed to air for a few minutes. On the other hand, exposure to air for 24 h led to the preferential formation of H3PO4, with complete removal of the electronic transitions from the mid-infrared spectral window, while a long (1 month) exposure to low O2 levels mainly led to the formation of P4O8 and P4O9 species. The SINS analysis allows correlating the morphology of oxidized samples to the oxide type, thus, contributing to a comprehensive characterization of the BP degradation process.

Muon Neutrino Disappearance Measurement at MINOS+

NASA Astrophysics Data System (ADS)

Carroll, T. J.

2017-09-01

We report new measurements of neutrino oscillation parameters from the MINOS+ experiment using the first two years of accelerator beam exposure combined with the complete set of accelerator and atmospheric data from MINOS. The analysis combined νµ disappearance and νe appearance data using the three-flavor oscillation formalism. Our results give the confidence limits ≤ft| {Δ m32^2} \\right| = ≤ft[ {2.33 - 2.51} \\right] × {10 - 3}{{ e}}{{{V}}^2} (68% C.L.) and sin2 θ 23 = 0.35 - 0.65 (90% C.L.) for normal hierarchy, and ≤ft| {Δ m32^2} \\right| = ≤ft[ {2.37 - 2.57} \\right] × {10 - 3}{{ e}}{{{V}}^2} (68% C.L.) and sin2 θ 23 = 0.35 - 0.66 (90% C.L.) for inverted hierarchy.

Observation of deficit in NuMI neutrino-induced rock and non-fiducial muons in MINOS Far Detector and measurement of neutrino oscillation parameters

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

McGowan, Aaron Michael

2007-08-01

The MINOS (Main Injector Neutrino Oscillation Search) experiment has observed muon neutrino disappearance consistent with the oscillation hypothesis tested by Super-Kamiokande and K2K. The survival probability for v μ is given approximately by 1 - sin2 2θ 23sin 2(1.27Δmmore » $$2\\atop{32}$$L/E), whereθ 23 and Δm$$2\\atop{32}$$ are the mixing angle and difference in mass squared in eV 2/c 4 between the mass eigenstates v 3 and v 2, L is the distance traveled in km, and E is the neutrino energy in GeV. In the Near Detector at Fermilab, a measurement of the energy spectrum of the NuMI neutrino beam is made 1 km from the beam target. The neutrinos travel to the Far Detector in the Soudan Underground Laboratory, where another measurement of the energy spectrum is made 735 km from the target. MINOS measures |Δm$$2\\atop{32}$$| and sin 22θ 23 by comparing the ND and FD neutrino energy spectra. In this dissertation, a n alternate method is presented that utilizes rock muons, a class of events that occur when a v μ interaction takes place in the rock surrounding the FD. Many muons that result from these interactions penetrate the rock and reach the detector. Muon events from v μ interactions in the non-fiducial volume of the FD are also used in this analysis. The distribution of reconstructed muon momentum and direction relative to the beam is predicted by Monte Carlo simulation, normalized by the measured v μ energy spectrum at the ND. In the first year of NuMI running (an exposure of 1.27x10 20 protons on target) 117 selected events are observed below 3.0 GeV/c, where 150.2±16.1 events are expected. When a fit is performed to events below 10.0 GeV/c, the null (no disappearance) hypothesis is ruled out at significance level α = 4.2 x 10 -3. The data are consistent with the oscillation hypothesis given parameter values |Δm$$2\\atop{32}$$| = 2.32 ±$$1.06\\atop{0.75}$$x 10 -3 eV 2/c 4 (stat+sys) and sin 22θ 23> 0.48 (68% CL) which is in agreement with the published MINOS result |Δm$$2\\atop{32}$$| = 2.74 ±$$0.44\\atop{0.26}$$ x 10 -3 eV 2/c 4 (stat+sys) and sin 22θ 23 > 0.87 (68% CL).« less

Effect of SiN x diffusion barrier thickness on the structural properties and photocatalytic activity of TiO2 films obtained by sol-gel dip coating and reactive magnetron sputtering.

PubMed

Ghazzal, Mohamed Nawfal; Aubry, Eric; Chaoui, Nouari; Robert, Didier

2015-01-01

We investigate the effect of the thickness of the silicon nitride (SiN x ) diffusion barrier on the structural and photocatalytic efficiency of TiO2 films obtained with different processes. We show that the structural and photocatalytic efficiency of TiO2 films produced using soft chemistry (sol-gel) and physical methods (reactive sputtering) are affected differentially by the intercalating SiN x diffusion barrier. Increasing the thickness of the SiN x diffusion barrier induced a gradual decrease of the crystallite size of TiO2 films obtained by the sol-gel process. However, TiO2 obtained using the reactive sputtering method showed no dependence on the thickness of the SiN x barrier diffusion. The SiN x barrier diffusion showed a beneficial effect on the photocatalytic efficiency of TiO2 films regardless of the synthesis method used. The proposed mechanism leading to the improvement in the photocatalytic efficiency of the TiO2 films obtained by each process was discussed.

Fuzzy adaptive integration scheme for low-cost SINS/GPS navigation system

NASA Astrophysics Data System (ADS)

Nourmohammadi, Hossein; Keighobadi, Jafar

2018-01-01

Due to weak stand-alone accuracy as well as poor run-to-run stability of micro-electro mechanical system (MEMS)-based inertial sensors, special approaches are required to integrate low-cost strap-down inertial navigation system (SINS) with global positioning system (GPS), particularly in long-term applications. This paper aims to enhance long-term performance of conventional SINS/GPS navigation systems using a fuzzy adaptive integration scheme. The main concept behind the proposed adaptive integration is the good performance of attitude-heading reference system (AHRS) in low-accelerated motions and its degradation in maneuvered or accelerated motions. Depending on vehicle maneuvers, gravity-based attitude angles can be intelligently utilized to improve orientation estimation in the SINS. Knowledge-based fuzzy inference system is developed for decision-making between the AHRS and the SINS according to vehicle maneuvering conditions. Inertial measurements are the main input data of the fuzzy system to determine the maneuvering level during the vehicle motions. Accordingly, appropriate weighting coefficients are produced to combine the SINS/GPS and the AHRS, efficiently. The assessment of the proposed integrated navigation system is conducted via real data in airborne tests.

Histone Deacetylase 3 Prepares Brown Adipose Tissue For Acute Thermogenic Challenge

PubMed Central

Emmett, Matthew J.; Lim, Hee-Woong; Jager, Jennifer; Richter, Hannah J.; Adlanmerini, Marine; Peed, Lindsey C.; Briggs, Erika R.; Steger, David J.; Ma, Tao; Sims, Carrie A.; Baur, Joseph A.; Pei, Liming; Won, Kyoung-Jae; Seale, Patrick; Gerhart-Hines, Zachary; Lazar, Mitchell A.

2017-01-01

Brown adipose tissue (BAT) is a thermogenic organ that dissipates chemical energy as heat to protect animals against hypothermia and to counteract metabolic disease1. However, the transcriptional mechanisms that determine BAT thermogenic capacity prior to environmental cold are unknown. Here we show that Histone Deacetylase 3 (HDAC3) is required to activate BAT enhancers to ensure thermogenic aptitude. Mice with BAT-specific genetic ablation of HDAC3 become severely hypothermic and succumb to acute cold exposure. UCP1 is nearly absent in BAT lacking HDAC3 and there is also marked down-regulation of mitochondrial oxidative phosphorylation (OXPHOS) genes resulting in diminished mitochondrial respiration. Remarkably, although HDAC3 acts canonically as a transcriptional corepressor2, it functions as a coactivator of Estrogen-Related Receptor α (ERRα) in BAT. HDAC3 coactivation of ERRα is mediated by deacetylation of PGC-1α and is required for the transcription of Ucp1, Pgc-1α and OXPHOS genes. Importantly, HDAC3 promotes the basal transcription of these genes independent of adrenergic stimulation. Thus, HDAC3 uniquely primes Ucp1 and the thermogenic transcriptional program to maintain a critical capacity for thermogenesis in BAT that can be rapidly engaged upon exposure to dangerously cold temperature. PMID:28614293

Vasodilator responses to nitric oxide are enhanced in mesenteric arteries of portal hypertensive rats.

PubMed

Heinemann, A; Stauber, R E

1996-09-01

Nitric oxide (NO) is discussed as a mediator of the splanchnic hyperaemia in portal hypertension. We assessed the vasorelaxation by the NO-dependent vasodilator acetylcholine, the NO donor 3-morpholino-sydnonimine (SIN-1) and forskolin, a stimulator of the adenylate cyclase pathway in potassium-preconstricted isolated perfused mesenteric arteries of portal vein-ligated and sham-operated rats. Dilator responses to acetylcholine and SIN-1 were significantly enhanced in vessels of portal vein-ligated rats as compared to sham-operated rats, whereas no difference was found in forskolin-induced vasodilatation. This suggests enhanced reactivity of the vasculature to NO in experimental portal hypertension.

First measurement of muon-neutrino disappearance in NOvA

NASA Astrophysics Data System (ADS)

Adamson, P.; Ader, C.; Andrews, M.; Anfimov, N.; Anghel, I.; Arms, K.; Arrieta-Diaz, E.; Aurisano, A.; Ayres, D. S.; Backhouse, C.; Baird, M.; Bambah, B. A.; Bays, K.; Bernstein, R.; Betancourt, M.; Bhatnagar, V.; Bhuyan, B.; Bian, J.; Biery, K.; Blackburn, T.; Bocean, V.; Bogert, D.; Bolshakova, A.; Bowden, M.; Bower, C.; Broemmelsiek, D.; Bromberg, C.; Brunetti, G.; Bu, X.; Butkevich, A.; Capista, D.; Catano-Mur, E.; Chase, T. R.; Childress, S.; Choudhary, B. C.; Chowdhury, B.; Coan, T. E.; Coelho, J. A. B.; Colo, M.; Cooper, J.; Corwin, L.; Cronin-Hennessy, D.; Cunningham, A.; Davies, G. S.; Davies, J. P.; Del Tutto, M.; Derwent, P. F.; Deepthi, K. N.; Demuth, D.; Desai, S.; Deuerling, G.; Devan, A.; Dey, J.; Dharmapalan, R.; Ding, P.; Dixon, S.; Djurcic, Z.; Dukes, E. C.; Duyang, H.; Ehrlich, R.; Feldman, G. J.; Felt, N.; Fenyves, E. J.; Flumerfelt, E.; Foulkes, S.; Frank, M. J.; Freeman, W.; Gabrielyan, M.; Gallagher, H. R.; Gebhard, M.; Ghosh, T.; Gilbert, W.; Giri, A.; Goadhouse, S.; Gomes, R. A.; Goodenough, L.; Goodman, M. C.; Grichine, V.; Grossman, N.; Group, R.; Grudzinski, J.; Guarino, V.; Guo, B.; Habig, A.; Handler, T.; Hartnell, J.; Hatcher, R.; Hatzikoutelis, A.; Heller, K.; Howcroft, C.; Huang, J.; Huang, X.; Hylen, J.; Ishitsuka, M.; Jediny, F.; Jensen, C.; Jensen, D.; Johnson, C.; Jostlein, H.; Kafka, G. K.; Kamyshkov, Y.; Kasahara, S. M. S.; Kasetti, S.; Kephart, K.; Koizumi, G.; Kotelnikov, S.; Kourbanis, I.; Krahn, Z.; Kravtsov, V.; Kreymer, A.; Kulenberg, Ch.; Kumar, A.; Kutnink, T.; Kwarciancy, R.; Kwong, J.; Lang, K.; Lee, A.; Lee, W. M.; Lee, K.; Lein, S.; Liu, J.; Lokajicek, M.; Lozier, J.; Lu, Q.; Lucas, P.; Luchuk, S.; Lukens, P.; Lukhanin, G.; Magill, S.; Maan, K.; Mann, W. A.; Marshak, M. L.; Martens, M.; Martincik, J.; Mason, P.; Matera, K.; Mathis, M.; Matveev, V.; Mayer, N.; McCluskey, E.; Mehdiyev, R.; Merritt, H.; Messier, M. D.; Meyer, H.; Miao, T.; Michael, D.; Mikheyev, S. P.; Miller, W. H.; Mishra, S. R.; Mohanta, R.; Moren, A.; Mualem, L.; Muether, M.; Mufson, S.; Musser, J.; Newman, H. B.; Nelson, J. K.; Niner, E.; Norman, A.; Nowak, J.; Oksuzian, Y.; Olshevskiy, A.; Oliver, J.; Olson, T.; Paley, J.; Pandey, P.; Para, A.; Patterson, R. B.; Pawloski, G.; Pearson, N.; Perevalov, D.; Pershey, D.; Peterson, E.; Petti, R.; Phan-Budd, S.; Piccoli, L.; Pla-Dalmau, A.; Plunkett, R. K.; Poling, R.; Potukuchi, B.; Psihas, F.; Pushka, D.; Qiu, X.; Raddatz, N.; Radovic, A.; Rameika, R. A.; Ray, R.; Rebel, B.; Rechenmacher, R.; Reed, B.; Reilly, R.; Rocco, D.; Rodkin, D.; Ruddick, K.; Rusack, R.; Ryabov, V.; Sachdev, K.; Sahijpal, S.; Sahoo, H.; Samoylov, O.; Sanchez, M. C.; Saoulidou, N.; Schlabach, P.; Schneps, J.; Schroeter, R.; Sepulveda-Quiroz, J.; Shanahan, P.; Sherwood, B.; Sheshukov, A.; Singh, J.; Singh, V.; Smith, A.; Smith, D.; Smolik, J.; Solomey, N.; Sotnikov, A.; Sousa, A.; Soustruznik, K.; Stenkin, Y.; Strait, M.; Suter, L.; Talaga, R. L.; Tamsett, M. C.; Tariq, S.; Tas, P.; Tesarek, R. J.; Thayyullathil, R. B.; Thomsen, K.; Tian, X.; Tognini, S. C.; Toner, R.; Trevor, J.; Tzanakos, G.; Urheim, J.; Vahle, P.; Valerio, L.; Vinton, L.; Vrba, T.; Waldron, A. V.; Wang, B.; Wang, Z.; Weber, A.; Wehmann, A.; Whittington, D.; Wilcer, N.; Wildberger, R.; Wildman, D.; Williams, K.; Wojcicki, S. G.; Wood, K.; Xiao, M.; Xin, T.; Yadav, N.; Yang, S.; Zadorozhnyy, S.; Zalesak, J.; Zamorano, B.; Zhao, A.; Zirnstein, J.; Zwaska, R.; NOvA Collaboration

2016-03-01

This paper reports the first measurement using the NOvA detectors of νμ disappearance in a νμ beam. The analysis uses a 14 kton-equivalent exposure of 2.74 ×1020 protons-on-target from the Fermilab NuMI beam. Assuming the normal neutrino mass hierarchy, we measure Δ m322=(2.52-0.18+0.20)×10-3 eV2 and sin2θ23 in the range 0.38-0.65, both at the 68% confidence level, with two statistically degenerate best-fit points at sin2θ23=0.43 and 0.60. Results for the inverted mass hierarchy are also presented.

Sinomenine attenuates renal fibrosis through Nrf2-mediated inhibition of oxidative stress and TGFβ signaling

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

Qin, Tian

Renal fibrosis is the common feature of chronic kidney disease and mainly mediated by TGFβ-associated pro-fibrogenic signaling, which causes excessive extracellular matrix accumulation and successive loss of kidney functions. Sinomenine (SIN), an alkaloid derived from medicinal herb extensively used in treatment of rheumatoid arthritis and various inflammatory disorders, displays renal protective properties in experimental animals; however its pharmacological potency against renal fibrosis is not explored. In this study we report that SIN possesses strong anti-renal fibrosis functions in kidney cell and in mouse fibrotic kidney. SIN beneficially modulated the pro-fibrogenic protein expression in TGFβ-treated kidney cells and attenuated the renalmore » fibrotic pathogenesis incurred by unilateral ureteral obstruction (UUO), which correlated with its activation of Nrf2 signaling - the key defender against oxidative stress with anti-fibrotic potentials. Further investigation on its regulation of Nrf2 downstream events revealed that SIN significantly balanced oxidative stress via improving the expression and activity of anti-oxidant and detoxifying enzymes, and interrupted the pro-fibrogenic signaling of TGFβ/Smad and Wnt/β-catenin. Even more impressively SIN achieved its anti-fibrotic activities in an Nrf2-dependent manner, suggesting that SIN regulation of Nrf2-associated anti-fibrotic activities constitutes a critical component of SIN's renoprotective functions. Collectively our studies have demonstrated a novel anti-fibrotic property of SIN and its upstream events and provided a molecular basis for SIN's potential applications in treatment of renal fibrosis-associated kidney disorders. - Highlights: • Sinomenine has strong potency of inhibiting renal fibrosis in UUO mouse kidney. • Sinomenine attenuates the expression of profibrogenic proteins. • Sinomenine balances renal fibrosis-associated oxidative stress. • Sinomenine mitigates profibrogenic signaling of TGBβ/Smad and Wnt/β-catenin. • Sinomenine exerts anti-renal fibrotic functions mainly via activating Nrf2 pathways.« less

Biofunctionalized silicon nitride platform for sensing applications.

PubMed

Hoi, Hiofan; Rezaie, Salva S; Gong, Lu; Sen, Payel; Zeng, Hongbo; Montemagno, Carlo; Gupta, Manisha

2018-04-15

Silicon nitride (SiN x ) based biosensors have the potential to converge on the technological achievements of semiconductor microfabrication and biotechnology. Development of biofunctionalized SiN x surface and its integration with other devices will allow us to integrate the biosensing capability with probe control, data acquisition and data processing. Here we use the hydrogen plasma generated by inductively coupled plasma-reactive ion etching (ICP-RIE) technique to produce amino-functionality on the surface of SiN x which can then be readily used for biomolecule immobilization. ICP-RIE produces high-density hydrogen ions/radicals at low energy, which produces high-density amino group on the SiN x surface within a short duration of time and with minimal surface damage. In this work, we have demonstrated selective amination of SiN x surface as compared to Si surface. The as-activated SiN x surface can be readily biofunctionalized with both protein and oligonucleotide through covalent immobilization. N-5-azido-2-nitrobenzoyloxysuccinimide, a photoactivable amino reactive bifunctional crosslinker, was used and greater than 90% surface coverage was achieved for protein immobilization. In addition, ssDNA immobilization and hybridization with its complemented strand was shown. Thus, we demonstrate a uniform, reliable, fast and economical technique for creating biofunctionalized SiN x surface that can be used for developing compact high-sensitivity biosensors. Copyright © 2017 Elsevier B.V. All rights reserved.

Measurement of sin2θefflept using e+e- pairs from γ*/Z bosons produced in p p ¯ collisions at a center-of-momentum energy of 1.96 TeV

NASA Astrophysics Data System (ADS)

Aaltonen, T.; Amerio, S.; Amidei, D.; Anastassov, A.; Annovi, A.; Antos, J.; Apollinari, G.; Appel, J. A.; Arisawa, T.; Artikov, A.; Asaadi, J.; Ashmanskas, W.; Auerbach, B.; Aurisano, A.; Azfar, F.; Badgett, W.; Bae, T.; Barbaro-Galtieri, A.; Barnes, V. E.; Barnett, B. A.; Barria, P.; Bartos, P.; Bauce, M.; Bedeschi, F.; Behari, S.; Bellettini, G.; Bellinger, J.; Benjamin, D.; Beretvas, A.; Bhatti, A.; Bland, K. R.; Blumenfeld, B.; Bocci, A.; Bodek, A.; Bortoletto, D.; Boudreau, J.; Boveia, A.; Brigliadori, L.; Bromberg, C.; Brucken, E.; Budagov, J.; Budd, H. S.; Burkett, K.; Busetto, G.; Bussey, P.; Butti, P.; Buzatu, A.; Calamba, A.; Camarda, S.; Campanelli, M.; Canelli, F.; Carls, B.; Carlsmith, D.; Carosi, R.; Carrillo, S.; Casal, B.; Casarsa, M.; Castro, A.; Catastini, P.; Cauz, D.; Cavaliere, V.; Cerri, A.; Cerrito, L.; Chen, Y. C.; Chertok, M.; Chiarelli, G.; Chlachidze, G.; Cho, K.; Chokheli, D.; Clark, A.; Clarke, C.; Convery, M. E.; Conway, J.; Corbo, M.; Cordelli, M.; Cox, C. A.; Cox, D. J.; Cremonesi, M.; Cruz, D.; Cuevas, J.; Culbertson, R.; d'Ascenzo, N.; Datta, M.; de Barbaro, P.; Demortier, L.; Deninno, M.; D'Errico, M.; Devoto, F.; Di Canto, A.; Di Ruzza, B.; Dittmann, J. R.; Donati, S.; D'Onofrio, M.; Dorigo, M.; Driutti, A.; Ebina, K.; Edgar, R.; Erbacher, R.; Errede, S.; Esham, B.; Farrington, S.; Fernández Ramos, J. P.; Field, R.; Flanagan, G.; Forrest, R.; Franklin, M.; Freeman, J. C.; Frisch, H.; Funakoshi, Y.; Galloni, C.; Garfinkel, A. F.; Garosi, P.; Gerberich, H.; Gerchtein, E.; Giagu, S.; Giakoumopoulou, V.; Gibson, K.; Ginsburg, C. M.; Giokaris, N.; Giromini, P.; Glagolev, V.; Glenzinski, D.; Gold, M.; Goldin, D.; Golossanov, A.; Gomez, G.; Gomez-Ceballos, G.; Goncharov, M.; González López, O.; Gorelov, I.; Goshaw, A. T.; Goulianos, K.; Gramellini, E.; Grosso-Pilcher, C.; Guimaraes da Costa, J.; Hahn, S. R.; Han, J. Y.; Happacher, F.; Hara, K.; Hare, M.; Harr, R. F.; Harrington-Taber, T.; Hatakeyama, K.; Hays, C.; Heinrich, J.; Herndon, M.; Hocker, A.; Hong, Z.; Hopkins, W.; Hou, S.; Hughes, R. E.; Husemann, U.; Hussein, M.; Huston, J.; Introzzi, G.; Iori, M.; Ivanov, A.; James, E.; Jang, D.; Jayatilaka, B.; Jeon, E. J.; Jindariani, S.; Jones, M.; Joo, K. K.; Jun, S. Y.; Junk, T. R.; Kambeitz, M.; Kamon, T.; Karchin, P. E.; Kasmi, A.; Kato, Y.; Ketchum, W.; Keung, J.; Kilminster, B.; Kim, D. H.; Kim, H. S.; Kim, J. E.; Kim, M. J.; Kim, S. H.; Kim, S. B.; Kim, Y. J.; Kim, Y. K.; Kimura, N.; Kirby, M.; Kondo, K.; Kong, D. J.; Konigsberg, J.; Kotwal, A. V.; Kreps, M.; Kroll, J.; Kruse, M.; Kuhr, T.; Kurata, M.; Laasanen, A. T.; Lammel, S.; Lancaster, M.; Lannon, K.; Latino, G.; Lee, H. S.; Lee, J. S.; Leo, S.; Leone, S.; Lewis, J. D.; Limosani, A.; Lipeles, E.; Lister, A.; Liu, Q.; Liu, T.; Lockwitz, S.; Loginov, A.; Lucchesi, D.; Lucà, A.; Lueck, J.; Lujan, P.; Lukens, P.; Lungu, G.; Lys, J.; Lysak, R.; Madrak, R.; Maestro, P.; Malik, S.; Manca, G.; Manousakis-Katsikakis, A.; Marchese, L.; Margaroli, F.; Marino, P.; Matera, K.; Mattson, M. E.; Mazzacane, A.; Mazzanti, P.; McNulty, R.; Mehta, A.; Mehtala, P.; Mesropian, C.; Miao, T.; Mietlicki, D.; Mitra, A.; Miyake, H.; Moed, S.; Moggi, N.; Moon, C. S.; Moore, R.; Morello, M. J.; Mukherjee, A.; Muller, Th.; Murat, P.; Mussini, M.; Nachtman, J.; Nagai, Y.; Naganoma, J.; Nakano, I.; Napier, A.; Nett, J.; Nigmanov, T.; Nodulman, L.; Noh, S. Y.; Norniella, O.; Oakes, L.; Oh, S. H.; Oh, Y. D.; Okusawa, T.; Orava, R.; Ortolan, L.; Pagliarone, C.; Palencia, E.; Palni, P.; Papadimitriou, V.; Parker, W.; Pauletta, G.; Paulini, M.; Paus, C.; Phillips, T. J.; Piacentino, G.; Pianori, E.; Pilot, J.; Pitts, K.; Plager, C.; Pondrom, L.; Poprocki, S.; Potamianos, K.; Pranko, A.; Prokoshin, F.; Ptohos, F.; Punzi, G.; Redondo Fernández, I.; Renton, P.; Rescigno, M.; Rimondi, F.; Ristori, L.; Robson, A.; Rodriguez, T.; Rolli, S.; Ronzani, M.; Roser, R.; Rosner, J. L.; Ruffini, F.; Ruiz, A.; Russ, J.; Rusu, V.; Sakumoto, W. K.; Sakurai, Y.; Santi, L.; Sato, K.; Saveliev, V.; Savoy-Navarro, A.; Schlabach, P.; Schmidt, E. E.; Schwarz, T.; Scodellaro, L.; Scuri, F.; Seidel, S.; Seiya, Y.; Semenov, A.; Sforza, F.; Shalhout, S. Z.; Shears, T.; Shepard, P. F.; Shimojima, M.; Shochet, M.; Shreyber-Tecker, I.; Simonenko, A.; Sliwa, K.; Smith, J. R.; Snider, F. D.; Song, H.; Sorin, V.; St. Denis, R.; Stancari, M.; Stentz, D.; Strologas, J.; Sudo, Y.; Sukhanov, A.; Suslov, I.; Takemasa, K.; Takeuchi, Y.; Tang, J.; Tecchio, M.; Teng, P. K.; Thom, J.; Thomson, E.; Thukral, V.; Toback, D.; Tokar, S.; Tollefson, K.; Tomura, T.; Tonelli, D.; Torre, S.; Torretta, D.; Totaro, P.; Trovato, M.; Ukegawa, F.; Uozumi, S.; Vázquez, F.; Velev, G.; Vellidis, C.; Vernieri, C.; Vidal, M.; Vilar, R.; Vizán, J.; Vogel, M.; Volpi, G.; Wagner, P.; Wallny, R.; Wang, S. M.; Waters, D.; Wester, W. C.; Whiteson, D.; Wicklund, A. B.; Wilbur, S.; Williams, H. H.; Wilson, J. S.; Wilson, P.; Winer, B. L.; Wittich, P.; Wolbers, S.; Wolfe, H.; Wright, T.; Wu, X.; Wu, Z.; Yamamoto, K.; Yamato, D.; Yang, T.; Yang, U. K.; Yang, Y. C.; Yao, W.-M.; Yeh, G. P.; Yi, K.; Yoh, J.; Yorita, K.; Yoshida, T.; Yu, G. B.; Yu, I.; Zanetti, A. M.; Zeng, Y.; Zhou, C.; Zucchelli, S.; CDF Collaboration

2016-06-01

At the Fermilab Tevatron proton-antiproton (p p ¯) collider, Drell-Yan lepton pairs are produced in the process p p ¯→e+e-+X through an intermediate γ*/Z boson. The forward-backward asymmetry in the polar-angle distribution of the e- as a function of the e+e--pair mass is used to obtain sin2θefflept, the effective leptonic determination of the electroweak-mixing parameter sin2θW. The measurement sample, recorded by the Collider Detector at Fermilab (CDF), corresponds to 9.4 fb-1 of integrated luminosity from p p ¯ collisions at a center-of-momentum energy of 1.96 TeV, and is the full CDF Run II data set. The value of sin2θefflept is found to be 0.23248 ±0.00053 . The combination with the previous CDF measurement based on μ+μ- pairs yields sin2θefflept=0.23221±0.00046 . This result, when interpreted within the specified context of the standard model assuming sin2θW=1 - MW2/MZ2 and that the W - and Z -boson masses are on-shell, yields sin2θW=0.22400 ±0.00045 , or equivalently a W -boson mass of 80.328 ±0.024 GeV /c2 .

Ultralow power switching in a silicon-rich SiNy/SiNx double-layer resistive memory device.

PubMed

Kim, Sungjun; Chang, Yao-Feng; Kim, Min-Hwi; Bang, Suhyun; Kim, Tae-Hyeon; Chen, Ying-Chen; Lee, Jong-Ho; Park, Byung-Gook

2017-07-26

Here we demonstrate low-power resistive switching in a Ni/SiN y /SiN x /p ++ -Si device by proposing a double-layered structure (SiN y /SiN x ), where the two SiN layers have different trap densities. The LRS was measured to be as low as 1 nA at a voltage of 1 V, because the SiN x layer maintains insulating properties for the LRS. The single-layered device suffers from uncontrollability of the conducting path, accompanied by the inherent randomness of switching parameters, weak immunity to breakdown during the reset process, and a high operating current. On the other hand, for a double-layered device, the effective conducting path in each layer, which can determine the operating current, can be well controlled by the I CC during the initial forming and set processes. A one-step forming and progressive reset process is observed for a low-power mode, which differs from the high-power switching mode that shows a two-step forming and reset process. Moreover, nonlinear behavior in the LRS, whose origin can be attributed to the P-F conduction and F-N tunneling driven by abundant traps in the silicon-rich SiN x layer, would be beneficial for next-generation nonvolatile memory applications by using a conventional passive SiN x layer as an active dielectric.

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

Wang, Cheng-hu; Cao, Guo-Fan; Jiang, Qin, E-mail: Jqin710@vip.sina.com

Highlights: Black-Right-Pointing-Pointer TNF-{alpha} induces MMP-9 expression and secretion to promote RPE cell migration. Black-Right-Pointing-Pointer MAPK activation is not critical for TNF-{alpha}-induced MMP-9 expression. Black-Right-Pointing-Pointer Akt and mTORC1 signaling mediate TNF-{alpha}-induced MMP-9 expression. Black-Right-Pointing-Pointer SIN1 knockdown showed no significant effect on MMP-9 expression by TNF-{alpha}. -- Abstract: Tumor necrosis factor-alpha (TNF-{alpha}) promotes in vitro retinal pigment epithelial (RPE) cell migration to initiate proliferative vitreoretinopathy (PVR). Here we report that TNF-{alpha} promotes human RPE cell migration by inducing matrix metallopeptidase 9 (MMP-9) expression. Inhibition of MMP-9 by its inhibitor or its neutralizing antibody inhibited TNF-{alpha}-induced in vitro RPE cell migration. Reversely, exogenously-addedmore » active MMP-9 promoted RPE cell migration. Suppression Akt/mTOR complex 1(mTORC1) activation by LY 294002 and rapamycin inhibited TNF-{alpha}-mediated MMP-9 expression. To introduce a constitutively active Akt (CA-Akt) in cultured RPE cells increased MMP-9 expression, and to block mTORC1 activation by rapamycin inhibited its effect. RNA interference (RNAi)-mediated silencing of SIN1, a key component of mTOR complex 2 (mTORC2), had no effect on MMP-9 expression or secretion. In conclusion, this study suggest that TNF-{alpha} promotes RPE cell migration by inducing MMP-9 expression through activation of Akt/ mTORC1, but not mTORC2 signaling.« less

Magnetic heading reference

NASA Technical Reports Server (NTRS)

Garner, H. D. (Inventor)

1983-01-01

Devices are disclosed for vectorially summing two signals. In a first embodiment, the vectorial summation is implemented by a mechanical sin/cos mechanism in which a crank drives two linear potentiometers out of phase. In a second embodiment, a polarized light resolver generates the sin and cos functions. In a third embodiment, a printed circuit resolver generates the sin and cos functions.

Lysine Methylation of Nuclear Co-repressor Receptor Interacting Protein 140

PubMed Central

Huq, MD Mostaqul; Ha, Sung Gil; Barcelona, Helene; Wei, Li-Na

2009-01-01

Receptor interacting protein 140 (RIP140) undergoes extensive posttranslational modifications (PTMs), including phosphorylation, acetylation, arginine methylation, and pyridoxylation. PTMs affect its sub-cellular distribution, protein-protein interaction, and biological activity in adipocyte differentiation. Arginine methylation on Arg240, Arg650, and Arg948 suppresses the repressive activity of RIP140. Here we find that endogenous RIP140 in differentiated 3T3-L1 cells is also modified by lysine methylation. Three lysine residues, Lys591, Lys653, and Lys757 are mapped as potential methylation sites by mass spectrometry. Site-directed mutagenesis study shows that lysine methylation enhances its gene repressive activity. Mutation of lysine methylation sites enhances arginine methylation, while mutation on arginine methylation sites has little effect on its lysine methylation, suggesting a relationship between lysine methylation and arginine methylation. Kinetic analysis of PTMs of endogenous RIP140 in differentiated 3T3-L1 cells demonstrates sequential modifications on RIP140, initiated from constitutive lysine methylation, followed by increased arginine methylation later in differentiation. This study reveals a potential hierarchy of modifications, at least for lysine and arginine methylation, which bi-directionally regulate the functionality of a non-histone protein. PMID:19216533

A Performance and Plume Comparison of Xenon and Krypton Propellant on the SPT-100

DTIC Science & Technology

2012-07-20

2 2 )sin()cos()()( )cos(     dvmr vmT mvm      dvvf vdvvf v )( )(     2/ 2/ 2 2/ 2/ 2 )sin()( )sin()()(       dmr

Constructing a Counternarrative: Students Informing Now (S.I.N.) Reframes Immigration and Education in the United States

ERIC Educational Resources Information Center

Dominguez, Neidi; Duarte, Yazmin; Espinosa, Pedro Joel; Martinez, Luis; Nygreen, Kysa; Perez, Renato; Ramirez, Izel; Saba, Mariella

2009-01-01

The work of Students Informing Now (S.I.N.), an immigrant student organization at the University of California, Santa Cruz, is described in this column. The authors argue that S.I.N.'s diverse activities and textual products construct a counternarrative that challenges and reframes the debate on undocumented students and immigration. Focusing on…

Strategies to alleviate original antigenic sin responses to influenza viruses.

PubMed

Kim, Jin Hyang; Davis, William G; Sambhara, Suryaprakash; Jacob, Joshy

2012-08-21

Original antigenic sin is a phenomenon wherein sequential exposure to closely related influenza virus variants reduces antibody (Ab) response to novel antigenic determinants in the second strain and, consequently, impairs the development of immune memory. This could pose a risk to the development of immune memory in persons previously infected with or vaccinated against influenza. Here, we explored strategies to overcome original antigenic sin responses in mice sequentially exposed to two closely related hemagglutinin 1 neuraminidase 1 (H1N1) influenza strains A/PR/8/34 and A/FM/1/47. We found that dendritic cell-activating adjuvants [Bordetella pertussis toxin (PT) or CpG ODN or a squalene-based oil-in-water nanoemulsion (NE)], upon administration during the second viral exposure, completely protected mice from a lethal challenge and enhanced neutralizing-Ab titers against the second virus. Interestingly, PT and NE adjuvants when administered during the first immunization even prevented original antigenic sin in subsequent immunization without any adjuvants. As an alternative to using adjuvants, we also found that repeated immunization with the second viral strain relieved the effects of original antigenic sin. Taken together, our studies provide at least three ways of overcoming original antigenic sin.

Targeted Disruption of the Basic Krüppel-Like Factor Gene (Klf3) Reveals a Role in Adipogenesis ▿ †

PubMed Central

Sue, Nancy; Jack, Briony H. A.; Eaton, Sally A.; Pearson, Richard C. M.; Funnell, Alister P. W.; Turner, Jeremy; Czolij, Robert; Denyer, Gareth; Bao, Shisan; Molero-Navajas, Juan Carlos; Perkins, Andrew; Fujiwara, Yuko; Orkin, Stuart H.; Bell-Anderson, Kim; Crossley, Merlin

2008-01-01

Krüppel-like factors (KLFs) recognize CACCC and GC-rich sequences in gene regulatory elements. Here, we describe the disruption of the murine basic Krüppel-like factor gene (Bklf or Klf3). Klf3 knockout mice have less white adipose tissue, and their fat pads contain smaller and fewer cells. Adipocyte differentiation is altered in murine embryonic fibroblasts from Klf3 knockouts. Klf3 expression was studied in the 3T3-L1 cellular system. Adipocyte differentiation is accompanied by a decline in Klf3 expression, and forced overexpression of Klf3 blocks 3T3-L1 differentiation. Klf3 represses transcription by recruiting C-terminal binding protein (CtBP) corepressors. CtBPs bind NADH and may function as metabolic sensors. A Klf3 mutant that does not bind CtBP cannot block adipogenesis. Other KLFs, Klf2, Klf5, and Klf15, also regulate adipogenesis, and functional CACCC elements occur in key adipogenic genes, including in the C/ebpα promoter. We find that C/ebpα is derepressed in Klf3 and Ctbp knockout fibroblasts and adipocytes from Klf3 knockout mice. Chromatin immunoprecipitations confirm that Klf3 binds the C/ebpα promoter in vivo. These results implicate Klf3 and CtBP in controlling adipogenesis. PMID:18391014

A redox-based mechanism for the contractile and relaxing effects of NO in the guinea-pig gall bladder

PubMed Central

Alcón, Soledad; Morales, Sara; Camello, Pedro J; Hemming, Jason M; Jennings, Lee; Mawe, Gary M; Pozo, María J

2001-01-01

The purpose of this study was to determine the effects of sodium nitroprusside (SNP), 2,2′-(hydroxynitrosohydrazino)bis-ethanamine (DETA/NO) and 3-morpholinosydnonimine (SIN-1), NO donors which yield different NO reactive species (NO+, NO. and peroxynitrite, respectively), as well as exogenous peroxynitrite, on gall bladder contractility. Under resting tone conditions, SNP induced a dose-dependent contraction with a maximal effect (10.3 ± 0.7 mN, s.e.m.) at 1 mm. Consistent with these findings, SNP caused a concentration-dependent depolarization of gall bladder smooth muscle. The excitatory effects of SNP were dependent on extracellular calcium entry through L-type Ca2+ channels. Furthermore, the contraction and depolarization were sensitive to tyrosine kinase blockade, and an associated increase in tyrosine phosphorylation was detected in Western blot studies. DETA/NO induced dose-dependent relaxing effects. These relaxations were sensitive to the guanylyl cyclase inhibitor 1H-[1,2,4]oxidiazolo[4,3-a]quinoxaline-1-one (ODQ, 2 μm) but they were not altered by treatment with the potassium channel blockers tetraethylammoniun (TEA, 5 mm) and 4-aminopyridine (4-AP, 5 mm). When tested in a reducing environment (created by 2.5 mm 1,4-dithiothreitol, DTT), SNP caused a relaxation of gall bladder muscle strips. Similarly, the SNP-induced contraction was converted to a relaxation, and associated hyperpolarization, when DTT was added during the steady state of an SNP-induced response. SIN-1 (0.1 mm), which has been shown to release peroxynitrite, induced relaxing effects that were enhanced by superoxide dismutase (SOD, 50 U ml−1). The relaxations induced by either SIN-1 alone or SIN-1 in the presence of SOD were strengthened by catalase (1000 U ml−1) and abolished by ODQ pretreatment. However, exogenous peroxynitrite induced a concentration-dependent contraction, which was dependent on activation of leukotriene (LT) metabolism and extracellular calcium. The peroxynitrite-induced contraction was abolished in the presence of the peroxynitrite scavenger melatonin. These results suggest that SIN-1 behaves as an NO. rather than a peroxynitrite source. We conclude that, depending on the redox state, NO has opposing effects on the motility of the gall bladder, being a relaxing agent when in NO. form and a contracting agent when in NO+ or peroxynitrite redox species form. Knowledge of the contrasting effects of the different redox forms of NO can clarify our understanding of the effects of NO donors on gall bladder and other smooth muscle cell types. PMID:11313447